scholarly journals Regulation of Neurogenesis in Mouse Brain by HMGB1

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1714 ◽  
Author(s):  
Xiang Zhao ◽  
Ari Rouhiainen ◽  
Zhilin Li ◽  
Su Guo ◽  
Heikki Rauvala
Keyword(s):  
Mouse Brain ◽  
Ex Vivo ◽  
Critical Role ◽  
High Mobility ◽  
Brain Cell ◽  
Null Mouse ◽  
Aberrant Expression ◽  
Developmental Defects ◽  
Neuronal Stem Cells ◽  
Nonhistone Protein

The High Mobility Group Box 1 (HMGB1) is the most abundant nuclear nonhistone protein that is involved in transcription regulation. In addition, HMGB1 has previously been found as an extracellularly acting protein enhancing neurite outgrowth in cultured neurons. Although HMGB1 is widely expressed in the developing central nervous system of vertebrates and invertebrates, its function in the developing mouse brain is poorly understood. Here, we have analyzed developmental defects of the HMGB1 null mouse forebrain, and further examined our findings in ex vivo brain cell cultures. We find that HMGB1 is required for the proliferation and differentiation of neuronal stem cells/progenitor cells. Enhanced apoptosis is also found in the neuronal cells lacking HMGB1. Moreover, HMGB1 depletion disrupts Wnt/β-catenin signaling and the expression of transcription factors in the developing cortex, including Foxg1, Tbr2, Emx2, and Lhx6. Finally, HMGB1 null mice display aberrant expression of CXCL12/CXCR4 and reduced RAGE signaling. In conclusion, HMGB1 plays a critical role in mammalian neurogenesis and brain development.

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

2019 ◽  
Vol 133 (22) ◽  
pp. 2283-2299
Author(s):  
Apabrita Ayan Das ◽  
Devasmita Chakravarty ◽  
Debmalya Bhunia ◽  
Surajit Ghosh ◽  
Prakash C. Mandal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Chronic Inflammation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Critical Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Tnf Α ◽  
Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

Antigene and Antiproliferative Effects of Triplex-Forming Oligonucleotide (TFO) Targeted on hmgb1 Gene in Human Hepatoma Cells

2020 ◽  
Vol 20 (16) ◽  
pp. 1943-1955
Author(s):  
Neelam Lohani ◽  
Moganty R. Rajeswari
Keyword(s):  
Apoptotic Cell ◽  
Isothermal Calorimetry ◽  
High Mobility ◽  
Rational Drug Design ◽  
Human Hepatoma Cells ◽  
Aberrant Expression ◽  
Bioinformatic Tools ◽  
Hmgb1 Expression ◽  
Dna Triplex ◽  
Triplex Forming Oligonucleotide

Background: The high mobility group box 1 (hmgb1) is one of the frequently over-expressed genes whose aberrant expression is reported in a number of human cancers. Various strategies are underway to inhibit hmgb1 expression in cancer cells having considerable therapeutic value. Objective: The present work involves selective transcriptional inhibition of the hmgb1 gene using selective DNA triplex structure-based gene technology. Here, the promoter region of the hmgb1 gene at position (-183 to -165) from the transcription start site as a target was selected using bioinformatic tools. Methods: The DNA triplex formation by the DNA of the target gene and TFO was confirmed using UV absorption spectroscopy, Circular Dichroism, and Isothermal Calorimetry. Results: Treatment of HepG2 cell with specific Triplex-forming Oligonucleotide significantly downregulated HMGB1 expression level at mRNA and protein levels by 50%, while the classical anticancer drugs, actinomycin/ adriamycin as positive controls showed 65% and the combination of TFO and drug decreased by 70%. The anti-proliferative effects of TFO correlated well with the fact of accumulation of cells in the Go phase and apoptotic cell death. Further, the binding of anti-cancer drugs to hmgb1 is stronger in DNA triplex state as compared to hmgb1 alone, suggesting the combination therapy as a better option. Conclusion: Therefore, the ability of hmgb1 targeted triplex-forming oligonucleotide in combination with triplex selective anticancer drug holds promise in the treatment of malignancies associated with hmgb1 overexpression. The result obtained may open up new vistas to provide a basis for the rational drug design and searching for high-affinity ligands with a high triplex selectivity.

scholarly journals Quantitative measurement of reactive oxygen species in ex vivo mouse brain slices

2021 ◽  
Vol 2 (1) ◽  
pp. 100332
Author(s):  
Chirag Vasavda ◽  
Solomon H. Snyder ◽  
Bindu D. Paul
Keyword(s):  
Reactive Oxygen Species ◽  
Mouse Brain ◽  
Quantitative Measurement ◽  
Ex Vivo ◽  
Brain Slices ◽  
Reactive Oxygen ◽  
Oxygen Species

scholarly journals Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Zetao Chen ◽  
Yihong Chen ◽  
Yan Li ◽  
Weidong Lian ◽  
Kehong Zheng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Strategy ◽  
Critical Role ◽  
Glioma Stem Cells ◽  
Promoter Regions ◽  
Aberrant Expression ◽  
Smad Pathway ◽  
Tgf Β1

AbstractGlioma is one of the most lethal cancers with highly vascularized networks and growing evidences have identified glioma stem cells (GSCs) to account for excessive angiogenesis in glioma. Aberrant expression of paired-related homeobox1 (Prrx1) has been functionally associated with cancer stem cells including GSCs. In this study, Prrx1 was found to be markedly upregulated in glioma specimens and elevated Prrx1 expression was inversely correlated with prognosis of glioma patients. Prrx1 potentiated stemness acquisition in non-stem tumor cells (NSTCs) and stemness maintenance in GSCs, accompanied with increased expression of stemness markers such as SOX2. Prrx1 also promoted glioma angiogenesis by upregulating proangiogenic factors such as VEGF. Consistently, silencing Prrx1 markedly inhibited glioma proliferation, stemness, and angiogenesis in vivo. Using a combination of subcellular proteomics and in vitro analyses, we revealed that Prrx1 directly bound to the promoter regions of TGF-β1 gene, upregulated TGF-β1 expression, and ultimately activated the TGF-β/smad pathway. Silencing TGF-β1 mitigated the malignant behaviors induced by Prrx1. Activation of this pathway cooperates with Prrx1 to upregulate the expression of stemness-related genes and proangiogenic factors. In summary, our findings revealed that Prrx1/TGF-β/smad signal axis exerted a critical role in glioma stemness and angiogeneis. Disrupting the function of this signal axis might represent a new therapeutic strategy in glioma patients.

scholarly journals Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yuen Gao ◽  
Natalia Duque-Wilckens ◽  
Mohammad B. Aljazi ◽  
Yan Wu ◽  
Adam J. Moeser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Normal Brain ◽  
Critical Function ◽  
Developmental Defects ◽  
Neurodevelopmental Disease ◽  
Developing Mouse Brain

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

A Novel Method for Ex-Vivo Latex Angiography of the Mouse Brain

2021 ◽  
pp. 109342
Author(s):  
Keyan Peterson ◽  
Stephanie Coffman ◽  
Stacey Wolfe ◽  
Zhidan Xiang
Keyword(s):  
Mouse Brain ◽  
Ex Vivo ◽  
Novel Method

scholarly journals The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4978-4987 ◽  
Author(s):  
Elzbieta Pluskota ◽  
James J. Dowling ◽  
Natalie Gordon ◽  
Jeffrey A. Golden ◽  
Dorota Szpak ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Critical Role ◽  
Integrin Αvβ3 ◽  
Tube Formation ◽  
Basement Membranes ◽  
Cytoskeletal Protein ◽  
Integrin Expression ◽  
Partial Reduction ◽  
Wild Type ◽  
Developmental Defects

Abstract Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice and causes severe developmental defects in zebrafish. Knockdown of kindlin-2 levels in endothelial cells resulted in defective adhesive and migratory responses, suggesting that angiogenesis might be aberrant even with partial reduction of kindlin-2. This hypothesis has now been tested in the kindlin-2+/− mice. RM1 prostate tumors grown in kindlin-2+/− mice had fewer blood vessels, which were thinner and shorter and supported less tumor growth compared with wild-type littermates. The vessels that did form in the kindlin-2+/− mice lacked smooth muscle cells and pericytes and had thinner basement membranes, indicative of immature vessels. VEGF-induced angiogenesis in matrigel implants was also abnormal in the kindlin-2+/− mice. Vessels in the kindlin-2+/− mice were leaky, and BM transplantation from kindlin-2+/− to WT mice did not correct this defect. Endothelial cells derived from kindlin-2+/− mice had integrin expression levels similar to WT mice but reduced αVβ3-dependent signaling, migration, adhesion, spreading, and tube formation. Developmental angiogenesis was markedly impaired by kindlin-2 morpholinos in zebrafish. Taken together, kindlin-2 plays an important role in pathologic and developmental angiogenesis, which arises from defective activation of integrin αVβ3.

scholarly journals Dosage-Dependent Effects of Akt1/Protein Kinase Bα (PKBα) and Akt3/PKBγ on Thymus, Skin, and Cardiovascular and Nervous System Development in Mice

2005 ◽  
Vol 25 (23) ◽  
pp. 10407-10418 ◽  
Author(s):  
Zhong-Zhou Yang ◽  
Oliver Tschopp ◽  
Nicolas Di-Poï ◽  
Elisabeth Bruder ◽  
Anne Baudry ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Cycle Progression ◽  
System Development ◽  
Critical Role ◽  
Nervous System Development ◽  
Mouse Development ◽  
Double Knockout ◽  
Developmental Defects ◽  
Regulation Of Metabolism ◽  
Survival And Development

ABSTRACT Akt/protein kinase B (PKB) plays a critical role in the regulation of metabolism, transcription, cell migration, cell cycle progression, and cell survival. The existence of viable knockout mice for each of the three isoforms suggests functional redundancy. We generated mice with combined mutant alleles of Akt1 and Akt3 to study their effects on mouse development. Here we show that Akt1 − / − Akt3 +/ − mice display multiple defects in the thymus, heart, and skin and die within several days after birth, while Akt1 +/ − Akt3 − / − mice survive normally. Double knockout (Akt1 − / − Akt3 − / −) causes embryonic lethality at around embryonic days 11 and 12, with more severe developmental defects in the cardiovascular and nervous systems. Increased apoptosis was found in the developing brain of double mutant embryos. These data indicate that the Akt1 gene is more essential than Akt3 for embryonic development and survival but that both are required for embryo development. Our results indicate isoform-specific and dosage-dependent effects of Akt on animal survival and development.

scholarly journals Calcium Signaling in Vertebrate Development and Its Role in Disease

2018 ◽  
Vol 19 (11) ◽  
pp. 3390 ◽  
Author(s):  
Sudip Paudel ◽  
Regan Sindelar ◽  
Margaret Saha
Keyword(s):  
Calcium Signaling ◽  
Critical Role ◽  
Molecular Techniques ◽  
Model Organisms ◽  
Vertebrate Development ◽  
Developmental Defects ◽  
Calcium Activity ◽  
Human Genes ◽  
Underlying Mechanisms

Accumulating evidence over the past three decades suggests that altered calcium signaling during development may be a major driving force for adult pathophysiological events. Well over a hundred human genes encode proteins that are specifically dedicated to calcium homeostasis and calcium signaling, and the majority of these are expressed during embryonic development. Recent advances in molecular techniques have identified impaired calcium signaling during development due to either mutations or dysregulation of these proteins. This impaired signaling has been implicated in various human diseases ranging from cardiac malformations to epilepsy. Although the molecular basis of these and other diseases have been well studied in adult systems, the potential developmental origins of such diseases are less well characterized. In this review, we will discuss the recent evidence that examines different patterns of calcium activity during early development, as well as potential medical conditions associated with its dysregulation. Studies performed using various model organisms, including zebrafish, Xenopus, and mouse, have underscored the critical role of calcium activity in infertility, abortive pregnancy, developmental defects, and a range of diseases which manifest later in life. Understanding the underlying mechanisms by which calcium regulates these diverse developmental processes remains a challenge; however, this knowledge will potentially enable calcium signaling to be used as a therapeutic target in regenerative and personalized medicine.

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