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1. Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain

   https://doi.org/10.3390/ijms23020620  

   Nguyen, Nam Phuong; Helmbrecht, Hawley; Ye, Ziming; Adebayo, Tolulope; Hashi, Najma; Doan, My-Anh; Nance, Elizabeth (January 2022, International Journal of Molecular Sciences)

   Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates. 

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2. Laser-Induced Nuclear Damage Signaling and Communication in Astrocyte Networks Through Parp-Dependent Calcium Oscillations

   https://doi.org/10.3389/fphy.2021.598930  

   Wakida, Nicole M.; Ha, Ryan D.; Kim, Edward K.; Kong, Xiangduo; Yokomori, Kyoko; Berns, Michael W. (April 2021, Frontiers in Physics)

   null (Ed.)

   Astrocytes are known to respond to various perturbations with oscillations of calcium, including to cellular injury. Less is known about astrocytes’ ability to detect DNA/nuclear damage. This study looks at changes in calcium signaling in response to laser-induced nuclear damage using a NIR Ti:Sapphire laser. Primary astrocytes derived from genetically engineered mice expressing G6Campf genetically encoded calcium indicator were imaged in response to laser induced injury. Combining laser nanosurgery with calcium imaging of primary astrocytes allow for spatial and temporal observation of the astrocyte network in response to nuclear damage. Nuclear damage resulted in a significant increase in calcium peak frequency, in nuclear damaged cells and astrocytes directly attached to it. The increase in calcium event frequency observed in response to damage and the transfer to neighboring cells was not observed in cytoplasm damaged cells. Targeted astrocytes and attached neighboring cells treated with Poly (ADP-ribose) polymerase inhibitor have a significantly lower peak frequency following laser damage to the nucleus. These results indicate the increase in calcium peak frequency following nuclear damage is poly (ADP-ribose) polymerase dependent. 

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3. Serum amyloid A and mitochondrial DNA in extracellular vesicles are novel markers for detecting traumatic brain injury in a mouse model

   https://doi.org/10.1016/j.isci.2024.108932  

   Tang, TZ; Zhao, Y; Agarwal, D; Tharzeen, A; Patrikeev, I; Zhang, Y; DeJesus, J; Bossmann, SH; Natarajan, B; Motamedi, M; et al (February 2024, iScience)

   This study investigates the potential use of circulating extracellular vesicles’ (EVs) DNA and protein content as biomarkers for traumatic brain injury (TBI) in a mouse model. Despite an overall decrease in EVs count during the acute phase, there was an increased presence of exosomes (CD63+ EVs) during acute and an increase in microvesicles derived from microglia/macrophages (CD11b+ EVs) and astrocytes (ACSA-2+ EVs) in post-acute TBI phases, respectively. Notably, mtDNA exhibited an immediate elevation post-injury. Neuronal (NFL) and microglial (Iba1) markers increased in the acute, while the astrocyte marker (GFAP) increased in post-acute TBI phases. Novel protein biomarkers (SAA, Hp, VWF, CFD, CBG) specific to different TBI phases were also identified. Biostatistical modeling and machine learning identified mtDNA and SAA as decisive markers for TBI detection. These findings emphasize the importance of profiling EVs’ content and their dynamic release as an innovative diagnostic approach for TBI in liquid biopsies 

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4. Cholesterol-rich naked mole-rat brain lipid membranes are susceptible to amyloid beta-induced damage in vitro

   https://doi.org/10.18632/aging.202138  

   Frankel, Daniel; Davies, Matthew; Bhushan, Bharat; Kulaberoglu, Yavuz; Urriola-Munoz, Paulina; Bertrand-Michel, Justine; Pergande, Melissa R.; Smith, Andrew A.; Preet, Swapan; Park, Thomas J.; et al (October 2020, Aging)

   null (Ed.)

   Naked mole-rats are extraordinarily long-lived rodents that offer unique opportunities to study the molecular origins of age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta (Aβ) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against Aβ neurotoxicity. Here we examine the composition, phase behaviour, and Aβ interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with the metabolism of ceramides, sphingomyelins and sphingosine-1-phosphate receptor 1 were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase extending to 80% of the supported lipid bilayer. These observations are consistent with the ‘membrane pacemaker’ hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. We also found that exposure to Aβ disrupts naked mole-rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon Aβ exposure. 

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5. RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy

   https://doi.org/10.3389/fgene.2021.628758  

   Iqbal, Waleed; Demidova, Elena V.; Serrao, Samantha; ValizadehAslani, Taha; Rosen, Gail; Arora, Sanjeevani (March 2021, Frontiers in Genetics)

   null (Ed.)

   RRM2B plays a crucial role in DNA replication, repair and oxidative stress. While germline RRM2B mutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA studies, we investigated RRM2B alterations in cancer. We found that RRM2B is highly amplified in multiple tumor types, particularly in MYC -amplified tumors, and is associated with increased RRM2B mRNA expression. We also observed that the chromosomal region 8q22.3–8q24, is amplified in multiple tumors, and includes RRM2B , MYC along with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cancers that have both RRM2B -amplified along with MYC have a distinct pattern of amplification compared to cancers that are unaltered or those that have amplifications in RRM2B or MYC only. Investigation of curated biological interactions revealed that gene products of the amplified 8q22.3–8q24 region have important roles in DNA repair, DNA damage response, oxygen sensing, and apoptosis pathways and interact functionally. Notably, RRM2B -amplified cancers are characterized by mutation signatures of defective DNA repair and oxidative stress, and at least RRM2B -amplified breast cancers are associated with poor clinical outcome. These data suggest alterations in RR2MB and possibly the interacting 8q-proteins could have a profound effect on regulatory pathways such as DNA repair and cellular survival, highlighting therapeutic opportunities in these cancers. 

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