Expression of Glutaminase and Vesicular Glutamate Transporter Type 2 Immunoreactivity in Rat Sacral Dorsal Root Ganglia Following a Surgical Tail Incision Final
This study examined the effects of a surgical tail incision on glutaminase (GLS) and vesicular glutamate transporter type 2 (VGluT2) expression in sacral dorsal root ganglia (DRG) neurons in rats. The researchers found that sacral DRG neurons innervate the area of surgical incision using retrograde tracing. Both GLS and VGluT2 immunoreactivity were elevated in sacral DRG neurons for up to 72 hours post-incision, while GLS mRNA levels rapidly decreased and remained depressed for at least 96 hours. The rapid depletion of GLS mRNA and subsequent elevation of GLS and VGluT2 proteins in sacral DRG neurons following surgical incision
Insights into the epigenetic mechanisms involving histone lysineashutosh mahale
1. The study investigated the role of histone lysine methylation and demethylation in an internal carotid artery occlusion (ICAO) mouse model of mild to moderate stroke.
2. The ICAO model resulted in neuronal damage to the striatum. Epigenetic markers like H3K9me2 were decreased after ischemia but recovered with time.
3. Inhibiting jmjD2 demethylases after ischemia prevented the decrease in H3K9me2, reduced neuronal cell death, and improved neurological outcomes, suggesting epigenetic mechanisms are implicated in stroke pathology and recovery.
1) STAT3 signaling plays a critical role in regulating astrocyte reactivity and scar formation after spinal cord injury.
2) Mice with conditional deletion of STAT3 from astrocytes showed attenuated upregulation of GFAP, failed astrocyte hypertrophy, and disrupted scar formation after injury.
3) These changes were associated with increased spread of inflammation and increased lesion size, with partially attenuated motor recovery over 28 days following injury.
This study investigated the effects of pro-inflammatory cytokines TNFα and IFNγ and the hormone testosterone on expression of the chemokine receptors CX3CR1 and CCR2 on THP-1 monocytes. Flow cytometry analysis confirmed that TNFα and IFNγ increase cell surface expression of CX3CR1 and CCR2, while testosterone decreases expression of these receptors. Additionally, pre-treating cells with testosterone before cytokine exposure continued to decrease CX3CR1 and CCR2 expression levels compared to cytokine treatment alone. Future work will utilize controls to ensure the testosterone effects are receptor-mediated and not due to conversion to estrogen.
This research paper examines the effects of activating small-conductance calcium-activated potassium (SK) channels in the spinal cord on reducing mechanical hypersensitivity in a rat model of inflammatory pain. The study finds that intrathecal administration of the SK channel activator NS309 dose-dependently attenuates mechanical hypersensitivity induced by complete Freund's adjuvant (CFA) inflammation. Additionally, coadministration of NS309 with the NMDA receptor antagonist DL-AP5 reduces the dose of DL-AP5 needed to produce antinociceptive effects in the CFA pain model. This suggests that activating SK channels in the spinal cord can modulate the effects of NMDA receptor antagonists and potentially reduce their unwanted side effects.
Temporal-Spatial Expressions of Spy1 in Rat Sciatic Nerve After CrushJiao Yang
1. The study examined the expression of the cell cycle protein Spy1 in a rat sciatic nerve crush injury model over time.
2. Spy1 expression was found to gradually increase after injury, peaking at day 3, due to increased expression in both axons and Schwann cells.
3. Spy1 expression correlated with Schwann cell proliferation after injury and Spy1 was found to localize in axons in the injured segment but did not co-localize with the growth protein GAP43.
This study examined expression of glutamate transporter proteins in the superior temporal gyrus and hippocampus in post-mortem brain samples from individuals with schizophrenia compared to controls. They found decreased expression of the glutamate transporters EAAT1 and EAAT2 in the superior temporal gyrus, and decreased EAAT2 in the hippocampus, in schizophrenia samples. They did not find changes in the neuronal transporter EAAT3 or the presynaptic vesicular glutamate transporters VGLUT1-2. This suggests abnormal buffering and reuptake but not presynaptic release of glutamate in temporal lobe synapses in schizophrenia.
This document summarizes research on how shear stress regulates SIRT1 and its role in vascular homeostasis. The key points are:
1) Applying laminar flow to endothelial cells in vitro increased SIRT1 levels and activity as well as mitochondrial biogenesis. Higher SIRT1 levels were observed under physiologically relevant pulsatile flow compared to pathophysiological oscillatory flow.
2) Laminar flow activated both AMPK and SIRT1 independently in endothelial cells. Knockdown and genetic ablation studies showed they do not regulate each other.
3) Laminar flow increased the association between SIRT1 and eNOS and decreased eNOS acetylation. AMPK
Insights into the epigenetic mechanisms involving histone lysineashutosh mahale
1. The study investigated the role of histone lysine methylation and demethylation in an internal carotid artery occlusion (ICAO) mouse model of mild to moderate stroke.
2. The ICAO model resulted in neuronal damage to the striatum. Epigenetic markers like H3K9me2 were decreased after ischemia but recovered with time.
3. Inhibiting jmjD2 demethylases after ischemia prevented the decrease in H3K9me2, reduced neuronal cell death, and improved neurological outcomes, suggesting epigenetic mechanisms are implicated in stroke pathology and recovery.
1) STAT3 signaling plays a critical role in regulating astrocyte reactivity and scar formation after spinal cord injury.
2) Mice with conditional deletion of STAT3 from astrocytes showed attenuated upregulation of GFAP, failed astrocyte hypertrophy, and disrupted scar formation after injury.
3) These changes were associated with increased spread of inflammation and increased lesion size, with partially attenuated motor recovery over 28 days following injury.
This study investigated the effects of pro-inflammatory cytokines TNFα and IFNγ and the hormone testosterone on expression of the chemokine receptors CX3CR1 and CCR2 on THP-1 monocytes. Flow cytometry analysis confirmed that TNFα and IFNγ increase cell surface expression of CX3CR1 and CCR2, while testosterone decreases expression of these receptors. Additionally, pre-treating cells with testosterone before cytokine exposure continued to decrease CX3CR1 and CCR2 expression levels compared to cytokine treatment alone. Future work will utilize controls to ensure the testosterone effects are receptor-mediated and not due to conversion to estrogen.
This research paper examines the effects of activating small-conductance calcium-activated potassium (SK) channels in the spinal cord on reducing mechanical hypersensitivity in a rat model of inflammatory pain. The study finds that intrathecal administration of the SK channel activator NS309 dose-dependently attenuates mechanical hypersensitivity induced by complete Freund's adjuvant (CFA) inflammation. Additionally, coadministration of NS309 with the NMDA receptor antagonist DL-AP5 reduces the dose of DL-AP5 needed to produce antinociceptive effects in the CFA pain model. This suggests that activating SK channels in the spinal cord can modulate the effects of NMDA receptor antagonists and potentially reduce their unwanted side effects.
Temporal-Spatial Expressions of Spy1 in Rat Sciatic Nerve After CrushJiao Yang
1. The study examined the expression of the cell cycle protein Spy1 in a rat sciatic nerve crush injury model over time.
2. Spy1 expression was found to gradually increase after injury, peaking at day 3, due to increased expression in both axons and Schwann cells.
3. Spy1 expression correlated with Schwann cell proliferation after injury and Spy1 was found to localize in axons in the injured segment but did not co-localize with the growth protein GAP43.
This study examined expression of glutamate transporter proteins in the superior temporal gyrus and hippocampus in post-mortem brain samples from individuals with schizophrenia compared to controls. They found decreased expression of the glutamate transporters EAAT1 and EAAT2 in the superior temporal gyrus, and decreased EAAT2 in the hippocampus, in schizophrenia samples. They did not find changes in the neuronal transporter EAAT3 or the presynaptic vesicular glutamate transporters VGLUT1-2. This suggests abnormal buffering and reuptake but not presynaptic release of glutamate in temporal lobe synapses in schizophrenia.
This document summarizes research on how shear stress regulates SIRT1 and its role in vascular homeostasis. The key points are:
1) Applying laminar flow to endothelial cells in vitro increased SIRT1 levels and activity as well as mitochondrial biogenesis. Higher SIRT1 levels were observed under physiologically relevant pulsatile flow compared to pathophysiological oscillatory flow.
2) Laminar flow activated both AMPK and SIRT1 independently in endothelial cells. Knockdown and genetic ablation studies showed they do not regulate each other.
3) Laminar flow increased the association between SIRT1 and eNOS and decreased eNOS acetylation. AMPK
Application of PEA reduces WDR RF size - Final editShaun Croft, MScR
This document describes a study that investigated whether the fatty acid amide N-palmitoylethanolamine (PEA) can reduce inflammation-induced expansion of wide dynamic range neurone (WDR) receptive fields (RFs) in rats. PEA is an endogenous ligand for peroxisome proliferator-activated receptor alpha (PPAR-α), which has anti-inflammatory effects. The study found that intraplantar injection of PEA prior to carrageenan-induced inflammation significantly reduced the expansion of WDR RFs and attenuated hyperalgesia. Blocking PPAR-α with GW6471 prevented the effects of PEA, suggesting PEA acts through PPAR-α activation to reduce
This study investigated how genetic variation in the serotonin transporter gene (Slc6a4) and integrin beta 3 gene (Itgb3) interact to modulate serotonin uptake and transporter expression in mouse brain synapses. The researchers prepared synaptoneurosomes (preserved pre- and post-synaptic structures) from mouse midbrain, hippocampus and cortex with different genotypes of Slc6a4 and Itgb3. They found reduced serotonin transporter expression and uptake activity in midbrain synaptoneurosomes of mice with both genes heterozygous, revealing an interaction between the two genes. In contrast, changes were driven mostly by Slc6a4 in the hippocampus. The study provides evidence that
Chen et al. JCI 2013 HRM Ago1 angiogenesisZhen Chen
Let-7 and miR-103/107 were found to be strongly induced microRNAs (HRMs) in vascular endothelial cells under hypoxic conditions. Bioinformatics analysis predicted that these HRMs target the 3' UTR of argonaute 1 (AGO1) mRNA. Experimental validation confirmed that the HRMs are induced by HIF1α and directly bind to the AGO1 3' UTR, reducing AGO1 protein levels. This translational de-repression of AGO1 increased VEGF expression and promoted angiogenesis both in vitro and in vivo. The findings suggest that HRMs play a role in hypoxia-induced gene expression and angiogenesis by targeting AGO1.
This study investigated how oxidative stress activates the PI3K pathway in neurons affected by neurodegenerative diseases. The researchers found that ingestion of the oxidative stress inducer Paraquat in Drosophila larvae caused axonal transport defects and neuronal cell death. Expressing active PI3K suppressed Paraquat-mediated cell death but not axonal blocks, indicating PI3K acts downstream of transport defects. Expression of active PI3K also suppressed cell death from polyQ protein expression but did not affect associated transport defects. Dominant negative PI3K disrupted normal transport of huntingtin protein, linking PI3K directly to transport. Together, the findings suggest axonal transport defects activate the PI3K pathway to decrease oxidative stress-induced
GAPDH, a well-known glycolytic enzyme, mediatesPei-Ju Chin
This document proposes experiments to investigate how the glycolytic enzyme GAPDH (TDH3 in yeast) mediates apoptosis through epigenetic mechanisms. The first aim is to test if the protein interaction between SET and GAPDH regulates caspase-independent apoptosis by regulating granzyme A activity. The second aim is to determine if GAPDH-mediated expression of histone H2B, influenced by redox status, exerts apoptotic potential in cadmium-stressed yeast cells. Experiments include in vitro and in vivo assays of granzyme A activity and use of yeast mutants and complementation to assess the roles of TDH3, SET and H2B in apoptosis.
This document summarizes Angela Sanchez's research on how temperature-regulated genes affect aging in C. elegans. Key findings include:
- Many proteostasis and protein synthesis genes are differentially expressed between 15°C and 25°C.
- Inhibition of certain temperature-regulated proteostasis genes, like cpr-7 and egl-45, causes earlier onset of paralysis at 15°C but not 25°C.
- A neuromuscular exam showed locomotion defects, especially in backward movement, precede paralysis upon proteostasis gene inhibition. This suggests the dysfunction starts in motor neurons.
- Motor neurons innervating the posterior half have fewer synaptic connections, which
OSU-03012 sensitizes breast cancers to lapatinib-induced cell killing: a role...Enrique Moreno Gonzalez
Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. In this study, we examined mechanisms
associated with enhancing the activity of lapatinib via combination with other therapies.
This document summarizes three genomic approaches: 1) Profiling downstream target genes of the Runx3 transcription factor in gastric cancer cells, identifying both up- and downregulated genes. 2) Constructing an shRNA library targeting the mouse kinome to discover regulators of osteogenesis through screening. 3) Investigating the protein interaction between Bmi1 and Pontin52, linking them to hematopoietic stem cell self-renewal and exploring their roles in cancer cell death.
In search of tissue specific regulators in periodontium - a bioinformatic ap...Agnieszka Caruso
This study aimed to identify regulatory elements that control gene expression in periodontal ligament and gingiva tissues. Gene expression profiling identified 292 genes differentially expressed between the two tissues. Promoter analysis of these genes found potential methylation sites and transcription factor binding sites, including Elk-1, that may regulate gene expression. Gene Ontology analysis revealed biological processes enriched in the up- and down-regulated genes. This study provides insights into transcriptional regulation of tissue-specific gene expression in the periodontium.
This document discusses the role of the guanine nucleotide exchange factor C3G in neuronal differentiation. It finds that C3G protein levels increase when human neuroblastoma cells are induced to differentiate through serum starvation or treatment with forskolin or nerve growth factor. Overexpression of C3G stimulates neurite growth and increases responsiveness to differentiation signals, in a process dependent on C3G's catalytic domain and the functions of Rap1 and Cdc42. Knockdown of C3G inhibits forskolin- and nerve growth factor-induced differentiation and enhances cell death from serum starvation. C3G phosphorylation and localization to the Golgi are increased by forskolin and nerve growth factor treatment, and C3G
This document summarizes experiments exploring the neuroprotective effects of progranulin in two models of environmental neurotoxicity: PC12 cells exposed to MPTP and mice exposed to BSSG. In PC12 cells, progranulin protected against cell death induced by the neurotoxin MPTP. In mice, BSSG exposure induced gait disturbances and locomotor changes that were partially attenuated by progranulin treatment via lentiviral delivery, though muscle strength was not affected. Further studies are needed to better understand the mechanisms and long-term effects of progranulin neuroprotection in these models.
This document provides a summary of established and emerging targeted agents for the treatment of soft tissue sarcomas (STS). It discusses approved agents such as olaratumab and pazopanib which target PDGFRα and multiple receptor tyrosine kinases respectively. Emerging agents targeting EZH2, XPO1, ALK, ROS1, NTRK1-3, and MET are discussed including their mechanisms of action and current clinical trial statuses. The identification of gene fusions such as NTRK fusions is also summarized, highlighting the potential for next-generation sequencing to efficiently detect these drivers across cancer types.
Integrin V can form heterodimers with several subunits to mediate cell-cell and cell-extracellular matrix interactions. During zebrafish gastrulation, V is expressed maternally and zygotically. Here, we used a morpholino-mediated V knockdown strategy to study V function. Although V morphants displayed vascular defects, they also exhibited left-right body asymmetry defects affecting multiple visceral organs. This was preceded by mislocalization of dorsal forerunner cells (DFCs) and malformation of the Kupffer’s vesicle (KV) laterality organ
This document summarizes a study that investigated how mechanical stressing of integrin receptors affects tyrosine phosphorylation in osteoblastic cells. The key findings were:
1) Mechanical stressing of both the β1 and α2 integrin subunits induced enhanced tyrosine phosphorylation of proteins compared to integrin clustering alone.
2) Applying cyclic forces at 1 Hz was more effective at inducing tyrosine phosphorylation than continuous stress.
3) Mechanically stressed cells showed tyrosine-phosphorylated proteins becoming anchored to the cytoskeleton in a calcium-dependent manner.
4) Mechanical stressing of integrins also increased phosphorylation of MAP kinases, suggesting it can induce downstream signaling events.
1) The document summarizes a study examining the regulation of MT1-MMP in mechanically stimulated bioengineered articular cartilage.
2) The study found that mechanical stimulation upregulates the transcription factor Egr-1, which binds to the MT1-MMP promoter and increases MT1-MMP expression.
3) Blocking Egr-1 binding or MT1-MMP expression prevented mechanical stimulation from increasing extracellular matrix production.
This document discusses cancer drug targets and profiling key genes related to cancer treatment. It begins with an overview of actively investigated cancer drug target genes across various categories like growth factors and receptors, protein kinases, apoptosis genes, and more. It then discusses profiling gene expressions using RT2 Profiler PCR Arrays which allow analyzing 84 pathway genes along with controls. The document also discusses detecting gene mutations using Cancer Mutation PCR Arrays designed around clinically relevant mutations. Finally, it discusses analyzing histone modifications of drug target genes using epigenetic approaches, as histone modifications influence gene transcription and cell response to drug regimens.
GABAB receptor-mediated selective peripheral analgesia by the non-proteinogen...Igor Putrenko
1) The document examines the hypothesis that the amino acid isovaline produces peripheral analgesia through GABAB receptors without affecting the central nervous system.
2) Experiments in mice found that isovaline, like the GABAB agonists baclofen and GABA, reduced pain-related behavior induced by prostaglandin E2 injection into the paw in a GABAB receptor-dependent manner, but unlike baclofen, isovaline did not produce sedation or hypothermia indicating a lack of central effects.
3) Immunohistochemistry revealed co-localization of GABAB1 and GABAB2 receptor subunits on fine nerve endings and keratinocytes in skin
This study identifies the zinc transporter ZIP4 as mediating tissue plasminogen activator (tPA)'s ability to promote zinc uptake into neurons in a neuroprotective manner. ZIP4 expression is increased after excitotoxin stimulation in mouse hippocampus. ZIP4 physically interacts with tPA, leading to increased intracellular zinc sequestration in lysosomes. This sequestration protects neurons from the toxic effects of excessive extracellular zinc levels released during seizures or excitotoxicity.
Role of Brain Derived Neurotrophic Factor (BDNF) in NEURODEVELOPMENTWasiu Adeseji
This document discusses brain-derived neurotrophic factor (BDNF), a protein important for brain development and function. It describes how BDNF is encoded by a gene on chromosome 11 and binds to two receptors, TrkB and p75. The document outlines BDNF's roles in cell survival, differentiation, migration and development. It also discusses BDNF's importance for learning, memory and synaptic plasticity, and implications in neurodegenerative diseases and neurogenesis.
The document discusses several studies on the uptake, use, and effectiveness of pre-exposure prophylaxis (PrEP) for HIV prevention. One key study examined PrEP use among HIV-negative individuals with HIV-positive partners. Another study looked at PrEP use among heterosexual men and women. A third study from AIDS (London) also provided relevant information. The main source of information for the dissertation was secondary data from clinical research on PrEP conducted internationally.
L-glutamic acid (Glu-glutamate) is one of the major and strongest stimulatory neurotransmitters (along with aspartic acid, chinolic acid and glicyne) at the majority of excitatory synapses in the Central Nervous System (CNS), Sympathetic Nervous System (SNS) and peripheral tissues and organs of mammals and well as non-mammals
Application of PEA reduces WDR RF size - Final editShaun Croft, MScR
This document describes a study that investigated whether the fatty acid amide N-palmitoylethanolamine (PEA) can reduce inflammation-induced expansion of wide dynamic range neurone (WDR) receptive fields (RFs) in rats. PEA is an endogenous ligand for peroxisome proliferator-activated receptor alpha (PPAR-α), which has anti-inflammatory effects. The study found that intraplantar injection of PEA prior to carrageenan-induced inflammation significantly reduced the expansion of WDR RFs and attenuated hyperalgesia. Blocking PPAR-α with GW6471 prevented the effects of PEA, suggesting PEA acts through PPAR-α activation to reduce
This study investigated how genetic variation in the serotonin transporter gene (Slc6a4) and integrin beta 3 gene (Itgb3) interact to modulate serotonin uptake and transporter expression in mouse brain synapses. The researchers prepared synaptoneurosomes (preserved pre- and post-synaptic structures) from mouse midbrain, hippocampus and cortex with different genotypes of Slc6a4 and Itgb3. They found reduced serotonin transporter expression and uptake activity in midbrain synaptoneurosomes of mice with both genes heterozygous, revealing an interaction between the two genes. In contrast, changes were driven mostly by Slc6a4 in the hippocampus. The study provides evidence that
Chen et al. JCI 2013 HRM Ago1 angiogenesisZhen Chen
Let-7 and miR-103/107 were found to be strongly induced microRNAs (HRMs) in vascular endothelial cells under hypoxic conditions. Bioinformatics analysis predicted that these HRMs target the 3' UTR of argonaute 1 (AGO1) mRNA. Experimental validation confirmed that the HRMs are induced by HIF1α and directly bind to the AGO1 3' UTR, reducing AGO1 protein levels. This translational de-repression of AGO1 increased VEGF expression and promoted angiogenesis both in vitro and in vivo. The findings suggest that HRMs play a role in hypoxia-induced gene expression and angiogenesis by targeting AGO1.
This study investigated how oxidative stress activates the PI3K pathway in neurons affected by neurodegenerative diseases. The researchers found that ingestion of the oxidative stress inducer Paraquat in Drosophila larvae caused axonal transport defects and neuronal cell death. Expressing active PI3K suppressed Paraquat-mediated cell death but not axonal blocks, indicating PI3K acts downstream of transport defects. Expression of active PI3K also suppressed cell death from polyQ protein expression but did not affect associated transport defects. Dominant negative PI3K disrupted normal transport of huntingtin protein, linking PI3K directly to transport. Together, the findings suggest axonal transport defects activate the PI3K pathway to decrease oxidative stress-induced
GAPDH, a well-known glycolytic enzyme, mediatesPei-Ju Chin
This document proposes experiments to investigate how the glycolytic enzyme GAPDH (TDH3 in yeast) mediates apoptosis through epigenetic mechanisms. The first aim is to test if the protein interaction between SET and GAPDH regulates caspase-independent apoptosis by regulating granzyme A activity. The second aim is to determine if GAPDH-mediated expression of histone H2B, influenced by redox status, exerts apoptotic potential in cadmium-stressed yeast cells. Experiments include in vitro and in vivo assays of granzyme A activity and use of yeast mutants and complementation to assess the roles of TDH3, SET and H2B in apoptosis.
This document summarizes Angela Sanchez's research on how temperature-regulated genes affect aging in C. elegans. Key findings include:
- Many proteostasis and protein synthesis genes are differentially expressed between 15°C and 25°C.
- Inhibition of certain temperature-regulated proteostasis genes, like cpr-7 and egl-45, causes earlier onset of paralysis at 15°C but not 25°C.
- A neuromuscular exam showed locomotion defects, especially in backward movement, precede paralysis upon proteostasis gene inhibition. This suggests the dysfunction starts in motor neurons.
- Motor neurons innervating the posterior half have fewer synaptic connections, which
OSU-03012 sensitizes breast cancers to lapatinib-induced cell killing: a role...Enrique Moreno Gonzalez
Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. In this study, we examined mechanisms
associated with enhancing the activity of lapatinib via combination with other therapies.
This document summarizes three genomic approaches: 1) Profiling downstream target genes of the Runx3 transcription factor in gastric cancer cells, identifying both up- and downregulated genes. 2) Constructing an shRNA library targeting the mouse kinome to discover regulators of osteogenesis through screening. 3) Investigating the protein interaction between Bmi1 and Pontin52, linking them to hematopoietic stem cell self-renewal and exploring their roles in cancer cell death.
In search of tissue specific regulators in periodontium - a bioinformatic ap...Agnieszka Caruso
This study aimed to identify regulatory elements that control gene expression in periodontal ligament and gingiva tissues. Gene expression profiling identified 292 genes differentially expressed between the two tissues. Promoter analysis of these genes found potential methylation sites and transcription factor binding sites, including Elk-1, that may regulate gene expression. Gene Ontology analysis revealed biological processes enriched in the up- and down-regulated genes. This study provides insights into transcriptional regulation of tissue-specific gene expression in the periodontium.
This document discusses the role of the guanine nucleotide exchange factor C3G in neuronal differentiation. It finds that C3G protein levels increase when human neuroblastoma cells are induced to differentiate through serum starvation or treatment with forskolin or nerve growth factor. Overexpression of C3G stimulates neurite growth and increases responsiveness to differentiation signals, in a process dependent on C3G's catalytic domain and the functions of Rap1 and Cdc42. Knockdown of C3G inhibits forskolin- and nerve growth factor-induced differentiation and enhances cell death from serum starvation. C3G phosphorylation and localization to the Golgi are increased by forskolin and nerve growth factor treatment, and C3G
This document summarizes experiments exploring the neuroprotective effects of progranulin in two models of environmental neurotoxicity: PC12 cells exposed to MPTP and mice exposed to BSSG. In PC12 cells, progranulin protected against cell death induced by the neurotoxin MPTP. In mice, BSSG exposure induced gait disturbances and locomotor changes that were partially attenuated by progranulin treatment via lentiviral delivery, though muscle strength was not affected. Further studies are needed to better understand the mechanisms and long-term effects of progranulin neuroprotection in these models.
This document provides a summary of established and emerging targeted agents for the treatment of soft tissue sarcomas (STS). It discusses approved agents such as olaratumab and pazopanib which target PDGFRα and multiple receptor tyrosine kinases respectively. Emerging agents targeting EZH2, XPO1, ALK, ROS1, NTRK1-3, and MET are discussed including their mechanisms of action and current clinical trial statuses. The identification of gene fusions such as NTRK fusions is also summarized, highlighting the potential for next-generation sequencing to efficiently detect these drivers across cancer types.
Integrin V can form heterodimers with several subunits to mediate cell-cell and cell-extracellular matrix interactions. During zebrafish gastrulation, V is expressed maternally and zygotically. Here, we used a morpholino-mediated V knockdown strategy to study V function. Although V morphants displayed vascular defects, they also exhibited left-right body asymmetry defects affecting multiple visceral organs. This was preceded by mislocalization of dorsal forerunner cells (DFCs) and malformation of the Kupffer’s vesicle (KV) laterality organ
This document summarizes a study that investigated how mechanical stressing of integrin receptors affects tyrosine phosphorylation in osteoblastic cells. The key findings were:
1) Mechanical stressing of both the β1 and α2 integrin subunits induced enhanced tyrosine phosphorylation of proteins compared to integrin clustering alone.
2) Applying cyclic forces at 1 Hz was more effective at inducing tyrosine phosphorylation than continuous stress.
3) Mechanically stressed cells showed tyrosine-phosphorylated proteins becoming anchored to the cytoskeleton in a calcium-dependent manner.
4) Mechanical stressing of integrins also increased phosphorylation of MAP kinases, suggesting it can induce downstream signaling events.
1) The document summarizes a study examining the regulation of MT1-MMP in mechanically stimulated bioengineered articular cartilage.
2) The study found that mechanical stimulation upregulates the transcription factor Egr-1, which binds to the MT1-MMP promoter and increases MT1-MMP expression.
3) Blocking Egr-1 binding or MT1-MMP expression prevented mechanical stimulation from increasing extracellular matrix production.
This document discusses cancer drug targets and profiling key genes related to cancer treatment. It begins with an overview of actively investigated cancer drug target genes across various categories like growth factors and receptors, protein kinases, apoptosis genes, and more. It then discusses profiling gene expressions using RT2 Profiler PCR Arrays which allow analyzing 84 pathway genes along with controls. The document also discusses detecting gene mutations using Cancer Mutation PCR Arrays designed around clinically relevant mutations. Finally, it discusses analyzing histone modifications of drug target genes using epigenetic approaches, as histone modifications influence gene transcription and cell response to drug regimens.
GABAB receptor-mediated selective peripheral analgesia by the non-proteinogen...Igor Putrenko
1) The document examines the hypothesis that the amino acid isovaline produces peripheral analgesia through GABAB receptors without affecting the central nervous system.
2) Experiments in mice found that isovaline, like the GABAB agonists baclofen and GABA, reduced pain-related behavior induced by prostaglandin E2 injection into the paw in a GABAB receptor-dependent manner, but unlike baclofen, isovaline did not produce sedation or hypothermia indicating a lack of central effects.
3) Immunohistochemistry revealed co-localization of GABAB1 and GABAB2 receptor subunits on fine nerve endings and keratinocytes in skin
This study identifies the zinc transporter ZIP4 as mediating tissue plasminogen activator (tPA)'s ability to promote zinc uptake into neurons in a neuroprotective manner. ZIP4 expression is increased after excitotoxin stimulation in mouse hippocampus. ZIP4 physically interacts with tPA, leading to increased intracellular zinc sequestration in lysosomes. This sequestration protects neurons from the toxic effects of excessive extracellular zinc levels released during seizures or excitotoxicity.
Role of Brain Derived Neurotrophic Factor (BDNF) in NEURODEVELOPMENTWasiu Adeseji
This document discusses brain-derived neurotrophic factor (BDNF), a protein important for brain development and function. It describes how BDNF is encoded by a gene on chromosome 11 and binds to two receptors, TrkB and p75. The document outlines BDNF's roles in cell survival, differentiation, migration and development. It also discusses BDNF's importance for learning, memory and synaptic plasticity, and implications in neurodegenerative diseases and neurogenesis.
Role of Brain Derived Neurotrophic Factor (BDNF) in NEURODEVELOPMENT
Similar to Expression of Glutaminase and Vesicular Glutamate Transporter Type 2 Immunoreactivity in Rat Sacral Dorsal Root Ganglia Following a Surgical Tail Incision Final
The document discusses several studies on the uptake, use, and effectiveness of pre-exposure prophylaxis (PrEP) for HIV prevention. One key study examined PrEP use among HIV-negative individuals with HIV-positive partners. Another study looked at PrEP use among heterosexual men and women. A third study from AIDS (London) also provided relevant information. The main source of information for the dissertation was secondary data from clinical research on PrEP conducted internationally.
L-glutamic acid (Glu-glutamate) is one of the major and strongest stimulatory neurotransmitters (along with aspartic acid, chinolic acid and glicyne) at the majority of excitatory synapses in the Central Nervous System (CNS), Sympathetic Nervous System (SNS) and peripheral tissues and organs of mammals and well as non-mammals
This document discusses a study examining the role of metallothionein-I/II (MT-I/II) in promoting axonal regeneration in the central nervous system after injury. The key findings are:
1) MT-I/II can overcome inhibition by myelin and myelin-associated glycoprotein (MAG) to promote neurite outgrowth from cortical, hippocampal and dorsal root ganglion neurons in vitro.
2) Intrathecal delivery of MT-I/II to dorsal root ganglion neurons promotes neurite outgrowth in the presence of MAG.
3) Mice deficient in MT-I/II show reduced neurite outgrowth on MAG and fail to regener
Effect of naringenin on 3 np induced huntington’s disease like symptoms by es...IJARIIT
The main aim of this study was to investigate the effect of Naringenin, a flavonoid on 3-Nitropropionic acid (3-NP)-
induced Huntington’s disease like symptoms by estimations of motor co-ordination and behavioral parameters. 3-NP is an
irreversible inhibitor of complex II in the mitochondria. 3-NP-induced neurodegeneration has been widely used as an animal
model of Huntington’s disease (HD). It replicates the pathology of HD by causing oxidative stress. Naringenin is a polyphenolic
compound, a bioflavonoid, known to have a neuroprotective effect in a rat model of Alzheimer’s disease. In the present study,
the neuroprotective effect of Naringenin on 3-NP induced oxidative stress in the rat was determined by behavioral parameters.
Rats were induced with 3-NP (15 mg/kg) intraperitoneally for 21 days and rats induced with 3-NP were treated with Naringenin
(25mg/kg and 75mg/kg) for 21 days. 3-NP caused a decline in motor function in the neurological score, locomotor activity, and
impaired rotarod activity. Naringenin treatment significantly improved grip strength indicating an improvement in motor
performance, alterations in % spontaneous alternations. These findings suggest the antioxidant potential of Naringenin
flavonoid against 3-Nitropionic acid induced neurotoxicity. However, more investigations are required to elucidate the cellular
mechanisms of Naringenin against 3-Nitropropionic acid induced Huntington’s disease like symptoms.
LncRNA WARS2-IT1 Functions as an Oncogene and is Associated with Poor Outcome...semualkaira
Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors in adults and has high mortality and relapse rates. Over the past few years, great advances have been made in the diagnosis and treatment of GBM, but unfortunately, the five-year overall survival rate of GBM patients is approximately 5.1%. Our study aimed to investigate the new mechanism of Long noncoding RNAs (lncRNAs) WARS2-IT1 regulate the malignant progression of Glioblastoma.
LncRNA WARS2-IT1 Functions as an Oncogene and is Associated with Poor Outcome...semualkaira
Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors in adults and has high mortality and relapse rates. Over the past few years, great advances have been made in the diagnosis and treatment of GBM, but unfortunately, the five-year overall survival rate of GBM patients is approximately 5.1%. Our study aimed to investigate the new mechanism of Long noncoding RNAs (lncRNAs) WARS2-IT1 regulate the malignant progression of Glioblastoma.
LncRNA WARS2-IT1 Functions as an Oncogene and is Associated with Poor Outcome...semualkaira
Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors in adults and has high mortality and relapse rates. Over the past few years, great advances have been made in the diagnosis and treatment of GBM, but unfortunately, the five-year overall survival rate of GBM patients is approximately 5.1%. Our study aimed to investigate the new mechanism of Long noncoding RNAs (lncRNAs) WARS2-IT1 regulate the malignant progression of Glioblastoma.
1) The study examined the effects of repeated MDMA exposure on glutamate release and parvalbumin-positive GABAergic cells in the rat hippocampus.
2) Treatment with non-selective and COX-2 selective cyclooxygenase inhibitors attenuated the MDMA-induced increase in hippocampal glutamate, but a COX-1 inhibitor did not.
3) Repeated MDMA exposure reduced the number of parvalbumin-positive GABA interneurons in the hippocampus, and this effect was attenuated by a cyclooxygenase inhibitor. However, the inhibitor did not prevent MDMA-induced depletion of serotonin in the hippocampus.
Introduction
Definition
History
Basic element in signal transduction
Basic Pathway of signal transduction
Types of signal transduction
Second messenger
Pathway of signal transduction
Conclusion
References
The document discusses two-component systems in bacteria. A two-component system consists of a sensor histidine kinase that autophosphorylates upon sensing a signal and transfers the phosphoryl group to a cognate response regulator. The response regulator then undergoes a conformational change and activates or represses target genes. The system allows bacteria to sense and adapt to various stressors like oxidative stress and nutrient starvation.
This document describes experiments characterizing mutations in the tiggrin gene in Drosophila. Tiggrin is a ligand for PS2 integrins and is required for proper muscle function. The authors generated a precise deletion of the tiggrin gene (called tigx) using flanking P-elements. Flies lacking tiggrin die as larvae or pupae, with a few adults emerging that have misshapen abdomens and occasional wing defects. Larvae lacking tiggrin have defective muscle connections, function, and morphology. Muscle contraction waves are slower. Transgenes expressing wild-type or mutant tiggrin can partially rescue tiggrin mutant phenotypes, indicating tiggrin
This study examined the effects of oxygen-glucose deprivation (OGD), a model of stroke, on microglial mobility and viability in developing mouse hippocampal tissue slices. The key findings were:
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2) OGD, but not hypoxia, significantly reduced microglial motility based on quantitative analysis of time-lapse imaging.
3) Some microglia retained or recovered motility during OGD and were able to engulf dead cells, while others
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2) Astrogliosis, a marker of synaptic deterioration, was also observed qualitatively and quantitatively increased in the striatum of mutant mice.
3) The results suggest that mutant mice exhibit a reduced number of corticostriatal glutamatergic synapses, potentially preceding neuronal cell loss in Huntington's disease.
Glypican and Biglycan in the Nuclei of Neurons and Glioma CellsYu Liang
This document describes a study that found glypican and biglycan, two proteoglycans, localized to the nuclei of neurons and glioma cells. The researchers identified nuclear localization signals in the amino acid sequences of both proteoglycans. They demonstrated that these signals were functional by showing nuclear localization of beta-galactosidase fusion proteins containing the sequences. Nuclear localization was reduced or abolished when the basic amino acids in the signals were mutated. Dynamic changes in glypican immunoreactivity in the nucleus of glioma cells were also observed during cell division and different phases of the cell cycle. The findings suggest glypican and biglycan may be involved in regulating cell division and survival by participating in nuclear processes in
The Role Of G Protein Coupled ReceptorssAngela Hays
- G protein-coupled receptors (GPCRs) are seven transmembrane receptors located on cell surfaces that play an important role in intracellular signaling pathways and crucial physiological processes.
- When a ligand binds to a GPCR, it activates a heterotrimeric G protein within the cell. This leads to the production of second messengers like DAG and IP3, which mediate different cellular functions such as muscle contraction.
- The IP3 receptor releases intracellular calcium stores when bound by IP3, increasing cytosolic calcium levels and activating calcium-dependent signaling pathways.
Its a brief ppt describing about the type of neurotansmitters in insect synapse and their respective receptors. It also sketches about the synaptic transmission in insect nervous system
This document summarizes a study examining the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) in protecting against brain injury caused by intracerebral hemorrhage (ICH) in mice. The study found that Nrf2 knockout mice exhibited larger brain injury volumes and greater neurological deficits 24 hours after ICH induction compared to wild-type mice. Additionally, Nrf2 knockout mice showed increased leukocyte infiltration, reactive oxygen species production, DNA damage, and cytochrome c release during the early post-ICH period. These results suggest that Nrf2 provides protection against ICH-induced early brain injury, likely by reducing leukocyte-mediated free radical oxidative damage.
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2. Even brief exposures to ketamine during development, such as a single 24-hour exposure in neonatal rhesus monkeys or 5 hours in fetal and neonatal rhesus macaques, can cause long-lasting cognitive deficits.
3. Ketamine activates glycogen synthase kinase-3β, which enhances neuroapoptosis. Inhibiting this pathway via lithium can attenuate ketamine-induced neuronal cell death in developing rat pups.
Cell signalling and signal transduction Communication between cells from karpNusrat Gulbarga
Virtually every activity in which a cell is engaged is regulated by signals originating at the cell surface. This overall process in which information carried by extracellular messenger molecules is translated into changes that occur in- side a cell is referred to as signal transduction.
Similar to Expression of Glutaminase and Vesicular Glutamate Transporter Type 2 Immunoreactivity in Rat Sacral Dorsal Root Ganglia Following a Surgical Tail Incision Final (20)
Cell signalling and signal transduction Communication between cells from karp
Expression of Glutaminase and Vesicular Glutamate Transporter Type 2 Immunoreactivity in Rat Sacral Dorsal Root Ganglia Following a Surgical Tail Incision Final
1. Pharmacy & Pharmacology International Journal
Expression of Glutaminase and Vesicular Glutamate
Transporter Type 2 Immunoreactivity in Rat Sacral
Dorsal Root Ganglia Following a Surgical Tail Incision
Volume 2 Issue 3 - 2015
Heith A Crosby1
*, Michael Ihnat2
, Diana
Spencer3
and Kenneth E Miller1
1
Department of Anatomy and Cell Biology, Oklahoma State
University-Center for Health Sciences, USA
2
Department of Pharmaceutical Sciences, University of
Oklahoma-Health Sciences Center, USA
3
Department of Biotechnology, Tulsa Community College, USA
*Corresponding author: Heith A Crosby, Oklahoma State
University-Center for Health Sciences, Department of
Anatomy and Cell Biology, 1111 West 17th
Street Tulsa,
Oklahoma 74107, USA, Tel: 918.561.5817; Email:
Received: February 26, 2015 | Published: June 16, 2015
Abstract
Glutamate is an excitatory neurotransmitter, released by primary sensory
peripheral nerve and spinal synaptic terminals during nociceptive (pain) signaling.
The primary source of neurotransmitter, glutamate, is provided from its synthetic
enzyme, glutaminase (GLS). Neurotransmitter glutamate is packaged into
synaptic vesicles in nociceptive neurons by the vesicular glutamate transporter
2 (VGluT2). Little is known, however, what effect a surgical incision has on GLS
and VGluT2 in primary afferent neurons. In this study, an aseptic, midline incision
in the proximal one-third of the rat-tail was examined to determine whether
sacral dorsal root ganglia innervate the area of surgical incision, utilizing the
retrograde tracer Fluoro-Gold™. Subsequently, the amount of VGluT2 and GLS
immunoreactivity (IR) in sacral dorsal root ganglia (DRG) was evaluated using
immunofluorescence with image analysis and Western immunoblotting with
density analysis. GLS messenger RNA (mRNA) changes were evaluated using real-
time reverse transcriptase polymerase chain reaction (RT2
-PCR). Our findings
revealed that sacral-1 (S1
) DRG neurons innervate the area of surgical incision.
Both GLS and VGluT2-ir are elevated post-surgical incision in S1
DRG neurons
for up to 72 hours, while GLS mRNA levels rapidly decreased post-incision and
remain depressed for at least 96 hours. Following a surgical incision of the tail,
sacral DRGs rapidly deplete their available supply of GLS mRNA and alter their
production of the synthetic enzyme, GLS and the vesicular transporter, VGluT2.
The rapid use of GLS mRNA and subsequent elevation of GLS protein, along with
VGluT2 protein may result in both increased glutamate production and release
at peripheral and central processes contributing to primary and secondary
sensitization, respectively.
Keywords: Glutaminase; Glutamate; Incision; Post-surgical pain; VGluT2; DRG;
Pain; mRNA; PPP; GLS
Submit Manuscript | http://medcraveonline.com Pharm Pharmacol Int J 2015, 2(3): 00023
Abbreviations: AIA: Adjuvant-induced Arthritis; BCA:
Bicinchonic Acid; BDNF: Brain Derived Neurotrophic Factor;
CCD: Charge-Coupled Device; DEP: Diethylpyrocarbonate; DRG:
Dorsal Root Ganglion; ECL: Enhanced Chemiluminescence;
GLS: Glutaminase; IR: Immunoreactivity; MGI: Mean Grayscale
Intensity; NGF: Nerve Growth Factor; PBS: Phosphate Buffered
Saline; PBS-T: Phosphate Buffered Saline with Triton X-100; pH-
RE: pH-response Element; PPP: Persistent Post-surgical Pain; PVP:
Polyvinylpyrollidone; ROI: Regions of Interest; RNA: Ribonucleic
Acid; RT2
-PCR: Real-time Reverse Transcriptase Polymerase
Chain Reaction; S1
: Sacral 1; TBS: Tris-buffered Saline; VGluT2:
Vesicular Glutamate Transporter 2
Introduction
Surgical procedures are common in the United States with
estimates at greater than 45 million per year and it is estimated
that the average American undergoes 9.2 surgical procedures
in his/her lifetime [1]. A serious clinical problem that can occur
as a result of surgery is the condition of persistent postsurgical
pain (PPP). This has been described and defined as pain that lasts
longer than 3 months after surgery. This chronic painful condition
can affect as much as 50% of surgical patients, with up to 10% of
the patients rating the pain as moderate to severe. Several surgical
procedures (e.g., inguinal herniotomy, leg amputation, breast
surgery and thoracotomy) have well documented persistent pain
syndromes [2]. The need to understand the underlying molecular
neurobiology after a surgical procedure is necessary in hopes of
identifying future pharmacological and treatment modalities.
Glutamate is the amino acid neurotransmitter used by
primary sensory neurons of the dorsal root ganglion (DRG).
Glutamate is produced by the mitochondrial metabolic enzyme,
glutaminase (GLS) via the hydrolytic deamination of glutamine.
Once produced, glutamate is packaged into synaptic vesicles by
vesicular glutamate transporter 2 (VGluT2) and released from
peripheral nerve terminals and spinal synaptic terminals during
nociceptive signaling [3]. GLS is elevated in both the cytoplasm
and mitochondria of primary afferent sensory neurons in the
adjuvant-induced arthritis (AIA) model in the rat. GLS first
appears elevated in the DRG cytoplasm between 1-2 days AIA
followed by an increase in the mitochondria between 2-4 days.
Enzyme activity, protein and immunoreactivity (IR) remained
elevated in the DRG neuronal cell bodies through days 2-8. GLS in
peripheral nerve terminals in skin also are elevated during AIA.
This elevation of GLS enzyme allows sensory nerves in the skin
to produce increased amounts of glutamate during inflammation.
Elevated glutamate production and release from sensory
nerves contributes, in part, to the enhanced pain sensitivities
of inflammation and helps maintain primary hyperalgesia [4,5].
Research Article