scholarly journals Prophylactic Activation of Shh Signaling Attenuates TBI-Induced Seizures in Zebrafish by Modulating Glutamate Excitotoxicity through Eaat2a

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 32
Author(s):  
James Hentig ◽  
Leah J. Campbell ◽  
Kaylee Cloghessy ◽  
Mijoon Lee ◽  
William Boggess ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Cognitive Deficits ◽  
The United States ◽  
Glutamate Excitotoxicity ◽  
Ionotropic Glutamate Receptors ◽  
Chemical Signaling ◽  
Shh Signaling ◽  
Central Nervous System Damage ◽  
Weight Drop ◽  
Post Traumatic

Approximately 2 million individuals experience a traumatic brain injury (TBI) every year in the United States. Secondary injury begins within minutes after TBI, with alterations in cellular function and chemical signaling that contribute to excitotoxicity. Post-traumatic seizures (PTS) are experienced in an increasing number of TBI individuals that also display resistance to traditional anti-seizure medications (ASMs). Sonic hedgehog (Shh) is a signaling pathway that is upregulated following central nervous system damage in zebrafish and aids injury-induced regeneration. Using a modified Marmarou weight drop on adult zebrafish, we examined PTS following TBI and Shh modulation. We found that inhibiting Shh signaling by cyclopamine significantly increased PTS in TBI fish, prolonged the timeframe PTS was observed, and decreased survival across all TBI severities. Shh-inhibited TBI fish failed to respond to traditional ASMs, but were attenuated when treated with CNQX, which blocks ionotropic glutamate receptors. We found that the Smoothened agonist, purmorphamine, increased Eaat2a expression in undamaged brains compared to untreated controls, and purmorphamine treatment reduced glutamate excitotoxicity following TBI. Similarly, purmorphamine reduced PTS, edema, and cognitive deficits in TBI fish, while these pathologies were increased and/or prolonged in cyclopamine-treated TBI fish. However, the increased severity of TBI phenotypes with cyclopamine was reduced by cotreating fish with ceftriaxone, which induces Eaat2a expression. Collectively, these data suggest that Shh signaling induces Eaat2a expression and plays a role in regulating TBI-induced glutamate excitotoxicity and TBI sequelae.

scholarly journals New Tricks for an Old (Hedge)Hog: Sonic Hedgehog Regulation of Astrocyte Function

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1353
Author(s):  
A. Denise R. Garcia
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Molecular Signaling ◽  
Synaptic Organization ◽  
Shh Signaling ◽  
Broad Array ◽  
And Function ◽  
Molecular Signaling Pathway

The Sonic hedgehog (Shh) molecular signaling pathway is well established as a key regulator of neurodevelopment. It regulates diverse cellular behaviors, and its functions vary with respect to cell type, region, and developmental stage, reflecting the incredible pleiotropy of this molecular signaling pathway. Although it is best understood for its roles in development, Shh signaling persists into adulthood and is emerging as an important regulator of astrocyte function. Astrocytes play central roles in a broad array of nervous system functions, including synapse formation and function as well as coordination and orchestration of CNS inflammatory responses in pathological states. Neurons are the source of Shh in the adult, suggesting that Shh signaling mediates neuron–astrocyte communication, a novel role for this multifaceted pathway. Multiple roles for Shh signaling in astrocytes are increasingly being identified, including regulation of astrocyte identity, modulation of synaptic organization, and limitation of inflammation. This review discusses these novel roles for Shh signaling in regulating diverse astrocyte functions in the healthy brain and in pathology.

Association Between Intimate Partner Violence Subtypes and Post-traumatic Stress Disorder Symptoms and Hazardous Substance Use

2021 ◽  
pp. 088626052110219
Author(s):  
Matthew M. Yalch ◽  
Sloane R. M. Rickman
Keyword(s):  
Substance Use ◽  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Partner Violence ◽  
The United States ◽  
Cumulative Effects ◽  
Hazardous Substance ◽  
Ptsd Symptoms ◽  
Post Traumatic Stress ◽  
Post Traumatic

Intimate partner violence (IPV) is a common problem for women in the United States and is associated with symptoms of post-traumatic stress disorder (PTSD) as well as hazardous use of substances like alcohol and drugs. However, not all subtypes of IPV (i.e., physical, sexual, and psychological) are equally predictive of PTSD and hazardous substance use. Although previous research suggests that psychological IPV has the strongest relative effect on PTSD symptoms and substance use, there is less research on IPV subtypes’ cumulative effects. In this study, we examined the relative and cumulative effects of physical, sexual, and psychological IPV on PTSD symptoms and hazardous substance use in a sample of women in the United States recruited via Amazon’s Mechanical Turk ( N = 793) using bootstrapped multiple regression and configural frequency analyses. Results suggest that physical IPV had the most pronounced influence (medium-large effect sizes) on substance use across women, but that the cumulative effects of all three IPV subtypes were most closely associated with diagnostic levels of both PTSD and substance use at the level of groups of women. These findings clarify and extend previous research on the differential effects of IPV subtypes and provide directions for future research and clinical intervention.

scholarly journals Psychosocial Outcomes in Adult Survivors of Retinoblastoma

2015 ◽  
Vol 33 (31) ◽  
pp. 3608-3614 ◽  
Author(s):  
Jennifer S. Ford ◽  
Joanne F. Chou ◽  
Charles A. Sklar ◽  
Kevin C. Oeffinger ◽  
Danielle Novetsky Friedman ◽  
...  
Keyword(s):  
Traumatic Stress ◽  
Medical Condition ◽  
Cancer Recurrence ◽  
Psychosocial Outcomes ◽  
The United States ◽  
Fear Of Cancer Recurrence ◽  
Chronic Medical Condition ◽  
Post Traumatic Stress ◽  
Stress Symptoms ◽  
Post Traumatic

Purpose Survival rates for individuals diagnosed with retinoblastoma (RB) exceed 95% in the United States; however, little is known about the long-term psychosocial outcomes of these survivors. Patients and Methods Adult RB survivors, diagnosed from 1932 to 1994 and treated in New York, completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study (CCSS), by mail or telephone. Psychosocial outcomes included psychological distress, anxiety, depression, somatization, fear of cancer recurrence, satisfaction with facial appearance, post-traumatic growth, and post-traumatic stress symptoms; noncancer CCSS siblings served as a comparison group. Results A total of 470 RB survivors (53.6% with bilateral RB; 52.1% female) and 2,820 CCSS siblings were 43.3 (standard deviation [SD], 11) years and 33.2 (SD, 8.4) years old at the time of study, respectively. After adjusting for sociodemographic factors, RB survivors did not have significantly higher rates of depression, somatization, distress, or anxiety compared with CCSS siblings. Although RB survivors were more likely to report post-traumatic stress symptoms of avoidance and/or hyperarousal (both P < .01), only five (1.1%) of 470 met criteria for post-traumatic stress disorder. Among survivors, having a chronic medical condition did not increase the likelihood of psychological problems. Bilateral RB survivors were more likely than unilateral RB survivors to experience fears of cancer recurrence (P < .01) and worry about their children being diagnosed with RB (P < .01). However, bilateral RB survivors were no more likely to report depression, anxiety, or somatic complaints than unilateral survivors. Conclusion Most RB survivors do not have poorer psychosocial functioning compared with a noncancer sample. In addition, bilateral and unilateral RB survivors seem similar with respect to their psychological symptoms.

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

2018 ◽  
Vol 48 (6) ◽  
pp. 456-464 ◽  
Author(s):  
Jin Sug Kim ◽  
Kyung Sook Cho ◽  
Seon Hwa Park ◽  
Sang Ho Lee ◽  
Ji Hwan Lee ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Isotonic Saline ◽  
Control Group ◽  
Protective Effects ◽  
Peritoneal Fibrosis ◽  
Shh Signaling ◽  
Itraconazole Treatment

Background: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. Methods: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. Results: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-β1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. Conclusion: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.

scholarly journals Evaluation of the effects of L-Theanine on neurobehavior in an adult male Sprague-Dawley Rat Model of PTSD

2019 ◽  
Vol 6 (3) ◽  
pp. 299-308
Author(s):  
John E Buonora ◽  
Patrick M Krum ◽  
Tomás Eduardo Ceremuga
Keyword(s):  
Spatial Memory ◽  
Traumatic Event ◽  
Forced Swim Test ◽  
The United States ◽  
Traumatic Experiences ◽  
Stress Model ◽  
Sprague Dawley ◽  
Post Traumatic Stress ◽  
Post Traumatic ◽  
Shock Stress

Post-traumatic stress disorder (PTSD) continues to be one of the most common mental health disorders in the United States and may occur in response to traumatic experiences. Currently, there are no interventions that prevent the development of PTSD. L-Theanine (L-Th), a major compound in green tea has been found to decrease anxiety and prevent memory impairment and may have potential effects in the prevention of PTSD. Sixty rats were divided into six experimental groups: control vehicle, control L-Th, control naïve, PTSD vehicle, PTSD Pre-L-Th (prophylactic), PTSD Post-L-Th (non-prophylactic). PTSD was induced by a 3-day restraint/tail shock stress model. The effects of L-Th on neurobehavior were evaluated by Elevated Plus-Maze (EPM), Morris Water Maze (MWM), and Forced Swim Test (FST). Our study found that the total food intake weight of PTSD Pre-L-Th (prophylactic) rats were significantly increased compared to that of PTSD vehicle rats (p = .04). Administration of L-Th 24 hours before the initial PTSD event or for 10 days following the last PTSD stress event did not statistically improve mean open arm exploration on the EPM, spatial memory, and learning in the MWM or behavioral despair measured by the FST (p > 0.05). Although the 3-day restraint/tail shock stress model caused stress in the rodents, it did not produce reported PTSD-like anxiety and depression or spatial memory loss. The effect of Pre-L-Th or Post-L-Th treatment, on the neurobehavioral functions could not be effectively evaluated. However, this study provides a foundation for future studies to try different rodent PTSD models to induce PTSD-like neurobehavioral impairments to explore dosage, frequency, as well as the duration of L-Th administration before and/or after the post-traumatic event. The 3-day restraint/tail shock stress model caused stress in the rodents, Pre-L-Theanine treatment preconditioned the PTSD rats to endure stress.

scholarly journals Non-cell autonomous inhibition of the Shh pathway due to impaired cholesterol biosynthesis requires Ptch1/2

2020 ◽  
Author(s):  
Carian Jägers ◽  
Henk Roelink
Keyword(s):  
Sonic Hedgehog ◽  
Birth Defects ◽  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Opitz Syndrome ◽  
Cholesterol Precursors ◽  
G Protein Coupled ◽  
Mutant Cells

AbstractBirth defects due to congenital errors in enzymes involved cholesterol synthesis like Smith-Lemli-Opitz syndrome (SLOS) and Lathosterolosis cause an accumulation of cholesterol precursors and a deficit in cholesterol. The phenotype of both SLOS and Lathosterolosis have similarities to syndromes associated with abnormal Sonic hedgehog (Shh) signaling, consistent with the notion that impaired cholesterol signaling can cause reduced Shh signaling. Two multipass membrane proteins play central roles in Shh signal transduction, the putative Resistance, Nodulation and Division (RND) antiporters Ptch1 and Ptch2, and the G-protein coupled receptor Smoothened (Smo). Sterols have been suggested as cargo for Ptch1, while Smo activity can affected both positively and negatively by steroidal molecules. We demonstrate that mESCs mutant for 7-dehydroxycholesterol reductase (7dhcr) or sterol-C5-desaturase (sc5d) reduce the Hh response in nearby wildtype cells when grown in mosaic organoids. This non-cell autonomous inhibitory activity of the mutant cells required the presence of both Ptch1 and Ptch2. These observations support a model in which late cholesterol precursors that accumulate in cells lacking 7DHCR are the cargo for Ptch1 and Ptch2 activity that mediates the non-cell autonomous inhibition of Smo.

Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation

Development ◽  
2000 ◽  
Vol 127 (8) ◽  
pp. 1593-1605 ◽  
Author(s):  
H.L. Park ◽  
C. Bai ◽  
K.A. Platt ◽  
M.P. Matise ◽  
A. Beeghly ◽  
...  
Keyword(s):  
Dna Binding ◽  
Sonic Hedgehog ◽  
Zinc Fingers ◽  
Branching Morphogenesis ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Shh Signaling ◽  
Anteroposterior Patterning ◽  
Gli Transcription Factors ◽  
Ventral Spinal Cord

The secreted factor Sonic hedgehog (SHH) is both required for and sufficient to induce multiple developmental processes, including ventralization of the CNS, branching morphogenesis of the lungs and anteroposterior patterning of the limbs. Based on analogy to the Drosophila Hh pathway, the multiple GLI transcription factors in vertebrates are likely to both transduce SHH signaling and repress Shh transcription. In order to discriminate between overlapping versus unique requirements for the three Gli genes in mice, we have produced a Gli1 mutant and analyzed the phenotypes of Gli1/Gli2 and Gli1/3 double mutants. Gli3(xt) mutants have polydactyly and dorsal CNS defects associated with ectopic Shh expression, indicating GLI3 plays a role in repressing Shh. In contrast, Gli2 mutants have five digits, but lack a floorplate, indicating that it is required to transduce SHH signaling in some tissues. Remarkably, mice homozygous for a Gli1(zfd)mutation that deletes the exons encoding the DNA-binding domain are viable and appear normal. Transgenic mice expressing a GLI1 protein lacking the zinc fingers can not induce SHH targets in the dorsal brain, indicating that the Gli1(zfd)allele contains a hypomorphic or null mutation. Interestingly, Gli1(zfd/zfd);Gli2(zfd/+), but not Gli1(zfd/zfd);Gli3(zfd/+) double mutants have a severe phenotype; most Gli1(zfd/zfd);Gli2(zfd/+) mice die soon after birth and all have multiple defects including a variable loss of ventral spinal cord cells and smaller lungs that are similar to, but less extreme than, Gli2(zfd/zfd) mutants. Gli1/Gli2 double homozygous mutants have more extreme CNS and lung defects than Gli1(zfd/zfd);Gli2(zfd/+) mutants, however, in contrast to Shh mutants, ventrolateral neurons develop in the CNS and the limbs have 5 digits with an extra postaxial nubbin. These studies demonstrate that the zinc-finger DNA-binding domain of GLI1 protein is not required for SHH signaling in mouse. Furthermore, Gli1 and Gli2, but not Gli1 and Gli3, have extensive overlapping functions that are likely downstream of SHH signaling.

Betrayal

2019 ◽  
pp. 74-84
Author(s):  
Andrew Marble
Keyword(s):  
United States ◽  
High School ◽  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Stress Disorder ◽  
High School Graduation ◽  
The United States ◽  
Post Traumatic Stress ◽  
Post Traumatic ◽  
School Graduation

Returning to Peoria, Illinois, on the morning after the June 1952 high school graduation, the chapter tells, through Donna Bechtold’s eyes, how John Shalikashvili fought to assimilate to life in the United States, how manipulative and strategic he could be and how this helped him to be well-liked at school, and how he struggled with demons from his wartime past (post-traumatic stress disorder, PTSD). It also reveals that Bechtold, despite all he has done for her, is set to betray him.

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