scholarly journals Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Rene Solano Fonseca ◽  
Patrick Metang ◽  
Nathan Egge ◽  
Yingjian Liu ◽  
Kielen R Zuurbier ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Electron Flux ◽  
Selective Vulnerability ◽  
Experimental Models ◽  
Complex Iv ◽  
C Elegans ◽  
Blunt Force Trauma ◽  
The Warburg Effect

Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

scholarly journals The Spatial Organization of the Intranuclear Structures of Human Brain Dopaminergic Neurons

Acta Naturae ◽  
2017 ◽  
Vol 9 (3) ◽  
pp. 81-88 ◽  
Author(s):  
D. E. Korzhevskii ◽  
V. V. Gusel’nikova ◽  
O. V. Kirik ◽  
E. G. Sukhorukova ◽  
I. P. Grigorev
Keyword(s):  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Spatial Organization ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Selective Vulnerability ◽  
Confocal Laser ◽  
Double Labeling ◽  
Dimensional Reconstruction ◽  
Marinesco Bodies

We studied the intranuclear localization of protein nucleophosmin (B23) and ubiquitin in the dopaminergic neurons of human substantia nigra (n = 6, age of 25-87 years) using immunohistochemistry and confocal laser microscopy. Intranuclear ubiquitin-immunopositive bodies that morphologically correspond to Marinesco bodies were found to be present in substantia nigra dopaminergic (tyrosine hydroxylase-immunopositive) neurons but absent in non-dopaminergic neurons. The number of bodies varied from 0 to 6 per cell nucleus. Nucleophosmin (B23) was found in the neuronal nucleolus, with the nucleolus size being constant in the nigral neurons of each individual brain. All the observed neurons had only one large nucleolus with intense nucleophosmin immunoreactivity and a lightly stained region (1-2 m in diameter) that apparently represents the giant fibrillar center (GFC). An intensely immunostained nucleophosmin-containing granule was often observed at the GFC periphery. Double labeling demonstrated that nucleophosmin-immunoreactive nucleolus and ubiquitin-immunoreactive Marinesco bodies can occur both closely to and remotely from each other. Three-dimensional reconstruction indicates that rounded Marinesco bodies are polymorphic and often have a complex shape, with some flattening and concavities, which may be associated with contact not only with the nucleolus, but also, presumably, with other intranuclear structures free of ubiquitin or nucleophosmin. Ubiquitin-immunoreactive structures with a relatively small size (up to 1 m in length) and various clastosome-like shapes (Lafarga et al., 2002) often occur near Marinesco bodies. There were no cases of detection of ubiquitin in the nucleoli of dopaminergic neurons and nucleophosmin/B23 in typical Marinesco bodies. The obtained information may be helpful in unraveling the molecular mechanisms of the selective vulnerability of substantia nigra dopaminergic neurons to damaging factors.

scholarly journals Swim exercise in C. elegans extends neuromuscular and intestinal healthspan, enhances learning ability, and protects against neurodegeneration

2019 ◽  
Author(s):  
Ricardo Laranjeiro ◽  
Girish Harinath ◽  
Jennifer E. Hewitt ◽  
Jessica H. Hartman ◽  
Mary Anne Royal ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Model ◽  
Animal Health ◽  
Early Adulthood ◽  
Learning Ability ◽  
Mitochondrial Morphology ◽  
Early Exercise ◽  
C Elegans ◽  
Exercise Adaptation

AbstractExercise can protect against cardiovascular disease, neurodegenerative disease, diabetes, cancer, and age-associated declines in muscle, immune, and cognitive function. In fact, regular physical exercise is the most powerful intervention known to enhance robustness of health and aging. Still, the molecular and cellular mechanisms that mediate system-wide exercise benefits remain poorly understood, especially as applies to “off target” tissues that do not participate directly in training activity. Elaborating molecular mechanisms of whole-animal exercise benefits is therefore of considerable importance to human health. The development of exercise protocols for short-lived genetic models holds great potential for deciphering fundamental mechanisms of exercise trans-tissue signaling during the entire aging process. Here, we report on the optimization of a long-term swim exercise protocol for C. elegans and we demonstrate its benefits to diverse aging tissues, even if exercise occurs only during a restricted phase during early adulthood. We found that multiple daily swim sessions are essential for exercise adaptation in C. elegans, leading to body wall muscle improvements in structural gene expression, locomotory performance, and mitochondrial morphology. Swim exercise training enhances whole-animal health parameters such as mitochondrial respiration and mid-life survival and increases the functional healthspan of pharynx and intestine. Importantly, we show that swim exercise also enhances nervous system health: exercise increases learning ability of adult animals and protects against neurodegeneration in C. elegans models of tauopathy, Alzheimer’s disease, and Huntington’s disease. An important point is that swim training only during C. elegans early adulthood induces long-lasting systemic benefits that in several cases are still detectable well into mid-life. Overall, our data reveal the broad impact of swim exercise in promoting extended healthspan of multiple C. elegans tissues, underscore the potency of early exercise experience to influence long-term health (even after cessation of exercise), and establish the foundation for exploiting the powerful advantages of this genetic model to dissect the exercise-dependent molecular circuitry that confers long-lasting system-wide health benefits to aging or diseased adults.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Molecular Mechanisms of Resistance in Testicular Germ Cell Tumors - clinical Implications

2018 ◽  
Vol 18 (10) ◽  
pp. 967-978 ◽  
Author(s):  
Katarina Kalavska ◽  
Vincenza Conteduca ◽  
Ugo De Giorgi ◽  
Michal Mego
Keyword(s):  
Germ Cell ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Apoptotic Cell ◽  
Germ Cell Tumors ◽  
Treatment Resistance ◽  
Experimental Models ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
Repair Capacity

Testicular germ cell tumors (TGCTs) represent the most common malignancy in men aged 15-35. Due to these tumors’ biological and clinical characteristics, they can serve as an appropriate system for studying molecular mechanisms associated with cisplatin-based treatment resistance. This review describes treatment resistance from clinical and molecular viewpoints. Cisplatin resistance is determined by various biological mechanisms, including the modulation of the DNA repair capacity of cancer cells, alterations to apoptotic cell death pathways, deregulation of gene expression pathways, epigenetic alterations and insufficient DNA binding. Moreover, this review describes TGCTs as a model system that enables the study of the cellular features of cancer stem cells in metastatic process and describes experimental models that can be used to study treatment resistance in TGCTs. All of the abovementioned aspects may help to elucidate the molecular mechanisms underlying cisplatin resistance and may help to identify promising new therapeutic targets.

scholarly journals Cardiac Cell Therapy: Insights into the Mechanisms of Tissue Repair

2021 ◽  
Vol 22 (3) ◽  
pp. 1201
Author(s):  
Hsuan Peng ◽  
Kazuhiro Shindo ◽  
Renée R. Donahue ◽  
Ahmed Abdel-Latif
Keyword(s):  
Stem Cell ◽  
Immune Responses ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Current Knowledge ◽  
Cell Delivery ◽  
Cardiac Cell Therapy ◽  
Stem Cell Treatment

Stem cell-based cardiac therapies have been extensively studied in recent years. However, the efficacy of cell delivery, engraftment, and differentiation post-transplant remain continuous challenges and represent opportunities to further refine our current strategies. Despite limited long-term cardiac retention, stem cell treatment leads to sustained cardiac benefit following myocardial infarction (MI). This review summarizes the current knowledge on stem cell based cardiac immunomodulation by highlighting the cellular and molecular mechanisms of different immune responses to mesenchymal stem cells (MSCs) and their secretory factors. This review also addresses the clinical evidence in the field.

scholarly journals Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

2021 ◽  
Author(s):  
Kinga K. Borowicz-Reutt ◽  
Monika Banach ◽  
Monika Rudkowska ◽  
Anna Stachniuk
Keyword(s):  
Antiepileptic Drugs ◽  
Second Generation ◽  
Antidepressant Drug ◽  
Experimental Models ◽  
Long Term Memory ◽  
Avoidance Task ◽  
Maximal Electroshock ◽  
Term Memory ◽  
The Brain

Abstract Background Due to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice. Materials and methods As a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry. Results Sotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study. Conclusion Sotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

scholarly journals RNAseq Reveals Differential Gene Expression Contributing to Phytophthora nicotianae Adaptation to Partial Resistance in Tobacco

Agronomy ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 656
Author(s):  
Jing Jin ◽  
Rui Shi ◽  
Ramsey Steven Lewis ◽  
Howard David Shew
Keyword(s):  
Partial Resistance ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Effective Means ◽  
Phytophthora Nicotianae ◽  
Economic Losses ◽  
Black Shank ◽  
Differential Gene ◽  
Go Terms

Phytophthora nicotianae is a devastating oomycete plant pathogen with a wide host range. On tobacco, it causes black shank, a disease that can result in severe economic losses. Deployment of host resistance is one of the most effective means of controlling tobacco black shank, but adaptation to complete and partial resistance by P. nicotianae can limit the long-term effectiveness of the resistance. The molecular basis of adaptation to partial resistance is largely unknown. RNAseq was performed on two isolates of P. nicotianae (adapted to either the susceptible tobacco genotype Hicks or the partially resistant genotype K 326 Wz/Wz) to identify differentially expressed genes (DEGs) during their pathogenic interactions with K 326 Wz/Wz and Hicks. Approximately 69% of the up-regulated DEGs were associated with pathogenicity in the K 326 Wz/Wz-adapted isolate when sampled following infection of its adapted host K 326 Wz/Wz. Thirty-one percent of the up-regulated DEGs were associated with pathogenicity in the Hicks-adapted isolate on K 326 Wz/Wz. A broad spectrum of over-represented gene ontology (GO) terms were assigned to down-regulated genes in the Hicks-adapted isolate. In the host, a series of GO terms involved in nuclear biosynthesis processes were assigned to the down-regulated genes in K 326 Wz/Wz inoculated with K 326 Wz/Wz-adapted isolate. This study enhances our understanding of the molecular mechanisms of P. nicotianae adaptation to partial resistance in tobacco by elucidating how the pathogen recruits pathogenicity-associated genes that impact host biological activities.

scholarly journals Vitamin D Deficiency in Testicular Cancer Survivors: A Systematic Review

2021 ◽  
Vol 22 (10) ◽  
pp. 5145
Author(s):  
Giuseppe Schepisi ◽  
Caterina Gianni ◽  
Sara Bleve ◽  
Silvia De Padova ◽  
Cecilia Menna ◽  
...  
Keyword(s):  
Vitamin D ◽  
Testicular Cancer ◽  
Vitamin D Deficiency ◽  
Molecular Mechanisms ◽  
Hypovitaminosis D ◽  
Young Males ◽  
Report Data ◽  
Testicular Cancer Survivors ◽  
Patients Experience

Testicular cancer (TC) is the most frequent tumor in young males. In the vast majority of cases, it is a curable disease; therefore, very often patients experience a long survival, also due to their young age at diagnosis. In the last decades, the role of the vitamin D deficiency related to orchiectomy has become an increasingly debated topic. Indeed, vitamin D is essential in bone metabolism and many other metabolic pathways, so its deficiency could lead to various metabolic disorders especially in long-term TC survivors. In our article, we report data from studies that evaluated the incidence of hypovitaminosis D in TC survivors compared with cohorts of healthy peers and we discuss molecular mechanisms and clinical implications.

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