Rattus rattus breed:Sprague Dawley
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA524718 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8649510_1.fastq.gz | Fastqsanger.gz | |||
| SRR8649510_2.fastq.gz | Fastqsanger.gz | |||
| SRR8649511_1.fastq.gz | Fastqsanger.gz | |||
| SRR8649511_2.fastq.gz | Fastqsanger.gz | |||
| SRR8649503_1.fastq.gz | Fastqsanger.gz |
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Project description:Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from primary progressive multiple sclerosis (PPMS) patient induced pluripotent stem (iPS) cell lines failed to promote oligodendrocyte progenitor cell (OPC) maturation whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS autopsy brain tissues and PPMS patient iPS-derived NPCs. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin which then enhanced PPMS NPC support for oligodendrocyte differentiation. A proteomic analysis of the PPMS NPC secretome identified high mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of oligodendrocyte differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in progressive MS which may impact how this disease is modeled and inform development of future myelin regeneration strategies.
2019-11-12 | PXD013060 | Pride
Project description:Carbon dioxide and isoflurane are widely used for killing rats, yet may not truly achieve "euthanasia", because they elicit aversion. The inhalant anesthetic desflurane is faster acting than isoflurane, representing a potential refinement. Using an aversion-avoidance paradigm, 24 rats were exposed to isoflurane or desflurane (n = 12 per group) at initial exposure. Fourteen rats were then re-exposed to isoflurane or desflurane (n = 7 per group), after a 7 days washout period. Initial exposure: time to recumbency was faster for desflurane than isoflurane (p = 0.0008, 95% CI [-12.9 to 32.6 s]), with 9/12 and 6/12 rats becoming recumbent, respectively. At initial exposure, there was no difference between groups in time to withdrawal (p = 0.714). At re-exposure, all rats withdrew and no rats became recumbent. Time to withdrawal at re-exposure did not differ between treatment groups (p = 0.083). Compared to initial exposure, time to withdrawal during re-exposure was similar for isoflurane (p = 0.228) and faster with desflurane (p = 0.012, 95% CI [19.1 to 49.5 s]). Isoflurane and desflurane are similarly aversive, with aversion increasing at re-exposure. The shorter time from exposure to recumbency with desflurane indicates that any distress is of a shorter duration when compared with isoflurane.
| S-EPMC7341512 | biostudies-literature
Project description:Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients. RNA sequencing of oligodendrocyte progenitor cells treated with vehicle, miconazole or clobetasol for 0, 2, 6, or 12 hours. Cells were plated 1.5 hours prior to addition of drug.
2015-04-13 | E-GEOD-63804 | biostudies-arrayexpress
Project description:In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet improvable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of ‘improved’ OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edited human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplanted them into rodent models of chronic lesions. Edited hOPCs displayed enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. This study demonstrates that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.
2023-08-23 | GSE241451 | GEO
Project description:Bile acid toxicity on intestinal Paneth Cells contributes to gut dysbiosis induced by high fat feeding
| PRJNA548503 | ENA
Project description:Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.
2015-04-13 | GSE63804 | GEO
Project description:In humans and other mammals, general anesthesia impairs thermoregulation, leading to warm core blood redistributing to the periphery. This redistribution is an important contributor to hypothermia that can be reduced with pre-warming before anesthesia. Additionally, sedation following premedication has been associated with hypothermia in dogs. In a prospective, randomized, cross-over study, 8 adult male and female rats (weighing 388 to 755 g) were sedated with intramuscular ketamine-midazolam-hydromorphone, then placed in an unwarmed cage or warmed box for 14 minutes, followed by 30 minutes of isoflurane anesthesia with active warming. Core body temperature was monitored throughout. After sedation, warmed rats gained 0.28°C ± 0.13°C and unwarmed rats lost 0.19°C ± 0.43°C, a significant difference between groups (P = 0.004). After anesthesia, warmed rats maintained higher core temperatures (P < 0.0001) with 2/8 and 6/8 of warmed and unwarmed rats becoming hypothermic, respectively. Pre-warming during sedation and active warming during general anesthesia is effective in minimizing hypothermia.
| S-EPMC7995546 | biostudies-literature
Project description:Anesthetic agents depress thermoregulatory mechanisms, causing hypothermia within minutes of induction of general anesthesia. The consequences of hypothermia include delayed recovery and increased experimental variability. Even when normothermia is maintained during anesthesia, hypothermia may occur during recovery. The primary aim of this study was to identify an effective warming period for maintaining normothermia during recovery. Adult male (n = 8) and female (n = 9) Sprague-Dawley rats were randomized to 30 min (post30) or 60 min (post60) of warming after recovery from anesthesia. During a 40-min anesthetic period, normothermia (target, 37.5 ± 1.1 °C) was maintained by manual adjustment of an electric heating pad in response to measured rectal temperatures (corrected to estimate core body temperature). Warming was continued in a recovery cage according to treatment group. Rectal temperature was measured for a total of 120 min after anesthesia. Heating pad performance was assessed by measuring temperatures at various sites over its surface. One female rat in the post30 group was excluded from analysis. Normothermia was effectively maintained during and after anesthesia without significant differences between groups. In the post60 group, core temperature was slightly but significantly increased at 90 and 100 min compared with baseline. One rat in each treatment group became hyperthermic (>38.6 °C) during recovery. During recovery, the cage floor temperature required approximately 30 min to stabilize. The heating pad produced heat unevenly over its surface, and measured temperatures frequently exceeded the programmed temperature. Providing 30 min of warming immediately after anesthesia effectively prevented hypothermia in rats. Shorter warming periods may be useful when recovery cages are preheated.
| S-EPMC5710158 | biostudies-literature
Project description:Genetic predisposition to high anxiety- and depression-like behavior coincides with diminished DNA methylation in the adult rat amygdala
| PRJNA344780 | ENA
Project description:Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represents an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis promote neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. We present the results of STEMS, a single dose escalation phase I clinical trial, evaluating the feasibility, safety, and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 PMS patients.
2022-11-18 | PXD034840 | Pride