Parp1 promotes sleep, which enhances DNA repair in neurons

What is your doctor's sleep protocol? Mine seemed to be, hand out sleeping pills like candy at 10pm, then have the vampire squad come in at 7am to steal blood from at least one person in the quad. Turning on the lights in the process, clinical staff efficiency, not patient wellbeing. 

Hope your doctors and hospital can get research initiated in humans.

Parp1 promotes sleep, which enhances DNA repair in neurons

 

Author links open overlay panelDavidZada¹YanivSela²NoaMatosevich²AdirMonsonego¹TaliLerer-Goldshtein¹YuvalNir²LiorAppelbaum¹³

https://doi.org/10.1016/j.molcel.2021.10.026Get rights and content

Referred to by

Ueli Schibler

PARP-1 drives slumber: A reciprocal relationship between sleep homeostasis and DNA damage repair

Molecular Cell, Volume 81, Issue 24, 16 December 2021, Pages 4958-4959

Highlights

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Neuronal DNA damage triggers sleep

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Sleep increases DNA repair and reduces cellular homeostatic pressure

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Activity of the DNA damage detector Parp1 increases with sleep deprivation

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Parp1 activity promotes sleep, chromosome dynamics, and DNA repair

Summary

The characteristics of the sleep drivers and the mechanisms through which sleep relieves the cellular homeostatic pressure are unclear. In flies, zebrafish, mice, and humans, DNA damage levels increase during wakefulness and decrease during sleep. Here, we show that 6 h of consolidated sleep is sufficient to reduce DNA damage in the zebrafish dorsal pallium. Induction of DNA damage by neuronal activity and mutagens triggered sleep and DNA repair. The activity of the DNA damage response (DDR) proteins Rad52 and Ku80 increased during sleep, and chromosome dynamics enhanced Rad52 activity. The activity of the DDR initiator poly(ADP-ribose) polymerase 1 (Parp1) increased following sleep deprivation. In both larva zebrafish and adult mice, Parp1 promoted sleep. Inhibition of Parp1 activity reduced sleep-dependent chromosome dynamics and repair. These results demonstrate that DNA damage is a homeostatic driver for sleep, and Parp1 pathways can sense this cellular pressure and facilitate sleep and repair activity.

Graphical abstract

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Neuroprotective Effect of Tephrosia purpurea Against Mitochondrial Dysfunction by Regulation of the Caspase3/9 and Pink1/Parkin Complexes

Lots of work for your doctor and stroke hospital to initiate. You don't want to get Parkinsons and this will eventually need to get to human testing. So if your hospital starts RIGHT NOW, in 15 years we might have results. So probably not in time for you but maybe in time for your children and grandchildren. 

Parkinson’s Disease May Have Link to Stroke March 2017 

HAS YOUR HOSPITAL DONE ONE DAMN THING IN THE PAST FOUR YEARS TO CREATE PROTOCOLS THAT PREVENT PARKINSONS? 

Or are you giving them a pass to be incompetent with no consequences except to you?

The latest here: 

 Neuroprotective Effect of Tephrosia purpurea Against Mitochondrial Dysfunction by Regulation of the Caspase3/9 and Pink1/Parkin Complexes

Swathi Kesh, Rajaretinam Rajesh Kannan Neuroscience Laboratory, Centre for Molecular and Nanomedical Sciences, School of Bio and Chemical Engineering, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India Date of Submission 07-Jan-2021 Date of Decision 01-Feb-2021 Date of Acceptance 16-Feb-2021 Date of Web Publication 22-Apr-2021 Correspondence Address: Rajaretinam Rajesh Kannan Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai 600119, Tamil Nadu India Login to access the Email id Source of Support: None, Conflict of Interest: None Crossref citations Check DOI: 10.4103/ijnpnd.ijnpnd_1_21 Rights and Permissions 

Abstract 

Background: 

Tephrosia pupurea is a perennial shrub that has been widely incorporated in Indian traditional medicine for its anti-inflammatory and hepatoprotective effects. Recent studies have identified T. purpurea as a source of acetylcholine esterase inhibitors. 

Aim: 

In this study, we have established the potential of T. purpurea as a potential source of drugs against Parkinsonism using an oxidopamine (6-OHDA) model. Methods: Metabolomics profiling of T. purpurea extract (TPE) was obtained using the HR-LCMS method. Enzymatic activities of Catalase, Glutathione, Superoxide Dismutase and Malondialdehyde were measured in vitro. Reactive Oxygen Species generation capacity and the mitochondrial membrane potential were also determined. The zebrafish embryos were treated with oxidopamine along with varying concentrations of T. purpurea extract and the swimming pattern and total distance travelled was evaluated. The mRNA expression of mitophagy related genes were measured using RT-PCR studies.  

Results: 

The metabolite profile of T. purpurea identified the presence of various polyphenols such as Genistein, Esculetin, and Chrysin that have neuroprotective effects. 6-OHDA-induced PD causes an increase in oxidative stress, reactive oxygen species generation, and affects mitochondrial stability. There was a significant increase in the catalase, glutathione, and superoxide dismutase levels and a decrease in Malondialdehyde and Reactive Oxygen Species levels in cells treated with TPE when compared to 6-OHDA treated cells. We then treated zebrafish embryos with 6-OHDA along with varying concentrations of T. purpurea extract, and the mRNA expression and swimming pattern were evaluated. The embryos cotreated with TPE showed improved swim pattern similar to untreated embryos, whereas those treated with the positive control failed to do so. T. purpurea extract also significantly decreased the expressions of casp3, casp9, lrrk2, and increased pink1 and parkin expression. 

Conclusion: 

Our study identifies Tephrosia purpurea extract as a viable candidate against 6-OHDA induced-neurotoxicity, and further studies of its effect in models of neurodegenerative diseases are required. Keywords: Caspases, oxidopamine, Pink1/Parkin, Tephrosia purpurea, zebrafish How to cite this article: Kesh S, Kannan RR. Neuroprotective Effect of Tephrosia purpurea Against Mitochondrial Dysfunction by Regulation of the Caspase3/9 and Pink1/Parkin Complexes. Int J Nutr Pharmacol Neurol Dis 2021;11:137-47 How to cite this URL: Kesh S, Kannan RR. Neuroprotective Effect of Tephrosia purpurea Against Mitochondrial Dysfunction by Regulation of the Caspase3/9 and Pink1/Parkin Complexes. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2021 Apr 26];11:137-47. Available from: https://www.ijnpnd.com/text.asp?2021/11/2/137/314375 

Injectable Functionalized Self-assembling Nanopeptide Hydrogel on Angiogenesis and Neurogenesis for Central Nervous System Regeneration

Ok, WHOM is going to follow this up in humans? Zebrafish are ok but we need to get to primates. 
http://pubs.rsc.org/en/content/articlelanding/2017/nr/c7nr06528k#!divAbstract
Could we do nasal route instead of injections?

Tzu-Wei Wang,  Kai-Chieh Chang,  Liang-Hsin Chen,  Shih-Yung Liao,  Chia-Wei Yeh  and  Yung-Jen Chuang 

Abstract

Brain injury is a devastating medical condition and represents a major health problem. For such disease, tissue and organ reconstruction has been regarded as a promising therapeutic strategy. Here, we propose a regenerative methodology focusing on the provision of functionalized nanopeptide scaffold to facilitate angiogenesis and neurogenesis at the brain injury site. The peptide, RADA16-SVVYGLR, undergoes self-assembling process to construct an interconnected network with intertwining nanofibers and can be controlled to display various physicochemical properties by the adjustment of microenvironmental factors such as pH value and ions concentration. Such scaffold is capable of supporting endothelial cells to form tube-like structure and neural stem cells to survive and proliferate. In in vivo zebrafish brain injury model, sprouting angiogenesis and developmental neurogenesis are achieved, and functional recovery of severed optic tectum is effectively enhanced in RADA16-SVVYGLR hydrogel-implanted group. Meanwhile, the nanopeptide hydrogel is non-toxic to zebrafish embryo during embryonic developmental stage. The angiogenic self-assembling peptide hydrogel has programmable physical properties, good biocompatibility, and regenerative ability for functional recovery in the injured brain. We suggest that functionalized self-assembling peptide encapsulated with neural stem cells or used alone could be an attractive and effective therapeutic modality for the applications in brain injury and diseases (viz., trauma, stroke, tumor, degenerative neurological disorder, etc).

Newly discovered scavenger brain cells could protect against stroke and dementia

Followup needed, but we have fucking failures of stroke associations that will do nothing with this information.
http://www.fiercebiotech.com/research/newly-discovered-scavenger-brain-cells-could-protect-against-stroke-and-dementia
by Arlene Weintraub |

May 1, 2017 11:01am

Lymphatic cells are the body’s garbage-disposal system: When fats and other waste products leak out of blood vessels, they mop them up so they don’t damage organs. These types of cells have not been seen in the brain, however, so scientists at the University of Queensland in Australia were surprised when they found a new type of lymphlike cell there.
By studying transparent zebrafish, the scientists observed scavenger cells surrounding the brain that clear out cellular waste. The cells are similar to "mato," or lipid-laden, cells in people, which were not previously known to be lymphatic, according to a press release. Ben Hogan, Ph.D., an associate professor in the university’s Institute for Molecular Bioscience, believes similar cells may be active in the human brain as well, protecting it against stroke and dementia by keeping harmful substances out.
Normally, lymphatic cells clump together, forming vessel-like structures that carry fluid, Hogan explained. But in zebrafish brains, “these cells exist individually, independent of vessels and collect waste that enter the brain from the bloodstream,” he said in the release.
Because zebrafish have many of the same cells and organs as people do, the discovery could enhance the study of brain disorders and treatments, Hogan added. The study was published in the journal Nature Neuroscience.
Zebrafish are being deployed in research for a range of diseases, from cancer to diabetes. Last year, scientists at Boston Children’s Hospital used the transparent creatures to visualize the spread of melanoma from a single cell, and in so doing identified genes involved in metastasis that they believe could be targets for new treatments. Researchers at the University of Oregon found a protein in zebrafish that seems to boost insulin production. And a team at Johns Hopkins has developed genetically modified zebrafish embryos that can be used in high-throughput screening for potential new drugs.
The University of Queensland team plans to expand upon their findings by studying how the cells they discovered function in people and how they influence neurological diseases such as stroke and dementia. They are also interested in learning whether existing drugs can directly control the scavenger cells in the brain, Hogan said.

 

Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis

I liked the words neurogenesis and liver in the same title.
http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.1156.html

Abstract

• Abstract
• Author information
• Supplementary information

Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development in an Lxr-dependent manner in zebrafish in vivo. Notably, each ligand selectively regulated the development of distinct midbrain neuronal populations. Whereas cholic acid increased survival and neurogenesis of Brn3a-positive red nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell type–specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of embryonic stem cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement and regenerative therapies for Parkinson's disease.

Ve-ptp Modulates Vascular Integrity by Promoting Adherens Junction Maturation

You doctor and researcher needs to inform you if this condition is a problem for you as a bleeder stroke. And what they are doing to correct it.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051245

Abstract

Background

Endothelial cell junctions control blood vessel permeability. Altered permeability can be associated with vascular fragility that leads to vessel weakness and haemorrhage formation. In vivo studies on the function of genes involved in the maintenance of vascular integrity are essential to better understand the molecular basis of diseases linked to permeability defects. Ve-ptp (Vascular Endothelial-Protein Tyrosine Phosphatase) is a transmembrane protein present at endothelial adherens junctions (AJs).

Methodology/Principal Findings

We investigated the role of Ve-ptp in AJ maturation/stability and in the modulation of endothelial permeability using zebrafish (Danio rerio). Whole-mount in situ hybridizations revealed zve-ptp expression exclusively in the developing vascular system. Generation of altered zve-ptp transcripts, induced separately by two different splicing morpholinos, resulted in permeability defects closely linked to vascular wall fragility. The ultrastructural analysis revealed a statistically significant reduction of junction complexes and the presence of immature AJs in zve-ptp morphants but not in control embryos.

Conclusions/Significance

Here we show the first in vivo evidence of a potentially critical role played by Ve-ptp in AJ maturation, an important event for permeability modulation and for the development of a functional vascular system.

Inflammation to Rebuild a Brain

You'll have to have your doctor to get the full article and apply it to your stroke protocol.
http://www.sciencemag.org/content/338/6112/1303.short

The overarching strategy of all immune systems is as predictable as the plot of an episode of Mission: Impossible. A short-lived message describing the problem reaches commanding immune cells. A team of specialized expert cells is then dispatched to deal with the problem. Once successfully addressed, the team disappears without leaving a trace. On page 1353 of this issue, Kyritsis et al. (1) characterize an astonishing type of immune response—a new team of “executioner” cells—that is implemented when the zebrafish brain is injured. By tricking the immune system into believing neuronal injury had occurred, the authors discovered that inflammation alone is sufficient to switch on neurogenesis. The molecular components used by the highly specialized immune cells that promote neurogenesis represent potential novel therapeutic targets that could promote brain repair.

Regenerative Neurogenesis from Neural Progenitor Cells Requires Injury-Induced Expression of Gata3

If zebrafish can regenerate neurons after injury study away.
http://www.sciencedirect.com/science/article/pii/S1534580712004777

Summary

The adult zebrafish brain, unlike mammalian counterparts, can regenerate after injury owing to the neurogenic capacity of stem cells with radial glial character. We hypothesized that injury-induced regenerative programs might be turned on after injury in zebrafish brain and enable regenerative neurogenesis. Here we identify one such gene—the transcription factor gata3—which is expressed only after injury in different zebrafish organs. Gata3 is required for reactive proliferation of radial glia cells, subsequent regenerative neurogenesis, and migration of the newborn neurons. We found that these regeneration-specific roles of Gata3 are dependent on the injury because Gata3 overexpression in the unlesioned adult zebrafish brain is not sufficient to induce neurogenesis. Thus, gata3 acts as a specific injury-induced proregenerative factor that is essential for the regenerative capacity in vertebrates.

What is neurogenesis?

Dr. Deb Stenkamp researches in her lab the complex process of neurogenesis in the zebra fish.
http://gocognitive.net/interviews/deb-stenkamp-neurogenesis

Animal Models of Angiogenesis and Lymphangiogenesis

A good explanation of what would need to occur in the brain for our purposes.
http://www.intechopen.com/source/pdfs/26387/InTech-Animal_models_of_angiogenesis_and_lymphangiogenesis.pdf
1. Introduction
Blood and lymphatic vessels are present in all tissues, and play important roles for their function, homeostasis and maintenance. Angiogenesis, the growth of new blood vessels, is therefore highly important during development, but is largely not observed in the adult, except for during the female reproduction cycle and during wound healing. In pathological situations, however, angiogenesis may be turned on, and in this case contribute to the onset and progression of most severe human pathologies characterized by high mortality, including cancer, diabetes, obesity and retinopathies (Carmeliet, 2003) or is insufficiently activated such as in the case of myocardial infarction and stroke (Y Cao et al, 2005). Thus, angiogenesis is one of the largest and fastest evolving areas of research today. Angiogenesis is a highly complicated process, involving many different cell types, and it is therefore highly recommended that researchers use in vivo animal models for their studies.
Accordingly, today there are many in vivo models available.
The aim of this chapter is to give insights into the most commonly used in vivo angiogenesis models in both mice and zebrafish. We will provide detailed descriptions and discussions of the adipose tissue-, tumor-, ischemic hind limb- wound healing- and corneal micropocket angiogenesis models in mice and developmental-, tumor-, hypoxia-induced retinal- and regenerating tail fin angiogenesis models in zebrafish. We will provide a base for comparison between the different assays to quickly identify which model is best suited for a particular research focus.
1.1 Basic mechanisms of angiogenesis
Angiogenesis is a multistep process which is tightly regulated by an intimate balance between pro- and anti-angiogenic factors. Angiogenesis is stimulated by angiogenic factors the most commonly studied being members of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor (TGF) or platelet derived growth factor (PDGF) families in the tissue.

Improved Understanding Of The Thalamus Offers Potential Stroke Therapy

At least these researchers are thinking about how to help recovery.
http://www.medicalnewstoday.com/releases/239237.php
The thalamus is the central translator in the brain: Specialized nerve cells (neurons) receive information from the sensory organs, process it, and transmit it deep into the brain. Researchers from the Institute of Toxicology and Genetics (ITG) of KIT have now identified the genetic factors Lhx2 and Lhx9 responsible for the development of these neurons. Their results contribute to understanding the development of the thalamus. In the long term, they are to help healing thalamic strokes.

With 100 billion nerve cells, the brain is the most complex organ in the human body. "We want to understand the development program behind," says Dr. Steffen Scholpp from the ITG. "We want to find out how individual parts of the brain develop, this means, what makes precursor cells build a specialized area such as the thalamus." Scholpp's group at ITG studies the development of the thalamus. "It is the central interface between the brain and the outer world: Everything that is perceived via eyes, ears or the tactile sense has to pass the thalamus before it is routed to the cerebral cortex for further processing."

In the long term, the scientists want to be able to heal damaged brain parts by a tissue replacement therapy. If, for example, brain tissue is damaged after an infarct, the body is not able to regenerate this tissue. "Today, stroke is the most frequent cause of disability acquired at adult age and due to its central role, damage of the thalamus is very serious," emphasizes Steffen Scholpp. "For this reason, we have to find a strategy to activate stem cells such that the damaged tissue can be replaced." Recently, an important step was made by the scientists: By studying zebrafish, they identified Lhx2 and Lhx9, the factors controlling the development of neurons in the thalamus. "Without these factors, the thalamus would accommodate undifferentiated nerve cells only - this means, the precursory cells lack the information required for specialization," explains the biologist. Analysis of brain development in zebrafish allows conclusions to be drawn with respect to the development in all vertebrates, including human. The results of the group are published in the current issue of the PLoS Biology journal.

In the same study, Scholpp and his team identified another factor that acts as "adhesive" in the thalamus: The cell adhesion molecule Pcdh10b ensures development of the thalamus without mixing with the surrounding brain areas. If this factor is lacking, the neurons differentiate, but do not find their target destination. It is now the objective of the researchers to activate these factors in the cultivating dish (in vitro) in undifferentiated cells first for new thalamus tissue to form. In close cooperation with engineers, the biologists are already developing 2-dimensional cell culture systems. In January, they will start a 3D cell cultivation project. "KIT offers excellent opportunities: Parallel to our research, materials researchers work on the development of various biomaterials (biopolymers) which will be tested in the cultivation experiments", says Scholpp.

Dr. Steffen Scholpp thinks that it will be possible to heal stroke patients in the future. "Of course, this will take some years. But it is our ultimate goal to take out quiescent stem cells from a stroke patient and to switch on the specific development biology program in these cells outside of the body. Finally, we plan to bring them back to the position of the damaged tissue. This would be real healing."

Genome-Wide Study Into New Gene Functions In The Formation Of Platelets

Needed research into how platelets clump or not clump. Tell your researcher to follow this.
http://www.medicalnewstoday.com/releases/238511.php
In a study into the genetics of blood cell formation, researchers have identified 68 regions of the genome that affect the size and number of platelets. Platelets are small cells that circulate in the blood and are key to the processes of blood clotting and wound healing.

In this genome-wide study, the team used a multidisciplinary approach to successfully identify new genetic variants involved in the formation of platelets and more importantly, defined the function of genes near these variants using a series of biological analyses.

Abnormally high or low platelet counts can lead to disease. An increase in the number of platelets, or an increase in their size can lead to an increased risk for thrombotic events, like heart attacks and strokes. A very low number of platelets or platelets that do not function well, increases the risk of bleeding.

"This is a detective story starting with the initial genetic discovery, allowing us to identify new genes that could contribute to platelet associated diseases," says Professor Willem H Ouwehand, senior co-author at the University of Cambridge and NHS Blood and Transplant. "Our aim of this genome-wide meta-analysis study was to discover which genes control the size and number of platelets, to understand how these genes instruct blood stem cells to orchestrate every day the formation of billions of platelets and finally to investigate whether genes associated with heart attacks and strokes overlap with the genes that affect platelet formation."

In this collaborative study, the team first developed a prioritisation strategy that allowed them to identify and pinpoint the genes underlying the formation of platelets through biological annotations of these genes. This effort laid the foundation for the construction of a protein-protein interaction network that shows how the different genetic players interact. Finally, they analysed the role of the genes in model organisms and found their function to be conserved in evolution.

The researchers found the newly identified genes associated with platelet characteristics overlap with other genes implicated in inherited bleeding disorders. This genetic overlap suggests that this study may help discover new genes implicated in severe forms of bleeding disorders, providing evidence that the new findings will be significant in clinical research for improvements in the care of patients.

This study involved about 68,000 individuals from different ancestries (European, South & East Asian) making it the largest genome-wide meta-analysis study to be conducted globally on platelet number and volume.

"This is the largest dataset of this type ever produced, and yields a wealth of new exciting biological discoveries and insights into the genetic control of blood cell formation," says Dr Nicole Soranzo, senior co-author from the Wellcome Trust Sanger Institute. "Our findings will be relevant not only to better understand the mechanisms leading to the formation of blood cells, but also to pinpoint new genes involved in diseases with altered blood clotting."

The team examined the role of the genes they identified in the fruit fly and zebrafish. They found that reducing the activity of one of these genes, arhgef3, in fish abrogates not only the production of platelets but also of red blood cells because the blood forming cells cannot capture iron. The study has shown that the human equivalent, ARHGEF3 gene is an important new regulator of the uptake of iron from the diet.

Tropomyosin 1 is a member of a family of genes already known to be involved in the regulation of muscle contraction and plays a role in an inherited form of heart disease. This study found a novel role for this well-known protein in platelet formation.

"This study provides a paradigm for how to successfully translate genome-wide association studies into function" says Dr Christian Gieger, senior co-author from the Institute of Genetic Epidemiology at the Helmholtz Center Munich. "We have shown that biologic and functional annotation can greatly enhance our ability to interpret genetic data."

"These genes could be used in the future as new targets to develop better and safer platelet inhibitors for treatments of patients with heart attacks or strokes."