Acute brain injuries trigger microglia as an additional source of the proteoglycan NG2

NG2 is a type I transmembrane glycoprotein known as chondroitin sulfate proteoglycan 4 (CSPG4). In the healthy central nervous system, NG2 is exclusively expressed by oligodendrocyte progenitor cells and by vasculature pericytes. A large body of immunohistochemical studies showed that under pathological conditions such as acute brain injuries and experimental autoimmune encephalomyelitis (EAE), a number of activated microglia were NG2 immuno-positive, suggesting NG2 expression in these cells. Alternative explanations for the microglial NG2 labeling consider the biochemical properties of NG2 or the phagocytic activity of activated microglia. Reportedly, the transmembrane NG2 proteoglycan can be cleaved by a variety of proteases to deposit the NG2 ectodomain into the extracellular matrix. The ectodomain, however, could also stick to the microglial surface. Since microglia are phagocytic cells engulfing debris of dying cells, it is difficult to identify a genuine expression of NG2. Recent studies showing (1) pericytes giving rise to microglial after stroke, and (2) immune cells of NG2-EYFP knock-in mice lacking NG2 expression in an EAE model generated doubts for the de novo expression of NG2 in microglia after acute brain injuries. In the current study, we took advantage of three knock-in mouse lines (NG2-CreERT2, CX3CR1-EGFP and NG2-EYFP) to study NG2 expression indicated by transgenic fluorescent proteins in microglia after tMCAO (transient middle cerebral artery occlusion) or cortical stab wound injury (SWI). We provide strong evidence that NG2-expressing cells, including OPCs and pericytes, did not differentiate into microglia after acute brain injuries, whereas activated microglia did express NG2 in a disease-dependent manner. A subset of microglia continuously activated the NG2 gene at least within the first week after tMCAO, whereas within 3 days after SWI a limited number of microglia at the lesion site transiently expressed NG2. Immunohistochemical studies demonstrated that these microglia with NG2 gene activity also synthesized the NG2 protein, suggesting activated microglia as an additional source of the NG2 proteoglycan after acute brain injuries

Research progress in the anti-cancer activity and related mechanisms of arenobufagin

Toad venom is an active extract of toad, which is processed by distilling or drying at high temperature the venom secreted from the skin glands and ear-side glands of Toad Chinensis. As a natural product that has been used to treat diseases in China for thousands of years, toad venom has many pharmacological effects such as heart strengthening, analgesia, anti-myocardial ischemia, anti-endotoxin shock, and anti-cancer. Arenobufagin (ARE) is one of the main chemical components of toad venom, and its anti-cancer mechanism has been increasingly clarified in the past decade. ARE can play an anti-cancer role through a variety of ways, such as inducing apoptosis and/or autophagy of cancer cells, necrosis, and cell cycle arrest, inhibiting cancer cell migration and invasion, and inhibiting angiogenesis. The current research on ARE mainly focuses on the selective toxicity of cancer cells and the molecular mechanism of anti-cancer, mostly at the cellular and animal levels. Due to the large toxic and side effects of ARE, unclear targets and unclear pharmacokinetic characteristics, ARE has not yet entered the clinical application in Western medicine. This article summarizes relevant research results on the anti-cancer activity and molecular mechanism of ARE, and its combination with other anti-cancer drugs in order to provide a new direction for improving the anti-cancer mechanism of ARE

Spontaneous Formation of One-Dimensional Hydrogen Gas Hydrate in Carbon Nanotubes

We present molecular dynamics simulation evidence of spontaneous formation of quasi-one-dimensional (Q1D) hydrogen gas hydrates within single-walled carbon nanotubes (SW-CNTs) of nanometer-sized diameter (1−1.3 nm) near ambient temperature. Contrary to conventional 3D gas hydrates in which the guest molecules are typically contained in individual and isolated cages in the host lattice, the guest H2 molecules in the Q1D gas hydrates are contained within a 1D nanochannel in which the H2 molecules form a molecule wire. In particular, we show that in the (15,0) zigzag SW-CNT, the hexagonal H2 hydrate tends to form, with one H2 molecule per hexagonal prism, while in the (16,0) zigzag SW-CNT, the heptagonal H2 hydrate tends to form, with one H2 molecule per heptagonal prism. In contrast, in the (17,0) zigzag SW-CNT, the octagonal H2 hydrate can form, with either one H2 or two H2 molecules per pentagonal prism (single or double occupancy). Interestingly, in the hexagonal or heptagonal ice nanotube, the H2 wire is solid-like as the axial diffusion constant is very low (× 10−10 cm2/s), whereas in the octagonal ice nanotube, the H2 wire is liquid-like as its axial diffusion constant is comparable to 10−5 cm2/s

A subset of OPCs do not express Olig2 during development which can be increased in the adult by brain injuries and complex motor learning

Oligodendrocyte precursor cells (OPCs) are uniformly distributed in the mammalian brain; however, their function is rather heterogeneous in respect to their origin, location, receptor/channel expression and age. The basic helix–loop–helix transcription factor Olig2 is expressed in all OPCs as a pivotal determinant of their differentiation. Here, we identified a subset (2%–26%) of OPCs lacking Olig2 in various brain regions including cortex, corpus callosum, CA1 and dentate gyrus. These Olig2 negative (Olig2neg) OPCs were enriched in the juvenile brain and decreased subsequently with age, being rarely detectable in the adult brain. However, the loss of this population was not due to apoptosis or microglia-dependent phagocytosis. Unlike Olig2pos OPCs, these subset cells were rarely labeled for the mitotic marker Ki67. And, accordingly, BrdU was incorporated only by a three-day long-term labeling but not by a 2-hour short pulse, suggesting these cells do not proliferate any more but were derived from proliferating OPCs. The Olig2neg OPCs exhibited a less complex morphology than Olig2pos ones. Olig2neg OPCs preferentially remain in a precursor stage rather than differentiating into highly branched oligodendrocytes. Changing the adjacent brain environment, for example, by acute injuries or by complex motor learning tasks, stimulated the transition of Olig2pos OPCs to Olig2neg cells in the adult. Taken together, our results demonstrate that OPCs transiently suppress Olig2 upon changes of the brain activity

Astrocytic p75NTR expression provoked by ischemic stroke exacerbates the blood-brain barrier disruption

The disruption of the blood–brain barrier (BBB) plays a critical role in the pathology of ischemic stroke. p75 neurotrophin receptor (p75NTR) contributes to the disruption of the blood-retinal barrier in retinal ischemia. However, whether p75NTR influences the BBB permeability after acute cerebral ischemia remains unknown. The present study investigated the role and underlying mechanism of p75NTR on BBB integrity in an ischemic stroke mouse model, middle cerebral artery occlusion (MCAO). After 24 h of MCAO, astrocytes and endothelial cells in the infarct-affected brain area up-regulated p75NTR. Genetic p75NTR knockdown (p75NTR+/ ) or pharmacological inhibition of p75NTR using LM11A-31, a selective inhibitor of p75NTR, both attenuated brain damage and BBB leakage in MCAO mice. Astrocyte-specific conditional knockdown of p75NTR mediated with an adeno-associated virus significantly ameliorated BBB disruption and brain tissue damage, as well as the neurological functions after stroke. Further molecular biological examinations indicated that astrocytic p75NTR activated NF-κB and HIF-1α signals, which upregulated the expression of MMP-9 and vascular endothelial growth factor (VEGF), subsequently leading to tight junction degradation after ischemia. As a result, increased leukocyte infiltration and microglia activation exacerbated brain injury after stroke. Overall, our results provide novel insight into the role of astrocytic p75NTR in BBB disruption after acute cerebral ischemia. The p75NTR may therefore be a potential therapeutic target for the treatment of ischemic stroke

Single-cell RNA sequencing reveals dynamic changes in A-to-I RNA editome during early human embryogenesis

BACKGROUND: A-to-I RNA-editing mediated by ADAR (adenosine deaminase acting on RNA) enzymes that converts adenosine to inosine in RNA sequence can generate mutations and alter gene regulation in metazoans. Previous studies have shown that A-to-I RNA-editing plays vital roles in mouse embryogenesis. However, the RNA-editing activities in early human embryonic development have not been investigated. RESULTS: Here, we characterized genome-wide A-to-I RNA-editing activities during human early embryogenesis by profiling 68 single cells from 29 human embryos spanning from oocyte to morula stages. We demonstrate dynamic changes in genome-wide RNA-editing during early human embryogenesis in a stage-specific fashion. In parallel with ADAR expression level changes, the genome-wide A-to-I RNA-editing levels in cells remained relatively stable until 4-cell stage, but dramatically decreased at 8-cell stage, continually decreased at morula stage. We detected 37 non-synonymously RNA-edited genes, of which 5 were frequently found in cells of multiple embryonic stages. Moreover, we found that A-to-I editings in miRNA-targeted regions of a substantial number of genes preferably occurred in one or two sequential stages. CONCLUSIONS: Our single-cell analysis reveals dynamic changes in genome-wide RNA-editing during early human embryogenesis in a stage-specific fashion, and provides important insights into early human embryogenesis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-016-3115-2) contains supplementary material, which is available to authorized users

Cdc42-Interacting Protein-4 Promotes TGF-Β1-Induced Epithelial-Mesenchymal Transition and Extracellular Matrix Deposition in Renal Proximal Tubular Epithelial Cells

Cdc42-interacting protein-4 (CIP4) is an F-BAR (Fer/CIP4 and Bin, amphiphysin, Rvs) family member that regulates membrane deformation and endocytosis, playing a key role in extracellular matrix (ECM) deposition and invasion of cancer cells. These processes are analogous to those observed during the initial epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. The role of CIP4 in renal tubular EMT and renal tubulointerstitial fibrosis was investigated over the course of the current study, demonstrating that the expression of CIP4 increased in the tubular epithelia of 5/6-nephrectomized rats and TGF-β1 treated HK-2 cells. Endogenous CIP4 evidenced punctate localization throughout the cytosol, with elevated levels observed in the perinuclear region of HK-2 cells. Subsequent to TGF-β1 treatment, CIP4 expression increased, forming clusters at the cell periphery that gradually redistributed into the cytoplasm. Simultaneously, EMT induction in cells was confirmed by the prevalence of morphological changes, loss of E-cadherin, increase in α-SMA expression, and secretion of fibronectin. Overexpression of CIP4 promoted characteristics similar to those commonly observed in EMT, and small interfering RNA (siRNA) molecules capable of CIP4 knockdown were used to demonstrate reversed EMT. Cumulatively, results of the current study suggest that CIP4 promotes TGF-β1-induced EMT in tubular epithelial cells. Through this mechanism, CIP4 is capable of inducing ECM deposition and exacerbating progressive fibrosis in chronic renal failure

Impaired bidirectional communication between interneurons and oligodendrocyte precursor cells affects social cognitive behavior

Cortical neural circuits are complex but very precise networks of balanced excitation and inhibition. Yet, the molecular and cellular mechanisms that form the balance are just beginning to emerge. Here, using conditional γ-aminobutyric acid receptor B1- deficient mice we identify a γ-aminobutyric acid/tumor necrosis factor superfamily member 12-mediated bidirectional communication pathway between parvalbumin-positive fast spiking interneurons and oligodendrocyte precursor cells that determines the density and function of interneurons in the developing medial prefrontal cortex. Interruption of the GABAergic signaling to oligodendrocyte precursor cells results in reduced myelination and hypoactivity of interneurons, strong changes of cortical network activities and impaired social cognitive behavior. In conclusion, glial transmitter receptors are pivotal elements in finetuning distinct brain functions

P2y12 inhibitor monotherapy after 1–3 months dual antiplatelet therapy in patients with coronary artery disease and chronic kidney disease undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials

IntroductionIn patients with coronary artery disease (CAD) and chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI), whether short-term dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitors confers benefits compared with standard DAPT remains unclear. This study aimed to assess the efficacy and safety of 1–3 months of DAPT followed by P2Y12 monotherapy in patients with CAD and CKD undergoing PCI.MethodsPubMed, Embase, and the Cochrane Library were searched to identify randomized controlled trials (RCTs) comparing the P2Y12 inhibitor monotherapy after a 1–3 months DAPT vs. DAPT in patients with CAD and CKD after PCI. The primary outcome was the incidence of major adverse cardiovascular events (MACEs), defined as a composite of all-cause mortality, myocardial infarction, stent thrombosis, target-vessel revascularization, and stroke. The safety outcome was the major bleeding events, defined as a composite of TIMI major bleeding or Bleeding Academic Research and Consortium (BARC) type 2, 3, or 5 bleeding. The pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated with a fixed- or random-effects model depending on the heterogeneity among studies.ResultsFour RCTs including 20,468 patients (2,833 patients with CKD and 17,635 without CKD) comparing P2Y12 inhibitor monotherapy with DAPT were included in our meta-analysis. Patients with CAD and CKD had higher risk of ischemic and bleeding events. P2Y12 inhibitor monotherapy after 1–3 months of DAPT significantly reduced the risk of major bleeding compared to DAPT in CKD patients (RR: 0.69, 95% CI: 0.51–0.95, P = 0.02) and non-CKD patients (RR: 0.66, 95% CI: 0.49–0.89, P = 0.01). No significant difference regarding MACEs between P2Y12 inhibitor monotherapy and DAPT was found in CKD patients (RR: 0.88, 95% CI: 0.59–1.31, P = 0.53) and non-CKD (RR: 0.91, 95% CI: 0.79–1.04, P = 0.17).ConclusionP2Y12 inhibitor monotherapy after 1–3 months of DAPT was an effective strategy for lowering major bleeding complications without increasing the risk of cardiovascular events in patients with CAD and CKD undergoing PCI as compared with DAPTSystematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, CRD42022355228