scholarly journals A Tale of Two Transmitters: Serotonin and Histamine as In Vivo Biomarkers of Chronic Stress in Mice

2021 ◽  
Author(s):  
Melinda Hersey ◽  
Melissa Reneaux ◽  
Shane Berger ◽  
Sergio Mena ◽  
Anna Marie Buchanan ◽  
...  
Keyword(s):  
Chronic Stress ◽  
High Accuracy ◽  
Mental Illnesses ◽  
Therapeutic Approaches ◽  
Mathematical Methods ◽  
Voltammetric Measurement ◽  
Public Health Challenges ◽  
Hypothalamic Histamine ◽  
Chemical Strategy

Abstract Background: Stress-induced mental illnesses (mediated by neuroinflammation) pose one of the world’s most urgent public health challenges. A reliable in vivo chemical biomarker of stress would significantly improve the clinical communities’ diagnostic and therapeutic approaches to illnesses like depression.Methods: Male and female C57BL/6J mice underwent a chronic stress paradigm. We paired innovative in vivo serotonin and histamine voltammetric measurement technologies, behavioral testing, and cutting-edge mathematical methods to correlate chemistry to stress and behavior.Results: Inflammation-induced increases in hypothalamic histamine were co-measured with decreased in vivo extracellular hippocampal serotonin in mice that underwent a chronic stress paradigm, regardless of behavioral phenotype. In animals with depression phenotypes, correlations were found between serotonin and the extent of behavioral indices of depression. We created a high accuracy algorithm that could predict whether animals had been exposed to stress or not based solely on the serotonin measurement. We next developed a model of serotonin and histamine modulation, which predicted that stress-induced neuroinflammation increases histaminergic activity, serving to inhibit serotonin. Finally, we created a mathematical index of stress, Si and predicted that during chronic stress, where Si is high, simultaneously increasing serotonin and decreasing histamine is the most effective chemical strategy to restoring serotonin to pre-stress levels. When we pursued this idea pharmacologically, our experiments were nearly identical to the model’s predictions.Conclusions: This work shines the light on two biomarkers of chronic stress, histamine and serotonin, and implies that both may be important in our future investigations of the pathology and treatment of inflammation-induced depression.

Psychiatric neuroimaging: Joining forces with epidemiology

2008 ◽  
Vol 23 (4) ◽  
pp. 315-319 ◽  
Author(s):  
David Glahn ◽  
Abraham Reichenberg ◽  
Sophia Frangou ◽  
Hans Ormel
Keyword(s):  
Phenotypic Expression ◽  
Mental Illnesses ◽  
Response To Treatment ◽  
Psychiatric Research ◽  
Therapeutic Approaches ◽  
Biological Mechanisms ◽  
Multiple Risk Factors ◽  
Genetic And Environmental Factors ◽  
The Relationship

AbstractSevere mental illnesses such as schizophrenia and mood disorders have a major impact on public health. Disease prevalence and phenotypic expression are the products of environment and gene interactions. However, our incomplete understanding of their aetiology and pathophysiology thwarts primary prevention and early diagnosis and limits the effective application of currently available treatments as well as the development of novel therapeutic approaches. Neuroimaging can provide detailed in vivo information about the biological mechanisms underpinning the relationship between genetic variation and clinical phenotypes or response to treatment. However, the biological complexity of severe mental illness results from unknown or unpredictable interactions between multiple genetic and environmental factors, many of which have only been partially identified. We propose that the use of epidemiological principles to neuroimaging research is a necessary next step in psychiatric research. Because of the complexity of mental disorders and the multiple risk factors involved only the use of large epidemiologically defined samples will allow us to study the broader spectrum of psychopathology, including sub-threshold presentation and explore pathophysiological processes and the functional impact of genetic and non-genetic factors on the onset and persistence of psychopathology.

scholarly journals Survival and Proliferation under Severely Hypoxic Microenvironments Using Cell-Laden Oxygenating Hydrogels

2021 ◽  
Vol 12 (2) ◽  
pp. 30
Author(s):  
Shabir Hassan ◽  
Berivan Cecen ◽  
Ramon Peña-Garcia ◽  
Fernanda Roberta Marciano ◽  
Amir K. Miri ◽  
...  
Keyword(s):  
Prolonged Release ◽  
Therapeutic Approaches ◽  
Encapsulated Cells ◽  
Hypoxic Conditions ◽  
Skeletal Myoblasts ◽  
Artificial Tissue ◽  
Delivery Platform ◽  
Living Tissues

Different strategies have been employed to provide adequate nutrients for engineered living tissues. These have mainly revolved around providing oxygen to alleviate the effects of chronic hypoxia or anoxia that result in necrosis or weak neovascularization, leading to failure of artificial tissue implants and hence poor clinical outcome. While different biomaterials have been used as oxygen generators for in vitro as well as in vivo applications, certain problems have hampered their wide application. Among these are the generation and the rate at which oxygen is produced together with the production of the reaction intermediates in the form of reactive oxygen species (ROS). Both these factors can be detrimental for cell survival and can severely affect the outcome of such studies. Here we present calcium peroxide (CPO) encapsulated in polycaprolactone as oxygen releasing microparticles (OMPs). While CPO releases oxygen upon hydrolysis, PCL encapsulation ensures that hydrolysis takes place slowly, thereby sustaining prolonged release of oxygen without the stress the bulk release can endow on the encapsulated cells. We used gelatin methacryloyl (GelMA) hydrogels containing these OMPs to stimulate survival and proliferation of encapsulated skeletal myoblasts and optimized the OMP concentration for sustained oxygen delivery over more than a week. The oxygen releasing and delivery platform described in this study opens up opportunities for cell-based therapeutic approaches to treat diseases resulting from ischemic conditions and enhance survival of implants under severe hypoxic conditions for successful clinical translation.

scholarly journals MBRS-48. IDENTIFICATION OF NOVEL THERAPEUTIC APPROACHES FOR MYC-DRIVEN MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii406-iii406
Author(s):  
Kübra Taban ◽  
David Pauck ◽  
Mara Maue ◽  
Viktoria Marquardt ◽  
Hua Yu ◽  
...  
Keyword(s):  
New Drugs ◽  
Current Therapy ◽  
Cancer Drug ◽  
Mrna Levels ◽  
Cell Models ◽  
Therapeutic Approaches ◽  
Group 3 ◽  
Novel Therapeutic

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and is frequently metastatic at diagnosis. Treatment with surgery, radiation and multi-agent chemotherapy may leave survivors of these brain tumors with long-term deficits as a consequence. One of the four consensus molecular subgroups of MB is the MYC-driven group 3 MB, which is the most malignant type and has a poor prognosis under current therapy. Thus, it is important to discover more effective targeted therapeutic approaches. We conducted a high-throughput drug screening to identify novel compounds showing efficiency in group 3 MB using both clinically established inhibitors (n=196) and clinically-applicable compounds (n=464). More than 20 compounds demonstrated a significantly higher anti-tumoral effect in MYChigh (n=7) compared to MYClow (n=4) MB cell models. Among these compounds, Navitoclax and Clofarabine showed the strongest effect in inducing cell cycle arrest and apoptosis in MYChigh MB models. Furthermore, we show that Navitoclax, an orally bioavailable and blood-brain barrier passing anti-cancer drug, inhibits specifically Bcl-xL proteins. In line, we found a significant correlation between BCL-xL and MYC mRNA levels in 763 primary MB patient samples (Data source: “R2 https://hgserver1.amc.nl”). In addition, Navitoclax and Clofarabine have been tested in cells obtained from MB patient-derived-xenografts, which confirmed their specific efficacy in MYChigh versus MYClow MB. In summary, our approach has identified promising new drugs that significantly reduce cell viability in MYChigh compared to MYClow MB cell models. Our findings point to novel therapeutic vulnerabilities for MB that need to be further validated in vitro and in vivo.

Gene therapeutic approaches—transfer in vivo☆

2006 ◽  
Vol 58 (2) ◽  
pp. 243-258 ◽  
Author(s):  
C EVANS ◽  
E GOUZE ◽  
J GOUZE ◽  
P ROBBINS ◽  
S GHIVIZZANI
Keyword(s):  
Therapeutic Approaches

scholarly journals Assessment of Immunological Potential of Glial Restricted Progenitor Graft In Vivo-Is Immunosuppression Mandatory?

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1804
Author(s):  
Urszula Kozlowska ◽  
Aleksandra Klimczak ◽  
Karolina Anna Bednarowicz ◽  
Tomasz Zalewski ◽  
Natalia Rozwadowska ◽  
...  
Keyword(s):  
Immune Reaction ◽  
Disease Model ◽  
Immunosuppressive Drugs ◽  
Therapeutic Approaches ◽  
Stem Cell Graft ◽  
Skeletal Muscle Loss ◽  
The Brain ◽  
Privileged Site ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, causing motor neuron and skeletal muscle loss and death. One of the promising therapeutic approaches is stem cell graft application into the brain; however, an immune reaction against it creates serious limitations. This study aimed to research the efficiency of glial restricted progenitors (GRPs) grafted into murine CNS (central nervous system) in healthy models and the SOD1G93A ALS disease model. The cellular grafts were administered in semiallogenic and allogeneic settings. To investigate the models of immune reaction against grafted GRPs, we applied three immunosuppressive/immunomodulatory regimens: preimplantation factor (PiF); Tacrolimus; and CTLA-4, MR1 co-stimulatory blockade. We tracked the cells with bioluminescence imaging (BLI) in vivo to study their survival. The immune response character was evaluated with brain tissue assays and multiplex ELISA in serum and cerebrospinal fluid (CSF). The application of immunosuppressive drugs is disputable when considering cellular transplants into the immune-privileged site/brain. However, our data revealed that semiallogenic GRP graft might survive inside murine CNS without the necessity to apply any immunomodulation or immunosuppression, whereas, in the situation of allogeneic mouse setting, the combination of CTLA-4, MR1 blockade can be considered as the best immunosuppressive option.

scholarly journals Modeling Human Cardiac Arrhythmias: Insights from Zebrafish

2022 ◽  
Vol 9 (1) ◽  
pp. 13
Author(s):  
Sébastien Gauvrit ◽  
Jaclyn Bossaer ◽  
Joyce Lee ◽  
Michelle M. Collins
Keyword(s):  
Public Health ◽  
Cardiac Arrhythmia ◽  
Cardiac Arrhythmias ◽  
Heart Rhythm ◽  
Therapeutic Strategies ◽  
Adult Zebrafish ◽  
Disease Mechanisms ◽  
New Models ◽  
Public Health Challenges

Cardiac arrhythmia, or irregular heart rhythm, is associated with morbidity and mortality and is described as one of the most important future public health challenges. Therefore, developing new models of cardiac arrhythmia is critical for understanding disease mechanisms, determining genetic underpinnings, and developing new therapeutic strategies. In the last few decades, the zebrafish has emerged as an attractive model to reproduce in vivo human cardiac pathologies, including arrhythmias. Here, we highlight the contribution of zebrafish to the field and discuss the available cardiac arrhythmia models. Further, we outline techniques to assess potential heart rhythm defects in larval and adult zebrafish. As genetic tools in zebrafish continue to bloom, this model will be crucial for functional genomics studies and to develop personalized anti-arrhythmic therapies.

scholarly journals Нейросетевой метод прогнозирования образования дефектов на поверхности тонких пленок ITO при механических нагрузках

2018 ◽  
Vol 44 (9) ◽  
pp. 81
Author(s):  
Д.А. Кириенко ◽  
О.Я. Березина
Keyword(s):  
Defect Density ◽  
Unit Length ◽  
High Accuracy ◽  
Mathematical Methods ◽  
Polymer Substrates ◽  
Transparent Conducting ◽  
Bending Radius ◽  
Conducting Coating ◽  
Average Defect ◽  
Transparent Conducting Coatings

AbstractA method for determining the number of defects arising under compressive and tensile stress in bended thin transparent conducting coatings on polymer substrates is proposed. This algorithm is based on the use of mathematical methods of artificial neural networks. The network is trained for calculating the average defect density per unit length at the input parameters corresponding to film and substrate sizes, surface resistance of the conducting coating, and bending radius. The application of this method allows one to determine the average defect density with high accuracy.

scholarly journals miR-135a Reduces Osteosarcoma Pulmonary Metastasis by Targeting Both BMI1 and KLF4

2021 ◽  
Vol 11 ◽  
Author(s):  
Chenglong Chen ◽  
Xingjia Mao ◽  
Caitong Cheng ◽  
Yurui Jiao ◽  
Yi Zhou ◽  
...  
Keyword(s):  
Cell Invasion ◽  
Tumor Recurrence ◽  
Response Rate ◽  
Ectopic Expression ◽  
Chemotherapy Treatment ◽  
Therapeutic Approaches ◽  
Inhibit Tumor Growth ◽  
And Function ◽  
Novel Therapeutic

Because of the modest response rate after surgery and chemotherapy, treatment of osteosarcoma (OS) remains challenging due to tumor recurrence and metastasis. miR-135a has been reported to act as an anticarcinogenic regulator of several cancers. However, its expression and function in osteosarcoma remain largely unknown. Here, we reported that abridged miR-135a expression in OS cells and tissues, and its expression is inversely correlated with the expression of BMI1 and KLF4, which are described as oncogenes in several cancers. Ectopic expression of miR-135a inhibited cell invasion and expression of BMI1 and KLF4 in OS cells. In vivo investigation confirmed that miR-135a acts as a tumor suppressor in OS to inhibit tumor growth and lung metastasis in xenograft nude mice. BMI1 and KLF4 were revealed to be direct targets of miR-135a, and miR-135a had a similar effect as the combination of si-BMI1 and si-KLF4 on inhibiting tumor progression and the expression of BMI1 and KLF4 in vivo. Altogether, our results demonstrate that the targeting of BMI1/KLF4 with miR-135a may provide an applicable strategy for exploring novel therapeutic approaches for OS.

scholarly journals Rotavirus Replication Factories Are Complex Ribonucleoprotein Condensates

2020 ◽  
Author(s):  
Florian Geiger ◽  
Guido Papa ◽  
William E. Arter ◽  
Julia Acker ◽  
Kadi L. Saar ◽  
...  
Keyword(s):  
Phase Separation ◽  
Unique Feature ◽  
Rna Viruses ◽  
Therapeutic Approaches ◽  
Subcellular Organelles ◽  
Selective Enrichment ◽  
Novel Therapeutic ◽  
Liquid Liquid Phase Separation

AbstractRNA viruses induce formation of subcellular organelles that provide microenvironments conducive to their replication. Here we show that replication factories of rotaviruses represent protein-RNA condensates that are formed via liquid-liquid phase separation. We demonstrate that rotavirus proteins NSP5 and NSP2 undergo phase separation in vitro and form RNA-rich condensates in vivo that can be reversibly dissolved by aliphatic diols. During infection, these RNA-protein condensates became less dynamic and impervious to aliphatic diols, indicating a transition from a liquid to solid state. Some aspects of assembly of rotavirus replication factories mirror the formation of cytoplasmic ribonucleoprotein granules, while the selective enrichment of viral transcripts appears to be a unique feature of these condensates. Such complex RNA-protein condensates that underlie replication of RNA viruses represent an attractive target for developing novel therapeutic approaches.

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