BackgroundTRPC6 channels are expressed in endothelial cells, smooth muscle cells, and macrophages within the atherosclerotic segments of conduit blood vessels. Genetic or pharmacological inactivation of TRPC6 was variably associated with the development of atherosclerosis, a risk factor for myocardial infarction, ischemic stroke, and/or peripheral vascular disease.MethodsWe used two genetically matched mouse strains, ApoE-/-;TRPC6-/- and ApoE-/-;TRPC6+/+, and investigated how genetic ablation of TRPC6 affects age-dependent progression of atherosclerosis in ApoE-/- mice. Aortas were isolated from the mice and subjected to histopathological investigation.ResultsWe assessed atherosclerotic lesion progression in mouse aortas by measuring their area, fibrous cap thickness, and calcification. We found that one-year-old mature mice had similar aortic atherosclerosis. However, aged 1.5-year-old ApoE-/-;TRPC6-/- mice exhibited significantly greater atherosclerosis than ApoE-/-;TRPC6+/+ mice. Averaged fibrous cap thickness was also larger in atherosclerotic lesions from ApoE-/-;TRPC6-/- mice compared to ApoE-/-;TRPC6+/+ mice, whereas calcification was not different between the two mouse strains at any age.ConclusionsAge-dependent, spontaneous atherosclerosis progression was greater in aged but not mature ApoE-/-;TRPC6-/- mice compared to ApoE-/-;TRPC6+/+ mice. Thus, genetic ablation or chronic inhibition of TRPC6 may facilitate the development of spontaneous atherosclerosis in aged ApoE-/- mice.

The long-term effects of non-convulsive status epilepticus (NCSE) and their mechanisms in the brain remain largely unknown. Such insight is needed to better shape the clinical approach to this condition. Here, we investigated long-term alterations in hippocampal transcriptomic profiles following an episode of limbic NCSE in periadolescent rats. Cortical and hippocampal mRNA expressions were measured 2 months following intrahippocampal kainic acid (NCSE group, n = 3) or saline injections (controls, n = 4). Compared to controls, NCSE-treated rodents exhibited a significant twofold downregulation in 126 genes in the CA1 hippocampal subfield, 11 in the CA2-3 region, and 21 in the dentate/hilar areas. Most of the identified genes are known to play an essential role in learning and hippocampal plasticity. Additional roles include modulation of inflammatory responses. Twenty altered genes are known to contribute to human intellectual and mental disease pathology, and nine out of these are direct causes of cognitive and neurodevelopmental brain disorders. Spatial deconvolution analyses revealed NCSE-related increases in CA2-3 microglia and hilar astrocytes coupled with increases in dentate GABAergic neurons. These long-term region-specific cellular and molecular hippocampal alterations may contribute to both inflammatory states and disturbances in neuronal function. Taken together, these gene expression changes are suggestive of neuroinflammation-driven synaptic dysfunction following NCSE.

AIMS:Pain is common among adults with heart failure (HF), but pain subtypes and associated biomarkers are understudied. The aims were to (i) characterize chronic pain severity, neuropathic pain quality, locations, and subtypes and (ii) compare pain severity and levels of biomarkers among pain subtypes. An exploratory aim was to correlate levels of biomarkers with pain severity. METHODS AND RESULTS:This pilot descriptive study included cross-sectional data from 60 adults with HF and chronic pain. Pain was evaluated using the PainDETECT questionnaire. Blood biomarkers included interleukin (IL)-10, IL-18, IL-1β, IL-33, IL-6, IL-8, tumour necrosis factor (TNF)-α, brain-derived neurotrophic factor, leptin, adiponectin, and C-reactive protein. Descriptive statistics, chi-square test of homogeneity, one-way analysis of variance, and Spearman correlation were used for analyses. The mean age was 70.45 (SD 7.92) years. The sample consisted of 63.3% women and 65.0% White race. Participants primarily reported nociceptive pain only (73.3%) with fewer reporting neuropathic pain only (6.7%) and mixed pain (20.0%). Current and 4-week mean pain severity scores were highest in the mixed pain subtype (P both < 0.05). No biomarkers were significantly different across the pain subtypes, but lower lL-10 (P = 0.049), and IL-33 (P = 0.014), were associated with higher pain severity. CONCLUSION:In this study, chronic pain and its association with underlying biomarkers were characterized. Future research with a larger sample is needed to understand the unique contributions of biomarkers with targeted pain phenotypes.

Non-coding RNA species, such as microRNA (miRNA), regulate multiple biological and pathological processes by binding to target mRNAs and facilitating alteration of translation levels via complexes such as RNA-induced silencing complex (RISC). Disrupting this process could contribute to AD pathogenesis by fostering aggregation of hyperphosphorylated microtubule-associated protein tau and amyloid-β (Aβ) peptides, and neuroinflammation. Understanding how these pathological changes are regulated remains our research focus. We report that miR298 plays a vital role in maintaining APP and tau homeostasis and that miR298 imbalances may impact AD progression. Levels of miR298 from non-cognitively impaired (NCI) and AD subject brain tissue samples from different recognized sources were measured by qRT-PCR and assessed for associations with AD risk and potential covariates such as age and APOE genotype. Other biomarkers were assessed in cortical samples from the same subjects, as we previously described. Further, APP, tau, and cytokines were profiled in miR298 mimic- or its antagomiR-expressing human neuronal and astrocyte cultures. Levels of miR298 varied in postmortem temporal lobe between AD patients and age-matched NCI controls. Higher brain miR298 levels were associated with a reduced risk of AD. Subject age and APOE genotype altered this association; specifically, greater age and dose of the APOEε4 allele were associated with an increased risk of AD. However, APOEε4 dose-associated risk reduced as age increased. We identified putative binding sites for miR298 on APP, BACE1, MAPT, IL1α, and IL6 mRNAs to form RISC. We showed that treatment by miR298 reduced tau, APP, and BACE1 proteins and mRNA levels in cell cultures. These studies suggest that miR298 regulates a coordinated network of AD-related proteins APP, BACE1, and tau. Hence, such network regulation may represent a rational therapeutic target for reducing AD risk and disease modification. In addition to late-onset cases, we will profile miR298 in brain tissue samples from early-onset AD cases. Future work involves testing miR298 in AD animal models, such as in human tau-overexpressing transgenic mice. We sincerely thank grant support from NIA/NIH.

The timely therapeutic targeting of the dysregulated immune response in sepsis is essential to restore immune homeostasis and prevent progression to organ dysfunction. In this study, we investigated whether a combination therapy with an antibiotic exhibiting anti-inflammatory properties and the anti-inflammatory compound dorzolamide will improve the bacterial sepsis outcome. Using an in-silico approach, we screened a structure library of FDA-approved antibiotics to identify those that can interact with the Toll/interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP), a protein regulating proinflammatory cytokine production in immune cells. Our virtual screening identified a broad-spectrum antibiotic, levofloxacin, as a candidate. We subsequently employed the cecum slurry (CS) septic mouse model to validate the candidates in vivo, while monitoring survival of mice, tissue mRNA expression, cell morphology, cytokine levels, and other biochemical markers. The in vivo studies confirmed that the combination of levofloxacin and dorzolamide (LeDoz) increased the survival rate of septic mice. Hematoxylin and eosin (H&E) tissue staining, cytokine levels, as well as immunofluorescence dual staining and serum biomarkers, all showed the reestablishment of homeostatic conditions in the LeDoz-treated group of septic mice compared to untreated septic mice. In vitro analyses also confirmed the ability of LeDoz to attenuate TIRAP-mediated inflammatory signaling. Thus, the combination of levofloxacin and dorzolamide exhibits both an antibacterial effect and a strong potential for synergistically reducing chronic inflammation in the host by inhibiting the activation of TIRAP.

The most common neurodegenerative disorders include Alzheimer's disease (AD), Lewy body and related dementias (ADRDs). Triggers of pathobiochemical changes in ADRDs remains unknown and appear numerous. Short non-coding RNAs, microRNA (miRNA), play a vital role in regulating biological and pathological processes leading to neurodegenerative diseases. Amyloid plaques, major hallmarks of AD, comprise abnormal aggregation of extracellular amyloid-β peptides (Aβ) derived from Aβ precursor protein (APP). Neurofibrillary tangles consist of filamentous hyper-phosphorylated tau proteins. Alpha-synuclein (SNCA) plays a critical role in the pathogenesis of Parkinson's and other synucleinopathies. Repressor Element 1-Silencing Transcription (REST) factor is altered in ADRDs. We studied the role of miR-153-3p in AD risk and in regulating levels of critical proteins. miR-153-3p reduced APP, SNCA and We measured miR153 levels in non-cognitively impaired (NCI) and AD subject brain tissue samples from different recognized sources by qRT-PCR as described (Wang et al). We utilized autopsy brain tissues and ADNI participants' genotyping and performed association studies of miR-153-3p and its single nucleotide polymorphisms (SNPs) with AD risk, and nine endophenotypes. We used iPSC-derived neuronal cells, human cell lines and miRNA transfections to study the mechanism of miR-153-3p Elevation of miR-153-3p is associated with a reduced probability of AD, while elevated REST associated with a greater likelihood of AD. MiR-153 gene SNPs are associated with nine AD-related endophenotypes. MiR-153-3p reduced REST, APP and SNCA 3’-UTR activities and respective protein levels. MiR-153-3p treatment altered REST and neuronal differentiation in iPSC-derived neuronal stem cells. RNA sequencing proteomics and interactome analysis revealed the role of miR-153-3p in axonal guidance. With the increased emphasis on comorbidities of AD and other neurodegenerative diseases, we identified that miR-153-3p, as a master regulator, reduced a key group of neurodegeneration-related proteins. MiR-153-3p reduces APP, SNCA and REST expression, all pointing towards a therapeutic and biomarker potential in ADRDs. In addition to late-onset cases, we will profile miR153 in brain tissue samples from early-onset AD cases.

Chronic pain is prevalent among U.S. military personnel and often accompanied by comorbid behavioral health disorders and other medical conditions that further complicate its management. According to the Centers for Disease Control and Prevention, the prevalence of chronic pain among active-duty Service members is 1.5 to 2 times higher than the 20% of American adults who live with chronic pain. Recent report findings determined that Service members make up a large population within the Military Health Systems (MHS), and that this population is disproportionately affected by lost duty days, early retirement, loss of readiness, and increased burden to the MHS. To date, the Department of Defense (DOD) and MHS have emphasized multimodal, multidisciplinary, stepped treatment for chronic pain that prioritizes nonpharmacologic therapies and non-opioid pain medications. Though the DOD and MHS have invested in several pain treatment types, our level of understanding needs to better distinguish between acute and chronic pain and identify risk factors and mechanisms responsible for the chronification of pain, as it is the chronic pain which compromises functioning and readiness to a greater degree across the force. The novel information generated by this study will enhance our understanding of how ankle fracture elicits pathological risk factors for bone fracture associated neuropathic pain (BFNP), which ultimately impairs health-related quality of life. Due to the high prevalence of ankle fractures and the subsequent risk of developing chronic pain after ankle fracture, we will utilize this patient population to provide the preliminary evidence on whether bone fracture and subsequent BFNP phenotypes are reflected in specific genetic profiles and activated states of immune cells.

Hypoxic encephalopathy of the newborn is associated with long-term neurodevelopmental behavioral deficits that lack a definitive "optimal" treatment approach. We previously demonstrated that periadolescent depressive-like behaviors occur in a rat model of early-life hypoxia. Here, we investigated the short-term effects of the selective serotonin reuptake inhibitor, sertraline, against later-life behavioral deficits. Rats were exposed to global hypoxia at postnatal day 10 (P10) and then received either sertraline or its vehicle (P24 to P30). Normoxic controls received sertraline or its vehicle. Depressive-like and anxiety-like behaviors were assessed using the forced swim test (FST) and open field test (OFT), respectively. The FST was conducted at P25-26 and the OFT at P27. Rats were sacrificed at P30 to assess hippocampal microRNA (miR) expression and to histologically evaluate hippocampal neuronal densities and synaptophysin (Syp) protein levels. Early-life hypoxic seizures resulted in increased immobility in the FST (p < 0.05) and decreased exploration in the OFT (p < 0.05). Hypoxia also resulted in chronic alterations in the expression of 25 miRs, 22 of which are known to modulate inflammatory responses and synaptic function. Sertraline treatment normalized hypoxia-induced increased immobility and reversed 17 out of 25 alterations in miR expression. However, sertraline potentiated hypoxia-induced exploratory deficits (p < 0.05). The drug treatment also resulted in OFT deficits in controls (p < 0.05) and 13 unique dysregulations in miR expression. Neuronal densities and Syp levels were comparable among all groups. We demonstrate that sertraline reverses hypoxia-induced depressive-like behaviors, possibly by targeting inflammation and synaptic remodeling. Sertraline-induced anxiety-like behaviors may reflect its known transient early side effects and warrant further research on long-term outcomes.

Lipoxins were discovered 40 years ago, and since then, their beneficial roles for human health have been confirmed in numerous studies. These small molecules belong to the eicosanoid class of compounds, which are generated metabolically by lipoxygenases. Lipoxins are released during various diseases and conditions, including but not limited to systemic inflammation, infection, asthma, cancer, diabetes, and cardiovascular disorders. Recently, several synthetic lipoxin analogs have been developed that also exhibit potent anti-inflammatory properties. In this review, we discuss the inflammation-resolving roles of lipoxins in various major diseases. Further, we summarize the latest reports on the use of synthetic lipoxins as potential therapeutic agents and discuss the role of aspirin-dependent lipoxin production in alleviating various diseases, including cancer.

Chronic pain impacts more than one in five adults in the United States (US) and the costs associated with the condition amount to hundreds of billions of dollars annually. Despite the tremendous impact of chronic pain globally, the standard of care for diagnosis depends on subjective self-reporting of pain state, with no objective assessment procedure available. This study investigated the application of signal processing and machine learning to electroencephalography (EEG) data for the development of classification algorithms capable of differentiating subjects with diverse chronic pain etiologies from pain-free subjects. The study population included participants experiencing various types of chronic pain, including nociceptive, neuropathic, and mixed etiological pain conditions. Chronic pain diagnoses were based on clinical evaluation by participating physicians and adhered to the International Association for the Study of Pain (IASP) definition, requiring pain persistence for >3 months and associated functional impairment or emotional distress. Data from 186 participants were used for algorithm development, including 35 healthy controls and 151 chronic pain patients. Machine learning methodologies were applied to the data, with Elastic Net chosen as the optimal methodology.. The classifier was able to differentiate pain versus no pain subjects with an accuracy of 79.6%, sensitivity of 82.2%, and specificity of 66.7%. This study incorporates the multidimensional nature of chronic pain, ensuring that our methods and interpretations align with current clinical and research standards. This study represents a step toward integrating EEG-based biomarkers into clinical workflows for chronic pain assessment, bridging the gap between subjective reporting and objective diagnostic tools.

Background: This study used diffusion tensor imaging (DTI) to detect brain microstructural changes in participants with mild traumatic brain injury (mTBI) who experienced post-traumatic headaches, a common issue that affects quality of life and rehabilitation. Despite its prevalence, the mechanisms behind post-traumatic headache are not well understood. Methods: Participants were recruited from Level 1 trauma centers, and MRI scans, including T1-weighted anatomical imaging and DTI, were acquired 1 month post-injury. Advanced imaging techniques corrected artifacts and extracted diffusion tensor measures reflecting white-matter integrity. Pain sensitivity assays were collected at 1 and 6 months post-injury, including quantitative sensory testing and psychological assessments. Results: Significant aberrations in axial diffusivity in the forceps major were observed in mTBI participants (n = 12) compared to healthy controls (n = 10) 1 month post-injury (p = 0.02). Within the mTBI group, DTI metrics at 1 month were significantly associated with pain-related and psychological outcomes at 6 months. Statistical models revealed group differences in the right sagittal stratum (p < 0.01), left insula (p < 0.04), and left superior longitudinal fasciculus (p < 0.05). Conclusions: This study shows that DTI metrics at 1 month post-injury are sensitive to mTBI and predictive of chronic pain and psychological outcomes at 6 months.

Theories of pain have been developed in several patient populations, but none currently exist for heart failure (HF) that include contributing factors and associated outcomes. We developed a situation-specific theory of pain in HF by adapting the biopsychosocial model of pain. Existing theoretical and empirical literature in HF samples was utilized to construct the new theory. Components, contributing factors, and associated outcomes of pain in HF are presented in the new theory. Areas in need of additional research are emphasized, and strengths and limitations are discussed. This theory could provide a foundation for future pain research initiatives in HF. Key words : pain, heart failure, theoretical model.

Background: TRPC5 proteins form plasma membrane cation channels and are expressed in the nervous and cardiovascular systems. TRPC5 activation leads to cell depolarization and increases neuronal excitability, whereas a homologous TRPC1 inhibits TRPC5 function via heteromerization. The mechanism underlying the inhibitory effect of TRPC1 in TRPC5/TRPC1 heteromers remains unknown. Methods: We used electrophysiological techniques to examine the roles of subunit stoichiometry and positively charged luminal residues of TRPC1 on TRPC5/TRPC1 function. We also performed molecular dynamics simulations. Results: We found that increasing the relative amount of TRPC1 in TRPC5/TRPC1 heteromers reduced histamine-induced cation influx through the heteromeric channels. Consistently, histamine-induced cation influx was small in cells co-expressing TRPC5-TRPC1 concatemers and TRPC1, and large in cells co-expressing TRPC5-TRPC1 concatemers and TRPC5. Molecular dynamics simulations revealed that the TRPC1 protein has two positively charged lysine residues that are facing the heteromeric channel pore lumen. Substitution of these lysines with asparagines decreased TRPC1’s inhibitory effect on TRPC5/TRPC1 function, indicating that these lysines may regulate cation influx through TRPC5/TRPC1 heteromers. Additionally, we established that extracellular Mg2+ inhibits cation influx through TRPC5/TRPC1, contributing to channel regulation. Conclusions: We revealed that the inhibitory effect of TRPC1 on heteromeric TRPC5/TRPC1 function likely involves luminal lysines of TRPC1.

Three review articles have been written that discuss the roles of the central and peripheral nervous systems in fracture healing. While content among the articles is overlapping, there is a key difference between them: the use of artificial intelligence (AI). In one paper, the first draft was written solely by humans. In the second paper, the first draft was written solely by AI using ChatGPT 4.0 (AI-only or AIO). In the third paper, the first draft was written using ChatGPT 4.0 but the literature references were supplied from the human-written paper (AI-assisted or AIA). This project was done to evaluate the capacity of AI to conduct scientific writing. Importantly, all manuscripts were fact checked and extensively edited by all co-authors rendering the final manuscript drafts significantly different from the first drafts. Unsurprisingly, the use of AI decreased the time spent to write a review. The two AI-written reviews took less time to write than the human-written paper; however, the changes and editing required in all three manuscripts were extensive. The human-written paper was edited the most. On the other hand, the AI-only paper was the most inaccurate with inappropriate reference usage and the AI-assisted paper had the greatest incidence of plagiarism. These findings show that each style of writing presents its own unique set of challenges and advantages. While AI can theoretically write scientific reviews, from these findings, the extent of editing done subsequently, the inaccuracy of the claims it makes, and the plagiarism by AI are all factors to be considered and a primary reason why it may be several years into the future before AI can present itself as a viable alternative for traditional scientific writing.

Purpose of Review Fractures are a prominent form of traumatic injury and shall continue to be for the foreseeable future. While the inflammatory response and the cells of the bone marrow microenvironment play significant roles in fracture healing, the nervous system is also an important player in regulating bone healing. Recent Findings Considerable evidence demonstrates a role for nervous system regulation of fracture healing in a setting of traumatic injury to the brain. Although many of the impacts of the nervous system on fracture healing are positive, pain mediated by the nervous system can have detrimental effects on mobilization and quality of life. Summary Understanding the role the nervous system plays in fracture healing is vital to understanding fracture healing as a whole and improving quality of life post-injury. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Purpose of Review The traditionally understated role of neural regulation in fracture healing is gaining prominence, as recent findings underscore the peripheral nervous system’s critical contribution to bone repair. Indeed, it is becoming more evident that the nervous system modulates every stage of fracture healing, from the onset of inflammation to repair and eventual remodeling. Recent Findings Essential to this process are neurotrophins and neuropeptides, such as substance P, calcitonin gene-related peptide, and neuropeptide Y. These molecules fulfill key roles in promoting osteogenesis, influencing inflammation, and mediating pain. The sympathetic nervous system also plays an important role in the healing process: while local sympathectomies may improve fracture healing, systemic sympathetic denervation impairs fracture healing. Furthermore, chronic activation of the sympathetic nervous system, often triggered by stress, is a potential impediment to effective fracture healing, marking an important area for further investigation. Summary The potential to manipulate aspects of the nervous system offers promising therapeutic possibilities for improving outcomes in fracture healing. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Purpose of Review Despite advances in orthopedics, there remains a need for therapeutics to hasten fracture healing. However, little focus is given to the role the nervous system plays in regulating fracture healing. This paucity of information has led to an incomplete understanding of fracture healing and has limited the development of fracture therapies that integrate the importance of the nervous system. This review seeks to illuminate the integral roles that the nervous system plays in fracture healing. Recent Findings Preclinical studies explored several methodologies for ablating peripheral nerves to demonstrate ablation-induced deficits in fracture healing. Conversely, activation of peripheral nerves via the use of dorsal root ganglion electrical stimulation enhanced fracture healing via calcitonin gene related peptide (CGRP). Investigations into TLR-4, TrkB agonists, and nerve growth factor (NGF) expression provide valuable insights into molecular pathways influencing bone mesenchymal stem cells and fracture repair. Finally, there is continued research into the connections between pain and fracture healing with findings suggesting that anti-NGF may be able to block pain without affecting healing. Summary This review underscores the critical roles of the central nervous system (CNS), peripheral nervous system (PNS), and autonomic nervous system (ANS) in fracture healing, emphasizing their influence on bone cells, neuropeptide release, and endochondral ossification. The use of TBI models contributes to understanding neural regulation, though the complex influence of TBI on fracture healing requires further exploration. The review concludes by addressing the neural connection to fracture pain. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Background:As 5-10% of fractures will not heal without medical intervention, there is an ongoing need for effective treatments to promote fracture healing. CTM Biomedical produces human placental tissue-derived allografts that are used clinically and may assist in healing; however, no pre-clinical studies assessing these products have been performed. Our study investigating the impact of CTM products on the healing of a standard femoral fracture and a critical sized femoral defect (CSD) aims to fill this gap. We hypothesize that CTM product application will improve fracture healing and reduce pain-related behaviors. Methods:Femoral fractures were induced in 45 mice. CTM membrane, CTM paste, a combination of CTM membrane and paste, or saline was applied to each fracture. X-rays were taken twice weekly over 22 days, and blinded modified Radiological Union Scale for Tibia (mRUST) fracture scoring was performed. Complete blood analysis was conducted weekly. Following euthanasia 23 days post-surgery, μCT and histomorphometric analyses were conducted. CSDs have also been surgically induced in the femurs of 95 mice, with plans for similar fracture analyses. Results:CTM product application did not significantly alter the levels of inflammatory cells, suggesting that the mice did not undergo immunological reactions. mRUST scoring indicated that CTM products may not alter fracture healing rates. However, combined application of CTM membrane and paste significantly increased the fracture callus’s mineralized volume (by ~90%) and the percent of the callus that was bone. CTM membrane and paste application also led to an increased threshold for hind paw withdrawal, suggesting that CTM products may decrease pain-related behaviors. Future Directions:We hypothesize that in our CSD model, mice treated with the combination of CTM membrane and paste will display improved fracture healing and decreased pain-related behaviors. If shown to be effective, CTM product use may decrease fracture nonunion risk and increase comfort.

Atherosclerosis is a chronic inflammatory disease in which fats, lipids, cholesterol, calcium, proliferating smooth muscle cells, and immune cells accumulate in the intima of the large arteries, forming atherosclerotic plaques. A complex interplay of various vascular and immune cells takes place during the initiation and progression of atherosclerosis. Multiple reports indicate that tight control of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) production is critical for maintaining vascular health. Unrestricted ROS and RNS generation may lead to activation of various inflammatory signaling pathways, facilitating atherosclerosis. Given these deleterious consequences, it is important to understand how ROS and RNS affect the signaling processes involved in atherogenesis. Conversely, RSS appears to exhibit an atheroprotective potential and can alleviate the deleterious effects of ROS and RNS. Herein, we review the literature describing the effects of ROS, RNS, and RSS on vascular smooth muscle cells, endothelial cells, and macrophages and focus on how changes in their production affect the initiation and progression of atherosclerosis. This review also discusses the contribution of ROS, RNS, and RSS in mediating various post -translational modifications, such as oxidation, nitrosylation, and sulfation, of the molecules involved in inflammatory signaling.

To optimize the clinical approach to non-convulsive status epilepticus (NCSE), it is essential to gain insight into its long-term effects on cognition and behaviors. Here, we investigated limbic NCSE-induced hippocampal injury and behavioral deficits in peri-adolescent rats. NCSE was induced in P43 Sprague Dawleyrats with intrahippocampal subconvulsive doses of kainic acid (NCSE group, n = 14) under continuous epidural cortical electroencephalography (EEG). Controls received volume-matched saline (n = 18). Following one month of continuous EEG monitoring, rats were sequentially subjected (P73-91) to the open field, the Morris water maze (MWM), and the modified two-way active avoidance (MAAV). Rats were sacrificed at P91 to histologically assess hippocampal injury with NeuN (neuronal nuclei) staining, levels of GFAP (glial fibrillary acidic protein), and synaptophysin (Syp). Following kainic acid administration, the NCSE group experienced electroclinical seizures characterized by behavioral arrest and oromotor automatisms without tonic-clonic activity (latency: 15.93 ± 4.70 min, duration: 68.35 ± 17.97 min). There were no seizure recurrences in the rest of the long-term recordings. Compared to controls, NCSE rats had impaired place learning in the MWM, and lower rates of context-cued shock avoidance in the MAAV (p < 0.05). The NCSE and control groups had comparable hippocampal neuronal densities and GFAP levels, but NCSE rats had significantly lower hilar Syp levels. One episode of limbic NCSE during peri-adolescence results in later life hippocampal synaptic dysfunction and contextual learning deficits. These data suggest that the diagnosis and treatment of NCSE should be prompt.