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Brain ischemia causes disruption in cerebral blood flow and blood–brain barrier integrity, which are normally maintained by astrocyte endfeet. Emerging evidence points to dysregulation of the astrocyte translatome during ischemia, but its effects on the endfoot translatome are unknown. In this study, we aimed to investigate the early effects of ischemia on the astrocyte endfoot translatome in a rodent cerebral ischemia and reperfusion model of stroke. To do so, we immunoprecipitated astrocyte-specific tagged ribosomes (RiboTag IP) from mechanically isolated brain microvessels. In mice subjected to middle cerebral artery occlusion and reperfusion and contralateral controls, we sequenced ribosome-bound RNAs from perivascular astrocyte endfeet and identified 205 genes that were differentially expressed in the endfoot translatome after ischemia. The main biological processes associated with these differentially expressed genes included proteostasis, inflammation, cell cycle/death, and metabolism. Transcription factors whose targets were enriched amongst upregulated translating genes included HSF1, the master regulator of the heat shock response. The most highly upregulated genes in the translatome were HSF1-dependent Hspa1a and Hspa1b, which encode the inducible HSP70. Using qPCR, Western blot, and immunohistochemistry, we confirmed that HSP70 is upregulated in astrocyte endfeet after ischemia. This coincided with an increase in ubiquitination across the proteome that suggests that ischemia induces a disruption in proteostasis in astrocyte endfeet. These findings suggest a robust proteostasis response to proteotoxic stress in the endfoot translatome after ischemia. Modulating proteostasis in endfeet may be a strategy to preserve endfoot function and BBB integrity after ischemic stroke. Full article

L-citrulline (L-CIT), a precursor to L-arginine (L-ARG), is a key contributor to the nitric oxide (NO) signaling pathway. Endothelial dysfunction, characterized by deficient nitric oxide synthesis, is implicated in the pathogenesis of various neonatal conditions such as necrotizing enterocolitis (NEC) and bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH). This review summarizes the current evidence around the possible role of L-CIT supplementation in the treatment of these conditions. Detoxification of endogenously produced superoxide radicals is inadequate in preterm infants due to immature antioxidants that leads to the production of peroxynitrite, a reactive oxygen-free radical that is cytotoxic and causes damage to organelles and cellular membranes, further disrupting the coupling of endothelial NO synthase enzyme and the generation of high levels of reactive nitrogen and oxygen species. Animal studies in lipopolysaccharide-induced models of chorioamnionitis and hyperoxia- and inflammation-induced BPD-PH in rodent lung models revealed that L-CIT supplementation significantly mitigated structural changes in the pulmonary vasculature, preserved alveolar growth, and increased vascular endothelial growth factor gene expression, highlighting the anti-inflammatory and antioxidant effects of L-CIT supplementation. Similar benefits were noted in newborn piglet models of chronic hypoxia-induced PH and NEC. Pharmacokinetic studies in neonates have shown doses of 100–300 mg/kg/day to be safe and well tolerated. A few studies have shown the beneficial effects of L-CIT supplementation in pulmonary hypertension secondary to congenital heart disease, but evidence of efficacy in the neonatal population is lacking. While L-CIT shows promise in the treatment of various neonatal conditions, adequately powered studies to evaluate the safety and efficacy of L-CIT supplementation post-surgical NEC and BPD ± PH in the extremely preterm population are needed to translate this novel therapy to clinical practice. Full article

Background/Objectives: Motor deficits following neonatal brain injury, from cerebral palsy to subtle deficits in motor planning, are common yet underreported. Rodent models of motor deficits in neonatal hypoxia–ischemia (HI) allow improved understanding of the underlying mechanisms and neuroprotective strategies. Our goal was to test motor performance and learning in a mouse model of neonatal HI. Methods: We induced HI in postnatal day (p)10 C57/Bl6 mice through unilateral carotid ligation followed by 60 min of 8% oxygen exposure, or a sham procedure. At p30, we assessed complex motor performance and learning using the accelerating rotarod and complex running wheel tasks. Results: In the rotarod task, HI mice performed worse than sham mice, with shorter latencies to fall (n = 6 sham, 9 HI; day 1, p = 0.033; day 2, p = 0.013; day 3, p = 0.023). Sham mice demonstrated improved performance across days (p = 0.005), and HI mice did not (p = 0.44). During the simple running wheel task, we observed no difference in wheel rotation and speed between groups (n = 5/group; day 1, p = 0.67; day 4, p = 0.53). However, when navigating a wheel with a random pattern of spokes removed (complex task), HI mice took longer than sham mice to reach a plateau in performance (n = 5/group; day 1, p = 0.02; day 4, p = 0.77). Conclusions: Our findings demonstrate that young adult mice exposed to HI exhibit significant deficits and delayed learning in complex motor performance compared to sham mice. HI mice do not show deficits in gross motor performance; however, more subtle impairments are present in complex motor performance and learning. This HI model exhibits subtle motor deficits relevant to findings in humans and may be a useful tool in testing further neuroprotective strategies. Full article

Electroretinography (ERG) is a non-invasive technique for evaluating the retinal function in various ocular diseases. Its results are useful for diagnosing ocular disorders and assessing disease progression or treatment effectiveness. Since numerous studies are based on animal models, validating the ERG results from animals is pivotal. The first part of this paper presents basic information on the types of ERG tests used on rodents, and the second part describes the recorded functional changes in rodents’ retinas when various antioxidant treatments for diabetic retinopathy were used. Our study showed that among the tests for diabetic retinopathy diagnosis in rodents, full-field ERG is accurate and the most commonly used, and pattern ERG and the photopic negative response of the flash ERG tests are rarely chosen. Furthermore, antioxidants generally protect retinas from functional losses. Their beneficial influence is expressed in the preserved amplitudes of the a- and b-waves and the oscillatory potentials. However, prolonging the drug exposure showed that the antioxidants could delay the onset of adverse changes but did not stop them. Future studies should concentrate on how long-term antioxidant supplementation affects the retinal function. Full article

Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs), with intraocular pressure (IOP) being its primary risk factor. Despite controlling IOP, the neurodegenerative process often continues. Therefore, substances with neuroprotective, antioxidant, and anti-inflammatory properties could protect against RGC death. This study investigated the neuroprotective effects on RGCs and visual pathway neurons of a compound consisting of citicoline and coenzyme Q10 (CoQ10) in a mouse model of unilateral, laser-induced ocular hypertension (OHT). Four groups of mice were used: vehicle group (n = 6), citicoline + CoQ10 group (n = 6), laser–vehicle group (n = 6), and laser–citicoline + CoQ10 group (n = 6). The citicoline + CoQ10 was administered orally once a day starting 15 days before laser treatment, continuing until sacrifice (7 days post-laser). Retinas, the dorsolateral geniculate nucleus (dLGN), the superior colliculus (SC), and the visual cortex (V1) were analyzed. The citicoline + CoQ10 compound used in the laser–citicoline + CoQ10 group demonstrated (1) an ocular hypotensive effect only at 24 h post-laser; (2) prevention of Brn3a+ RGC death in OHT eyes; and (3) no changes in NeuN+ neurons in the dLGN. This study demonstrates that the oral administration of the citicoline + CoQ10 combination may exert a neuroprotective effect against RGC death in an established rodent model of OHT. Full article

Sepsis, a life-threatening condition characterized by dysregulated host responses to infection, often leads to multi-organ dysfunction, including kidney injury. Kidney damage in sepsis can have severe consequences and is associated with high mortality rates. This study aimed to investigate the potential therapeutic effects of fosfomycin (FOS), a broad-spectrum antibiotic with immunomodulatory properties, on kidney damage induced by cecal ligation and puncture (CLP)-induced sepsis in a rodent model. In total, 24 rats were randomly divided into three groups. Group 1 (n = 8), the healthy control group (C), received a single dose of 0.9% NaCl (saline) solution via an intraperitoneal (i.p.) route. To group 2 (n = 8), the CLP group, CLP-induced sepsis was applied without medication, and a single dose of 0.9% NaCl (saline) solution was applied i.p. before induction. To group 3 (n = 8), the CLP + FOS (500 mg/kg) group, a single dose of 500 mg/kg FOS was administered i.p. before sepsis induction. The effects of fosfomycin on kidney function, histopathological changes, inflammatory markers, oxidative stress, and apoptosis were assessed. In the fosfomycin-treated group, the histological analysis results demonstrated reduction in kidney tissue damage and inflammation. Additionally, fosfomycin attenuated the upregulation of pro-inflammatory cytokines and reduced oxidative stress markers in kidney tissue. Furthermore, fosfomycin treatment was associated with a decrease in apoptotic cell death in the kidney. These findings suggest that fosfomycin may have a protective effect on kidney damage caused by CLP-induced sepsis. The potential mechanisms underlying this protection include the modulation of inflammation, reduction of oxidative stress, and inhibition of apoptosis. Full article

Background/Objectives: Rodents provide a useful translational model of fear- and anxiety-related behaviors. Previously stressed animals exhibit physiological and behavioral stress responses that parallel those observed in anxious humans. Patients diagnosed with post-traumatic stress disorder (PTSD) present with a spectrum of debilitating anxiety symptoms that result from exposure to one or more traumatic events, with individuals exposed to early adverse experiences and women having increased vulnerability for diagnoses; however, the mechanisms of this increased vulnerability remain unknown. PTSD involves a complex network of highly interconnected brain regions, including the bed nucleus of the stria terminalis (BNST). Serotonin (5-HT) release into the BNST yields an increased expression of both fear and anxiety, specifically through 5-HT_2C receptor signaling. The present experiment addressed whether 5-HT_2C receptor signaling in the BNST is necessary for the acquisition of early-life stress (ELS)-induced enhancements in adult contextual fear learning. Methods: Rats received 0 or 15 footshocks on postnatal day 17, an established model of acute ELS (aELS) that yields enhanced adult fear learning. In adulthood, rats received bilateral infusions of a vehicle, a 5-HT_2C receptor antagonist (RS-102221), or a 5-HT_2C receptor agonist (MK-212) into the BNST 15 min prior to one-footshock contextual fear conditioning in a novel context. The next day, rats were returned to the fear-conditioning context to assess their fear memory (freezing). Results: Females demonstrated aELS-induced enhancement in contextual fear learning, while males did not. BNST infusions of RS-102221 reduced contextual fear conditioning, independent of aELS condition and sex. Infusions of MK-212 had no effect. Conclusions: Taken together, these data suggest that serotonergic signaling through 5-HT_2C receptors in the BNST contributes to contextual fear conditioning, but not aELS-induced stress-enhanced fear learning (SEFL). Full article

Beer and its components show potential for reducing hepatic steatosis in rodent models through multiple mechanisms. This study aimed to evaluate beer’s anti-steatotic effects in a high-fat diet (HFD)-induced mouse model of Metabolic dysfunction-Associated Liver Disease (MASLD) and to explore the underlying mechanisms. In the HFD group, steatosis was confirmed by altered blood parameters, weight gain, elevated liver lipid content, and histological changes. These markers were normalized in the HFD+beer group, reaching levels similar to the control (CTR) group. Protein carbonylation and lipid peroxidation levels were consistent across all groups, suggesting that the model represents an early stage of MASLD without oxidative stress. Transcriptomic and CpG methylation analyses revealed clear distinctions between the CTR and HFD groups. RNA sequencing identified 162 differentially expressed genes (DEGs) between the CTR and HFD groups, primarily related to inflammation and lipid regulation. Beer consumption modified the health of the HFD mice, affecting inflammation but not lipid homeostasis (CTR vs. HFD+beer, DEGs = 43). The CpG methylation analysis indicated that beer lowered methylation, impacting genes linked to lipid accumulation and inflammation. A cecal metabolite analysis suggested that beer improved short-chain fatty acid metabolism (SCFA). In summary, a moderate beer intake may mitigate MASLD by modulating lipid metabolism and SCFA pathways, likely through polyphenol activity. Full article

Background/Objectives: Allergic contact dermatitis (ACD), an inflammatory skin condition, is commonly treated with topical corticosteroids; however, long-term use of these drugs is associated with various risks, such as skin atrophy and steroid resistance. Triacetin (TA), a triglyceride metabolized to acetate, exerts anti-inflammatory affects by activating AMP-activated protein kinase (AMPK) and suppressing mast cell degranulation. Here, we aimed to assess the immediate and long-term effects of TA on ACD suppression, focusing on AMPK activation, using a 2,4-dinitrofluorobenzene-induced rodent model. Methods: Various concentrations of TA were topically applied to rats with 2,4-dinitrofluorobenzene-induced dermatitis. Ear thickness was measured, and histological analysis was performed to assess the inflammation, mast cell infiltration, and degranulation in the established models. AMPK activation was analyzed via Western blotting, and TA degradation was assessed via gas chromatography-mass spectrometry. Dorsomorphin (an AMPK inhibitor) was used to evaluate the effects of AMPK on ACD. Results: TA significantly inhibited inflammation and mast cell degranulation in a dose-dependent manner, with 0.25 mmol/L showing the most potent effects. It also activated AMPK activation. Notably, AMPK inhibition reversed the effects of TA. Conclusions: Overall, TA exerted immediate and long-term anti-inflammatory effects via AMPK activation and inhibition of mast cell degranulation, showing potential as a non-steroidal therapeutic for ACD. Full article

Background: Sleep, a process physiologically vital for mental health, faces disruptions in various sleep disorders linked to metabolic and neurodegenerative risks. Zizyphus seed (Zizy) has long been recognized for its diverse pharmacological attributes, including analgesic, sedative, insomnia, and anxiety alleviation. Objectives: In this study, the sleep-prolonging effects of Zizy extract (100, 200 mg/kg), along with their characterizing compounds jujuboside A (JuA) (5, 10 mg/kg), were evaluated in a mouse model under a pentobarbital-induced sleep. Additionally, the efficacy of Zizy extract was examined on caffeine-induced insomnia in mice. Methods: To confirm the efficacy of Zizy extract on the structure and quality of sleep, an electroencephalogram (EEG) analysis of rats was performed using the MATLAB algorithm. Additionally, Western blot analysis and measurement of intracellular chloride influx were performed to confirm whether these effects acted through the gamma-aminobutyric acid (GABA)ergic system. Administration of Zizy extract showed no effect on the locomotor performance of mice, but the extract and their characteristic compounds significantly prolonged sleep duration in comparison to the pentobarbital alone group in the pentobarbital-induced sleep mouse model. Furthermore, this extract alleviated caffeine-induced insomnia in mice. Results: The administration of Zizy extract extended non-rapid eye movement sleep (NREMS) duration without inducing significant changes in the brain wave frequency. Zizy extract regulated the expression of GABA_A receptor subunits and GAD65/67 in specific brain regions (frontal cortex, hippocampus, and hypothalamus). JuA increased intracellular chloride influx in human SH-SY5Y cells, and it was reduced by GABA_A receptor antagonists. These results suggest that the sleep-maintaining effects of Zizy extract may entail GABAergic regulation. In summary, Zizy extract demonstrated sleep-prolonging properties, improved insomnia, and regulated sleep architecture through GABAergic system modulation. Conclusions: These findings suggest that Zizy extract has potential as a therapeutic agent for stress-related neuropsychiatric conditions such as insomnia. Full article

Rodents play a significant role in the transmission of zoonotic diseases; anthropization has increased human contact with these animals, vectors of infectious agents. However, the processes driving parasitism of hosts remains poorly understood. Yersinia pestis, Rickettsia spp., and Francisella tularensis are three infectious agents transmitted to humans through ectoparasites, with rodents serving as the primary reservoirs. To explore the relationship between both intrinsic and extrinsic factors on host pathogen status, we evaluated heteromyid rodents in the Chihuahuan desert (ChD). From December 2022 to May 2023, we sampled 213 rodents at three locations with different anthropization levels. A total of 103 rodent blood samples, 84 organ samples, and 204 collected ectoparasites were analyzed for molecular detection of infectious agents (Y. pestis, Rickettsia spp., and F. tularensis) with PCR. We captured seven species of rodents (Dipodomys ordii, D. merriami, D. spectabilis, Chaetodipus hispidus, Ch. eremicus, Perognathus flavus, and P. flavescens) and identified one tick (Rhipicephalus sanguineus), two fleas (Meringis altipecten and M. dipodomys) and one louse (Fahrenholzia spp.). Molecular analyses yielded positive for Y. pestis, Rickettsia spp., and negative for F. tularensis. We then modelled the pathogen status as a function of intrinsic (body condition and sex) and extrinsic factors (locality, anthropization level, season, sample type, and parasite-infestation status). We found that non-parasite-infested individuals with better body condition have a higher probability of pathogen infection. Furthermore, we observed that blood samples had a higher probability of detecting pathogen-infected individuals, as compared to spleen or liver samples. Our results offer important insights into host–pathogen interactions and the role of body condition in the pathogen status. Full article

Background/Objectives: This study aims to investigate the effects of 4-methylumbelliferone (4-MU) on islet morphology, cell phenotype and function, and to explore possible mechanisms of β cell regeneration. Methods: The Type 1 diabetes (T1D) model was induced by continuous dose injection of streptozotocin (STZ), and mice were treated with 4-MU for 3 weeks. Plasma insulin level, islet cell phenotype and immune infiltration were determined by IPGTT, ELISA, HE and immunofluorescence. The Ins2^Cre/+/Rosa26-eGFP transgenic mice model was used to detect β identity change. Primary rodent islets were incubated with 4-MU or vehicle in the presence or absence of STZ, AO/PI staining, and a scanning electron microscope (SEM), PCR and ELISA were used to evaluated islet viability, islet morphology, the specific markers of islet β cells and insulin secretion. Results: Treatment with 4-MU significantly decreased blood glucose and increased plasma insulin levels in STZ-induced diabetes. The plasma insulin level in the STZ group was 7.211 ± 2.602 ng/mL, which was significantly lower than the control group level (26.94 ± 4.300 ng/mL, p < 0.001). In contrast, the plasma insulin level in the STZ + 4-MU group was 22.29 ± 7.791 ng/mL, which was significantly higher than the STZ group (p < 0.05). The 4-MU treatment increased islet and β cells numbers and decreased α cell numbers in STZ-induced diabetes. Conclusions: Islet inflammation as indicated by insulin and CD3 was caused by infiltrates, and the β cell proliferation as indicated by insulin and Ki67 was boosted by 4-MU. β cell dedifferentiation was inhibited by 4-MU as assessed by insulin and glucagon double-positive cells and confirmed by Ins2^Cre/+/Rosa26-eGFP mice. In cultured primary rodent islets, 4-MU restored islet viability, protected islet morphology, inhibited β-cell dedifferentiation, and promoted insulin secretion. The benefits of 4-MU in T1D have been proved to be associated with β cells self-replication, dedifferentiation inhibition and immune progression suppression, which help to maintain β cell mass. Full article

Post-Traumatic Stress Disorder (PTSD) is a multifaceted psychiatric disorder triggered by traumatic events, leading to prolonged psychological distress and varied symptoms. Rat models have been extensively used to explore the biological, behavioral, and neurochemical underpinnings of PTSD. This review critically examines the strengths and limitations of commonly used rat models, such as single prolonged stress (SPS), stress–re-stress (S-R), and predator-based paradigms, in replicating human PTSD pathology. While these models provide valuable insights into neuroendocrine responses, genetic predispositions, and potential therapeutic targets, they face challenges in capturing the full complexity of PTSD, particularly in terms of ethological relevance and translational validity. We assess the degree to which these models mimic the neurobiological and behavioral aspects of human PTSD, highlighting areas where they succeed and where they fall short. This review also discusses future directions in refining these models to improve their utility for translational research, aiming to bridge the gap between preclinical findings and clinical applications. Full article

Background: Fibromyalgia (FM) is characterized by chronic pain, significantly affecting the quality of life and functional capabilities of patients. In addition to pain, patients may experience insomnia, chronic fatigue, depression, anxiety, and headaches, further complicating their overall well-being. The Transient Receptor Potential Vanilloid 1 (TRPV1) receptor responds to various noxious stimuli and plays a key role in regulating pain sensitivity and inflammation. Thus, targeting TRPV1 may provide analgesic and anti-inflammatory benefits. This study investigates the efficacy of electroacupuncture (EA) in alleviating chronic pain in FM through TRPV1 and its downstream molecules in the central nervous system (CNS). Methods: To model FM, we subjected mice to intermittent cold stress (ICS) for three days. The study comprised five rodent groups: Control (CON), ICS, ICS + EA, ICS + Sham EA, and ICS + KO (TRPV1 knockout mice). Results: Our findings revealed that ICS induced allodynia and hyperalgesia in mice by day four, persisting until day 21. EA at 2 Hz and TRPV1 KO significantly decreased both mechanical and thermal hypersensitivity (Withdrawal—Day 14: 2.43 ± 0.19 g; Day 21: 5.88 ± 0.47 g, n = 6, p < 0.05; Latency—Day 14: 2.77 ± 0.22 s; Day 21: 5.85 ± 0.41 s, n = 6, p < 0.05). In contrast, sham EA did not produce significant effects. Additionally, TRPV1 and several pain-related proteins were significantly elevated in the thalamus, somatosensory cortex (SSC), medial prefrontal cortex (mPFC), hippocampus, hypothalamus, cerebellum regions V (CB V), VI (CB VI) and VII (CB VII) after the ICS model. Both EA at the ST36 acupoint and TRPV1 KO mice showed diminished overexpression of pain-related proteins, with the sham EA group showing no significant changes compared to the ICS group. Conclusions: Chronic widespread pain was reduced by EA and TRPV1 KO, with the effects of EA on the TRPV1 pain pathway clearly evident in the CNS after 21 days. Full article

Glaucoma is a heterogenous group of optic neuropathies characterized by the degeneration of optic nerve axons and the progressive loss of retinal ganglion cells (RGCs), which could ultimately lead to vision loss. Elevated intraocular pressure (IOP) is a major risk factor in the development of glaucoma, and reducing IOP remains the main therapeutic strategy. Endothelin-1 (ET-1), a potent vasoactive peptide, has been shown to produce neurodegenerative effects in animal models of glaucoma. However, the detailed mechanisms underlying ET-1-mediated neurodegeneration in glaucoma are not completely understood. In the current study, using a Seahorse Mitostress assay, we report that ET-1 treatment for 4 h and 24 h time points causes a significant decline in various parameters of mitochondrial function, including ATP production, maximal respiration, and spare respiratory capacity in cultured RGCs. This compromise in mitochondrial function could trigger activation of mitophagy as a quality control mechanism to restore RGC health. Contrary to our expectation, we observed a decrease in mitophagy following ET-1 treatment for 24 h in cultured RGCs. Using Morrison’s model of ocular hypertension in rats, we investigated here, for the first time, changes in mitophagosome formation by analyzing the co-localization of LC-3B and TOM20 in RGCs. We also injected ET-1 (24 h) into transgenic GFP-LC3 mice to analyze the formation of mitophagosomes in vivo. In Morrison’s model of ocular hypertension, as well as in ET-1 injected GFP-LC3 mice, we found a decrease in co-localization of LC3 and TOM20, indicating reduced mitophagy. Taken together, these results demonstrate that both ocular hypertension and ET-1 administration in rats and mice lead to reduced mitophagy, thus predisposing RGCs to neurodegeneration. Full article