TET3-Interacting LncRNA TILR Is Essential for DNA Hydroxymethylation-Mediated Neuroprotection After Ischemic Stroke.

Background: Epigenetic modifications 5-methylcytosine and 5-hydroxymethylcytosine in DNA regulate neuronal survival under ischemic stress. We previously showed that TET3 (ten-eleven translocase 3)-mediated 5-methylcytosine to 5-hydroxymethylcytosine conversion induces neuroprotective gene transcription after stroke. As TET3 neuronal isoform lacks the DNA-binding domain, how TET3 drives 5-hydroxymethylcytosine-mediated transcriptional induction in the ischemic brain remains unclear.

FTO promotes post-stroke neuroprotection by mA demethylation of c-Jun.

-methyladenosine (mA) is a critical epitranscriptomic regulator of neuronal function. Cerebral ischemia induces mA hypermethylation due to decreased expression of mA demethylase fat mass and obesity-associated (FTO) protein. Previously, we showed that cerebral overexpression of FTO with an adeno-associated virus (AAV) 9 protects the post-stroke brain.

Stroke triggers dynamic mA reprogramming of cerebral circular RNAs.

We previously showed that stroke alters circular RNA (circRNA) expression profiles. Many circRNAs undergo epitranscriptomic modifications, particularly methylation of adenosine to form N-methyladenosine (mA). This modification significantly influences the circRNA metabolism and functionality.

Intermittent fasting induced cerebral ischemic tolerance altered gut microbiome and increased levels of short-chain fatty acids to a beneficial phenotype.

Preconditioning-induced cerebral ischemic tolerance is known to be a beneficial adaptation to protect the brain in an unavoidable event of stroke. We currently demonstrate that a short bout (6 weeks) of intermittent fasting (IF; 15 h fast/day) induces similar ischemic tolerance to that of a longer bout (12 weeks) in adult C57BL/6 male mice subjected to transient middle cerebral artery occlusion (MCAO). In addition, the 6 weeks IF regimen induced ischemic tolerance irrespective of age (3 months or 24 months) and sex.

Loss of Epitranscriptomic Modification N-Methyladenosine (mA) Reader YTHDF1 Exacerbates Ischemic Brain Injury in a Sexually Dimorphic Manner.

N-Methyladenosine (mA) is a neuronal-enriched, reversible post-transcriptional modification that regulates RNA metabolism. The mA-modified RNAs recruit various mA-binding proteins that act as readers. Differential mA methylation patterns are implicated in ischemic brain damage, yet the precise role of mA readers in propagating post-stroke mA signaling remains unclear.

Role of transcription factors, noncoding RNAs, epitranscriptomics, and epigenetics in post-ischemic neuroinflammation.

Post-stroke neuroinflammation is pivotal in brain repair, yet persistent inflammation can aggravate ischemic brain damage and hamper recovery. Following stroke, specific molecules released from brain cells attract and activate central and peripheral immune cells. These immune cells subsequently release diverse inflammatory molecules within the ischemic brain, initiating a sequence of events, including activation of transcription factors in different brain cell types that modulate gene expression and influence outcomes; the interactive action of various noncoding RNAs (ncRNAs) to regulate multiple biological processes including inflammation, epitranscriptomic RNA modification that controls RNA processing, stability, and translation; and epigenetic changes including DNA methylation, hydroxymethylation, and histone modifications crucial in managing the genic response to stroke.

The role of family support in the self-rated health of older adults in eastern Nepal: findings from a cross-sectional study.

Background: Nepal's low fertility rate and increasing life expectancy have resulted in a burgeoning older population. For millennia, filial piety shaped family cohesion and helped Nepali older adults achieve positive outcomes, but recently, it has been eroding. Furthermore, there are not enough institutional support options or alternatives to family-based care to deal with the biosocial needs of older adults.

Therapeutic Potential of Intravenous miR-21 Mimic after Stroke Following STAIR Criteria.

The microRNA-21 (miR-21) levels in the brain are crucial in determining post-stroke brain damage and recovery. The miR-21 exerts neuroprotection by targeting mRNAs that translate proteins that mediate brain damage. We currently determined the efficacy and efficiency of intravenously administered miR-21 mimic after focal cerebral ischemia in mice.

Post-stroke brain can be protected by modulating the lncRNA FosDT.

We previously showed that knockdown or deletion of Fos downstream transcript (FosDT; a stroke-induced brain-specific long noncoding RNA) is neuroprotective. We presently tested the therapeutic potential of FosDT siRNA in rodents subjected to transient middle cerebral artery occlusion (MCAO) using the Stroke Treatment Academic Industry Roundtable criteria, including sex, age, species, and comorbidity. FosDT siRNA (IV) given at 30 min of reperfusion significantly improved motor function recovery (rotarod test, beam walk test, and adhesive removal test) and reduced infarct size in adult and aged spontaneously hypertensive rats of both sexes.

CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability.

Transient focal ischemia decreased microRNA-7 (miR-7) levels, leading to derepression of its major target α-synuclein (α-Syn) that promotes secondary brain damage. Circular RNA CDR1as is known to regulate miR-7 abundance and function. Hence, we currently evaluated its functional significance after focal ischemia.

Cerebroprotective Role of -Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) After Experimental Stroke.

Background: FTO (fat mass and obesity-associated protein) demethylates -methyladenosine (mA), which is a critical epitranscriptomic regulator of neuronal function. We previously reported that ischemic stroke induces mA hypermethylation with a simultaneous decrease in FTO expression in neurons. Currently, we evaluated the functional significance of restoring FTO with an adeno-associated virus 9, and thus reducing mA methylation in poststroke brain damage.

MMP-12 knockdown prevents secondary brain damage after ischemic stroke in mice.

We previously reported that increased expression of matrix metalloproteinase-12 (MMP-12) mediates blood-brain barrier disruption via tight junction protein degradation after focal cerebral ischemia in rats. Currently, we evaluated whether MMP-12 knockdown protects the post-stroke mouse brain and promotes better functional recovery. Adult male mice were injected with negative siRNA or MMP-12 siRNA (intravenous) at 5 min of reperfusion following 1 h transient middle cerebral artery occlusion.

Dysregulation of the Epitranscriptomic Mark mA in Ischemic Stroke.

Methylation of adenosine at N1 position yields N-methyladenosine (mA), which is an epitranscriptomic modification that regulates mRNA metabolism. Recent studies showed that altered mA methylation promotes acute and chronic neurological diseases. We currently evaluated the effect of focal ischemia on cerebral mA methylome and its machinery.

MicroRNA miR-7 Is Essential for Post-stroke Functional Recovery.

Transient focal ischemia induces a sustained downregulation of miR-7 leading to derepression of its target α-synuclein (α-Syn), which promotes neuronal death. We previously showed that treatment with miR-7 mimic prevents α-Syn induction and protects brain after stroke in rodents irrespective of age and sex. To further decipher the role of miR-7, we currently studied infarction and motor function in miR-7 double knockout mice (lack both miR-7a and miR-7b) subjected to focal ischemia.

Tenascin-C induction exacerbates post-stroke brain damage.

The role of tenascin-C (TNC) in ischemic stroke pathology is not known despite its prognostic association with cerebrovascular diseases. Here, we investigated the effect of TNC knockdown on post-stroke brain damage and its putative mechanism of action in adult mice of both sexes. Male and female C57BL/6 mice were subjected to transient middle cerebral artery occlusion and injected (i.

Ubisol Coenzyme Q10 promotes mitochondrial biogenesis in HT22 cells challenged by glutamate.

Glutamate-induced excitotoxicity is a well-recognized cause of neuronal cell death. Nutritional supplementation with Coenzyme Q10 (CoQ10) has been previously demonstrated to serve neuro-protective effects against glutamate-induced excitotoxicity. The aim of the present study was to determine whether the protective effect of CoQ10 against glutamate toxicity could be attributed to stimulating mitochondrial biogenesis.

Perceived fear of COVID-19 and its associated factors among Nepalese older adults in eastern Nepal: A cross-sectional study.

Background: Coronavirus disease 2019 (COVID-19) has affected all age groups worldwide, but older adults have been affected greatly with an increased risk of severe illness and mortality. Nepal is struggling with the COVID-19 pandemic. The normal life of older adults, one of the vulnerable populations to COVID-19 infection, has been primarily impacted.

Noncoding RNA crosstalk in brain health and diseases.

The mammalian brain expresses several classes of noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). These ncRNAs play vital roles in regulating cellular processes by RNA/protein scaffolding, sponging and epigenetic modifications during the pathophysiological conditions, thereby controlling transcription and translation. Some of these functions are the result of crosstalk between ncRNAs to form a competitive endogenous RNA network.

Epitranscriptomic Modifications Modulate Normal and Pathological Functions in CNS.

RNA is more than just a combination of four genetically encoded nucleobases as it carries extra information in the form of epitranscriptomic modifications. Diverse chemical groups attach covalently to RNA to enhance the plasticity of cellular transcriptome. The reversible and dynamic nature of epitranscriptomic modifications allows RNAs to achieve rapid and context-specific gene regulation.

Long Noncoding RNA Fos Downstream Transcript Is Developmentally Dispensable but Vital for Shaping the Poststroke Functional Outcome.

Background And Purpose: Stroke induces the expression of several long noncoding RNAs in the brain. However, their functional significance in poststroke outcome is poorly understood. We recently observed that a brain-specific long noncoding RNA called Fos downstream transcript (FosDT) is induced rapidly in the rodent brain following focal ischemia.

Using a co-design process to develop an integrated model of care for delivering self-management intervention to multi-morbid COPD people in rural Nepal.

Background: People with chronic obstructive pulmonary disease (COPD) in Nepal are not receiving adequate support to self-manage their chronic conditions, and primary health care can play a key role in the effective management of these. In this study, we aimed to develop a model of care, using a co-design approach, for delivering evidence-based biomedical and psycho-social care to support self-management for people with multi-morbid COPD in rural Nepal.

Methods: A co-design approach, guided by the five stages of the design thinking model, was used for this study.

Antioxidant Combo Therapy Protects White Matter After Traumatic Brain Injury.

Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal.

Epitranscriptomic regulation by mA RNA methylation in brain development and diseases.

Cellular RNAs are pervasively tagged with diverse chemical moieties, collectively called epitranscriptomic modifications. The methylation of adenosine at N position generates N-methyladenosine (mA), which is the most abundant and reversible epitranscriptomic modification in mammals. The mA signaling is mediated by a dedicated set of proteins comprised of writers, erasers, and readers.