Investigation the mechanism of iron overload-induced colonic inflammation following ferric citrate exposure.

Iron overload occurs due to excessive iron intake compared to the body's demand, leading to iron deposition and impairment of multiple organ functions. Our previous study demonstrated that chronic oral administration of ferric citrate (FC) caused colonic inflammatory injury. However, the precise mechanism underlying this inflammatory response remains unclear. The current study aims to investigate the mechanism by which iron overload induced by FC exposure leads to colonic inflammation. To accomplish this, mice were orally exposed to three different concentrations of FC (71 mg/kg/bw (L), 143 mg/kg/bw (M) and 286 mg/kg/bw (H)) for continuous 16 weeks, with the control group receiving ultrapure water (C). Exposure to FC caused disturbances in the excretory system, altered colonic flora alpha diversity, and enriched pathogenic bacteria, such as Mucispirillum, Helicobacter, Desulfovibrio, and Shigella. These changes led to structural disorders of the colonic flora and an inflammatory response phenotype characterized by inflammatory cells infiltration, atrophy of intestinal glands, and irregular thickening of the intestinal wall. Mechanistic studies revealed that FC-exposure activated the NF-κB signaling pathway by up-regulating TLR4, MyD88, and NF-κB mRNA levels and protein expression. This activation resulted in increased production of pro-inflammatory cytokines, further contributing to the colonic inflammation. Additionally, in vitro experiments in SW480 cells confirmed the activation of NF-κB signaling pathway by FC exposure, consistent with the in vivo findings. The significance of this study lies in its elucidation of the mechanism by which iron overload caused by FC exposure leads to colonic inflammation. By identifying the role of pathogenic bacteria and the NF-κB signaling pathway, this study could potentially offer a crucial theoretical foundation for the research on iron overload, as well as provide valuable insights for clinical iron supplementation.

Ultra-short T2 components imaging of the whole brain using 3D dual-echo UTE MRI with rosette k-space pattern.

PURPOSE: This study aimed to develop a new 3D dual-echo rosette k-space trajectory, specifically designed for UTE MRI applications. The imaging of the ultra-short transverse relaxation time (uT2 ) of brain was acquired to test the performance of the proposed UTE sequence. THEORY AND METHODS: The rosette trajectory was developed based on rotations of a "petal-like" pattern in the kx -ky plane, with oscillated extensions in the kz -direction for 3D coverage. Five healthy volunteers underwent 10 dual-echo 3D rosette UTE scans with various TEs. Dual-exponential complex model fitting was performed on the magnitude data to separate uT2 signals, with the output of uT2 fraction, uT2 value, and long-T2 value. RESULTS: The 3D rosette dual-echo UTE sequence showed better performance than a 3D radial UTE acquisition. More significant signal intensity decay in white matter than gray matter was observed along with the TEs. The white matter regions had higher uT2 fraction values than gray matter (10.9% ± 1.9% vs. 5.7% ± 2.4%). The uT2 value was approximately 0.10 ms in white matter . CONCLUSION: The higher uT2 fraction value in white matter compared to gray matter demonstrated the ability of the proposed sequence to capture rapidly decaying signals.

Ferric citrate-induced colonic mucosal damage associated with oxidative stress, inflammation responses, apoptosis, and the changes of gut microbial composition.

Ferric citrate (FC) has been used as an iron fortifier and nutritional supplement, which is reported to induce colitis in rats, however the underlying mechanism remains to be elucidated. We performed a 16-week study of FC in male healthy C57BL/6 mice (nine-month-old) with oral administration of Ctr (0.9 % NaCl), 1.25 % FC (71 mg/kg/bw), 2.5 % FC (143 mg/kg/bw) and 5 % FC (286 mg/kg/bw). FC-exposure resulted in colon iron accumulation, histological alteration and reduce antioxidant enzyme activities, such as glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC), together with enhanced lipid peroxidation level, including malondialdehyde (MDA) level and 4-Hydroxynonenal (4-HNE) protein expression. Exposure to FC was associated with upregulated levels of the interleukin (IL)- 6, IL-1ß, IL-18, IL-8 and tumor necrosis factor α (TNF-α), while down-regulated levels of IL-4 and IL-10. Exposure to FC was positively associated with the mRNA and protein expressions of cysteine-aspartic proteases (Caspase)- 9, Caspase-3, Bcl-2-associated X protein (Bax), while negatively associated with B-cell lymphoma 2 (Bcl2) in mitochondrial apoptosis signaling pathway. FC-exposure changed the diversity and composition of gut microbes. Additionally, the serum lipopolysaccharide (LPS) contents increased in FC-exposed groups when compared with the control group, while the expression of colonic tight junction proteins (TJPs), such as Claudin-1 and Occludin were decreased. These findings indicate that the colonic mucosal injury induced by FC-exposure are associated with oxidative stress generation, inflammation response and cell apoptosis, as well as the changes in gut microbes diversity and composition.

TRIM67 Implicates in Regulating the Homeostasis and Synaptic Development of Mitral Cells in the Olfactory Bulb.

In recent years, olfactory dysfunction has attracted increasingly more attention as a hallmark symptom of neurodegenerative diseases (ND). Deeply understanding the molecular basis underlying the development of the olfactory bulb (OB) will provide important insights for ND studies and treatments. Now, with a genetic knockout mouse model, we show that TRIM67, a new member of the tripartite motif (TRIM) protein family, plays an important role in regulating the proliferation and development of mitral cells in the OB. TRIM67 is abundantly expressed in the mitral cell layer of the OB. The genetic deletion of TRIM67 in mice leads to excessive proliferation of mitral cells in the OB and defects in its synaptic development, resulting in reduced olfactory function in mice. Finally, we show that TRIM67 may achieve its effect on mitral cells by regulating the Semaphorin 7A/Plexin C1 (Sema7A/PlxnC1) signaling pathway.

Deficiency of autism-related Scn2a gene in mice disrupts sleep patterns and circadian rhythms.

Autism spectrum disorder (ASD) affects ~2% of the population in the US, and monogenic forms of ASD often result in the most severe manifestation of the disorder. Recently, SCN2A has emerged as a leading gene associated with ASD, of which abnormal sleep pattern is a common comorbidity. SCN2A encodes the voltage-gated sodium channel NaV1.2. Predominantly expressed in the brain, NaV1.2 mediates the action potential firing of neurons. Clinical studies found that a large portion of children with SCN2A deficiency have sleep disorders, which severely impact the quality of life of affected individuals and their caregivers. The underlying mechanism of sleep disturbances related to NaV1.2 deficiency, however, is not known. Using a gene-trap Scn2a-deficient mouse model (Scn2atrap), we found that Scn2a deficiency results in increased wakefulness and reduced non-rapid-eye-movement (NREM) sleep. Brain region-specific Scn2a deficiency in the suprachiasmatic nucleus (SCN) containing region, which is involved in circadian rhythms, partially recapitulates the sleep disturbance phenotypes. At the cellular level, we found that Scn2a deficiency disrupted the firing pattern of spontaneously firing neurons in the SCN region. At the molecular level, RNA-sequencing analysis revealed differentially expressed genes in the circadian entrainment pathway including core clock genes Per1 and Per2. Performing a transcriptome-based compound discovery, we identified dexanabinol (HU-211), a putative glutamate receptor modulator, that can partially reverse the sleep disturbance in mice. Overall, our study reveals possible molecular and cellular mechanisms underlying Scn2a deficiency-related sleep disturbances, which may inform the development of potential pharmacogenetic interventions for the affected individuals.

Polyphyllin I Promotes Autophagic Cell Death and Apoptosis of Colon Cancer Cells via the ROS-Inhibited AKT/mTOR Pathway.

Colon cancer is a common malignant tumor of the digestive tract, and it is considered among the biggest killers. Scientific and reasonable treatments can effectively improve the survival rate of patients if performed in the early stages. Polyphyllin I (PPI), a pennogenyl saponin isolated from Paris polyphylla var. yunnanensis, has exhibited strong anti-cancer activities in previous studies. Here, we report that PPI exhibits a cytotoxic effect on colon cancer cells. PPI suppressed cell viability and induced autophagic cell death in SW480 cells after 12 and 24 h, with the IC50 values 4.9 ± 0.1 µmol/L and 3.5 ± 0.2 µmol/L, respectively. Furthermore, we found PPI induced time-concentration-dependent autophagy and apoptosis in SW480 cells. In addition, down-regulated AKT/mTOR activity was found in PPI-treated SW480 cells. Increased levels of ROS might link to autophagy and apoptosis because reducing the level of ROS by antioxidant N-acetylcysteine (NAC) treatment mitigated PPI-induced autophagy and apoptosis. Although we did not know the molecular mechanism of how PPI induced ROS production, this is the first study to show that PPI induces ROS production and down-regulates the AKT/mTOR pathway, which subsequently promotes the autophagic cell death and apoptosis of colon cancer cells. This present study reports PPI as a potential therapeutic agent for colon cancer and reveals its underlying mechanisms of action.

TRIM67 Deficiency Exacerbates Hypothalamic Inflammation and Fat Accumulation in Obese Mice.

Obesity has achieved the appearance of a global epidemic and is a serious cause for concern. The hypothalamus, as the central regulator of energy homeostasis, plays a critical role in regulating food intake and energy expenditure. In this study, we show that TRIM67 in the hypothalamus was responsive to body-energy homeostasis whilst a deficiency of TRIM67 exacerbated metabolic disorders in high-fat-diet-induced obese mice. We found exacerbated neuroinflammation and apoptosis in the hypothalamus of obese TRIM67 KO mice. We also found reduced BDNF in the hypothalamus, which affected the fat sympathetic nervous system innervation and contributed to lipid accumulation in adipose tissue under high-fat-diet exposure. In this study, we reveal potential implications between TRIM67 and the hypothalamic function responding to energy overuptake as well as a consideration for the therapeutic diagnosis of obesity.

Longitudinal auditory pathophysiology following mild blast-induced trauma.

Blast-induced hearing difficulties affect thousands of veterans and civilians. The long-term impact of even a mild blast exposure on the central auditory system is hypothesized to contribute to lasting behavioral complaints associated with mild blast traumatic brain injury (bTBI). Although recovery from mild blast has been studied separately over brief or long time windows, few, if any, studies have investigated recovery longitudinally over short-term and longer-term (months) time windows. Specifically, many peripheral measures of auditory function either recover or exhibit subclinical deficits, masking deficits in processing complex, real-world stimuli that may recover differently. Thus, examining the acute time course and pattern of neurophysiological impairment using appropriate stimuli is critical to better understanding and intervening in bTBI-induced auditory system impairments. Here, we compared auditory brainstem response, middle-latency auditory-evoked potentials, and envelope following responses. Stimuli were clicks, tone pips, amplitude-modulated tones in quiet and in noise, and speech-like stimuli (iterated rippled noise pitch contours) in adult male rats subjected to mild blast and sham exposure over the course of 2 mo. We found that blast animals demonstrated drastic threshold increases and auditory transmission deficits immediately after blast exposure, followed by substantial recovery during the window of 7-14 days postblast, although with some deficits remaining even after 2 mo. Challenging conditions and speech-like stimuli can better elucidate mild bTBI-induced auditory deficit during this period. Our results suggest multiphasic recovery and therefore potentially different time windows for treatment, and deficits can be best observed using a small battery of sound stimuli.NEW & NOTEWORTHY Few studies on blast-induced hearing deficits go beyond simple sounds and sparsely track postexposure. Therefore, the recovery arc for potential therapies and real-world listening is poorly understood. Evidence suggested multiple recovery phases over 2 mo postexposure. Hearing thresholds largely recovered within 14 days and partially explained recovery. However, midlatency responses, responses to amplitude modulation in noise, and speech-like pitch sweeps exhibited extended changes, implying persistent central auditory deficits and the importance of subclinical threshold shifts.

Multi-Electrode Array of Sensory Neurons as an In Vitro Platform to Identify the Nociceptive Response to Pharmaceutical Buffer Systems of Injectable Biologics.

PURPOSE: Pharmaceutical buffer systems, especially for injectable biologics such as monoclonal antibodies, are an important component of successful FDA-approved medications. Clinical studies indicate that buffer components may be contributing factors for increased injection site pain. METHODS: To determine the potential nociceptive effects of clinically relevant buffer systems, we developed an in vitro multi-electrode array (MEA) based recording system of rodent dorsal root ganglia (DRG) sensory neuron cell culture. This system monitors sensory neuron activity/firing as a surrogate of nociception when challenged with buffer components used in formulating monoclonal antibodies and other injectable biologics. RESULTS: We show that citrate salt and citrate mannitol buffer systems cause an increase in mean firing rate, burst frequency, and burst duration in DRG sensory neurons, unlike histidine or saline buffer systems at the same pH value. Lowering the concentration of citrate leads to a lower firing intensity of DRG sensory neurons. CONCLUSION: Increased activity/firing of DRG sensory neurons has been suggested as a key feature underlying nociception. Our results support the utility of an in vitro MEA assay with cultured DRG sensory neurons to probe the nociceptive potential of clinically relevant buffer components used in injectable biologics.

Evidence of acrolein in synovial fluid of dogs with osteoarthritis as a potential inflammatory biomarker.

BACKGROUND: Acrolein is a known pro-inflammatory toxic aldehyde, propagating cellular damage and tissue inflammation in humans and animal models of various diseases. Osteoarthritis (OA) has a significant inflammatory component; however, presence of acrolein in synovial fluid of joints with OA has not been previously reported. The first aim of this study was to evaluate evidence of acrolein in the synovial fluid of dogs with OA as well as in Control joints. The second aim was to determine if evidence of acrolein can be detected in synovial fluid samples that have been in a frozen state for long periods of time. METHODS: In this pilot clinical study, synovial fluid samples were prospectively collected (i.e., New samples) from a single joint of both clinically healthy (New Control, n = 5) and dogs with OA (New OA, n = 16) and frozen until the time of analysis. Additionally, frozen synovial fluid samples from a biobank (i.e., Old samples) were used to evaluate ability to detect evidence of acrolein in long-term stored samples (median of 4.89 years) in Old Control (n = 5) and Old OA (n = 5) samples. Measurements of acrolein in all synovial fluid samples was based on detection of its major protein adduct, N ε - (3-formyl-3, 4-dehydropiperidino)lysine (FDP-lysine), using the western blot method. Synovial fluid matrix metalloproteinase 2 (MMP2) was measured in all samples using the western blot method as a positive control of OA inflammation. RESULTS: Acrolein-lysine adduct was detected in both Control (n = 10) and OA (n = 21) groups in both Old and New samples. Acrolein-lysine adduct and MMP2 were detectable at a lower level in the Old compared to New synovial fluid samples; however, the differences were not statistically significant (p > 0.1). The measured MMP2 levels were significantly higher in the OA compared to Control group samples (p = 0.033), but not for acrolein-lysine adduct (p = 0.30). CONCLUSIONS: This study confirmed evidence of acrolein in canine synovial fluid of both OA and Control groups. Freezing of synovial fluid for up to 5 years does not appear to significantly affect the ability to detect acrolein-lysine adduct and MMP2 in these samples.

Acrolein-mediated alpha-synuclein pathology involvement in the early post-injury pathogenesis of mild blast-induced Parkinsonian neurodegeneration.

Survivors of blast-induced traumatic brain injury (bTBI) have increased susceptibility to Parkinson's disease (PD), characterized by α-synuclein aggregation and the progressive degeneration of nigrostriatal dopaminergic neurons. Using an established bTBI rat model, we evaluated the changes of α-synuclein and tyrosine hydroxylase (TH), known hallmarks of PD, and acrolein, a reactive aldehyde and marker of oxidative stress, with the aim of revealing key pathways leading to PD post-bTBI. Indicated in both animal models of PD and TBI, acrolein is likely a point of pathogenic convergence. Here we show that after a single mild bTBI, acrolein is elevated up to a week, systemically in urine, and in whole brain tissue, specifically the substantia nigra and striatum. Acrolein elevation is accompanied by heightened α-synuclein oligomerization, dopaminergic dysregulation, and acrolein/α-synuclein interaction in the same brain regions. We further show that acrolein can directly modify and oligomerize α-synuclein in vitro. Taken together, our data suggests acrolein likely plays an important role in inducing PD pathology following bTBI by encouraging α-synuclein aggregation. These results are expected to advance our understanding of the long-term post-bTBI pathological changes leading to the development of PD, and suggest intervention targets to curtail such pathology.

Point-of-Care Tissue Analysis Using Miniature Mass Spectrometer.

The combination of direct sampling ionization and miniature mass spectrometer presents a promising technical pathway of point-of-care analysis in clinical applications. In this work, a miniature mass spectrometry system was used for analysis of tissue samples. Direct tissue sampling coupled with extraction spray ionization was used with a home-built miniature mass spectrometer, Mini 12. Lipid species in tissue samples were well profiled in rat brain, kidney, and liver in a couple of minutes. By incorporating a photochemical (Paternò-Büchi) reaction, fast identification of lipid C═C location was realized. Relative quantitation of the lipid C═C isomer was performed by calculating the intensity ratio C═C diagnostic product ions, by which FA 18:1 (Δ9)/FA 18:1 (Δ11) was found to change significantly in mouse cancerous breast tissue samples. Accumulation of 2-hydroxylglutarate in human glioma samples, not in normal brains, can also be easily identified for rapid diagnosis.

Mapping Lipid C=C Location Isomers in Organ Tissues by Coupling Photochemical Derivatization and Rapid Extractive Mass Spectrometry.

Lipid desaturation plays important roles in biological processes and the disease states. Here, we report a simple but efficient method for mapping unsaturated phospholipids including the spatial distribution of lipid C=C location isomers in animal organs by coupling the C=C specific derivatization with direct analysis mass spectrometry (MS). Lipids are sampled directly by a stainless-steel wire from rat brain or kidney, extracted, and derivatized via the Paternò-Büchi reaction in a glass emitter of the nanoelectrospray ionization (nanoESI) source. Subsequent analysis by nanoESI-tandem mass spectrometry reveals C=C locations and relative quantities of lipid C=C location isomers. Unsaturated lipids, such as phospholipids and free fatty acids, have been identified with ion intensities spanning two orders of magnitude in rat brain. Typical sample consumption is less than 10 µg/measurement and the time for each analysis is about 3 min. This method should serve as a complementary method to high spatial resolution mass spectrometry imaging techniques, because it offers a streamlined experimental workflow for rapid profiling of lipids with C=C specificity to enable such applications as point-of-care disease diagnostics.

Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease.

Growing evidence suggests that oxidative stress plays a critical role in neuronal destruction characteristic of Parkinson's disease (PD). However, the molecular mechanisms of oxidative stress-mediated dopaminergic cell death are far from clear. In the current investigation, we tested the hypothesis that acrolein, an oxidative stress and lipid peroxidation (LPO) product, is a key factor in the pathogenesis of PD. Using a combination of in vitro, in vivo, and cell free models, coupled with anatomical, functional, and behavioral examination, we found that acrolein was elevated in 6-OHDA-injected rats, and behavioral deficits associated with 6-OHDA could be mitigated by the application of the acrolein scavenger hydralazine, and mimicked by injection of acrolein in healthy rats. Furthermore, hydralazine alleviated neuronal cell death elicited by 6-OHDA and another PD-related toxin, rotenone, in vitro. We also show that acrolein can promote the aggregation of alpha-synuclein, suggesting that alpha-synuclein self-assembly, a key pathological phenomenon in human PD, could play a role in neurotoxic effects of acrolein in PD models. These studies suggest that acrolein is involved in the pathogenesis of PD, and the administration of anti-acrolein scavengers such as hydralazine could represent a novel strategy to alleviate tissue damage and motor deficits associated with this disease.

Identification and quantitation of lipid C=C location isomers: A shotgun lipidomics approach enabled by photochemical reaction.

The field of lipidomics has been significantly advanced by mass spectrometric analysis. The distinction and quantitation of the unsaturated lipid isomers, however, remain a long-standing challenge. In this study, we have developed an analytical tool for both identification and quantitation of lipid C=C location isomers from complex mixtures using online Paternò-Büchi reaction coupled with tandem mass spectrometry (MS/MS). The potential of this method has been demonstrated with an implementation into shotgun lipid analysis of animal tissues. Among 96 of the unsaturated fatty acids and glycerophospholipids identified from rat brain tissue, 50% of them were found as mixtures of C=C location isomers; for the first time, to our knowledge, the quantitative information of lipid C=C isomers from a broad range of classes was obtained. This method also enabled facile cross-tissue examinations, which revealed significant changes in C=C location isomer compositions of a series of fatty acids and glycerophospholipid (GP) species between the normal and cancerous tissues.

Determination of acrolein-associated T1 and T2 relaxation times and noninvasive detection using nuclear magnetic resonance and magnetic resonance spectroscopy.

An estimated 3.3 million people are living with a traumatic brain injury (TBI)-associated morbidity. Currently, only invasive and sacrificial methods exist to study neurochemical alterations following TBI. Nuclear magnetic resonance methods-magnetic resonance imaging (MRI) and spectroscopy (MRS)-are powerful tools which may be used non-invasively to diagnose a range of medical issues. These methods can be utilized to explore brain functionality, connectivity, and biochemistry. Unfortunately, many of the commonly studied brain metabolites (e.g., N-acetyl-aspartate, choline, creatine) remain relatively stable following mild to moderate TBI and may not be suitable for longitudinal assessment of injury severity and location. Therefore, a critical need exists to investigate alternative biomarkers of TBI, such as acrolein. Acrolein is a byproduct of lipid peroxidation and accumulates following damage to neuronal tissue. Acrolein has been shown to increase in post-mortem rat brain tissue following TBI. However, no methods exist to noninvasively quantify acrolein in vivo. Currently, we have characterized the T1 and T2 of acrolein via NMR saturation recovery and Carr-Purcell-Meiboom-Gill experiments, accordingly, to maximize the signal-to-noise ratio of acrolein obtained with MRS. Additionally, we have quantified acrolein in water and whole-brain phantom using PRESS MRS and standard post-processing methods. With this potential novel biomarker for assessing TBI, we can investigate methods for predicting acute and chronic neurological dysfunction in humans and animal models. By quantifying and localizing acrolein with MRS, and investigating neurological outcomes associated with in vivo measures, patient-specific interventions could be developed to decrease TBI-associated morbidity and improve quality of life.

Rapid In Situ Profiling of Lipid C═C Location Isomers in Tissue Using Ambient Mass Spectrometry with Photochemical Reactions.

Rapid and in situ profiling of lipids using ambient mass spectrometry (AMS) techniques has great potential for clinical diagnosis, biological studies, and biomarker discovery. In this study, the online photochemical reaction involving carbon-carbon double bonds was coupled with a surface sampling technique to develop a direct tissue-analysis method with specificity to lipid C═C isomers. This method enabled the in situ analysis of lipids from the surface of various tissues or tissue sections, which allowed the structural characterization of lipid isomers within 2 min. Under optimized reaction conditions, we have established a method for the relative quantitation of lipid C═C location isomers by comparing the abundances of the diagnostic ions arising from each isomer, which has been proven effective through the established linear relationship ( R2 = 0.999) between molar ratio and diagnostic ion ratio of the FA 18:1 C═C location isomers. This method was then used for the rapid profiling of unsaturated lipid C═C isomers in the sections of rat brain, lung, liver, spleen, and kidney, as well as in normal and diseased rat tissues. Quantitative information on FA 18:1 and PC 16:0-18:1 C═C isomers was obtained, and significant differences were observed between different samples. To the best of our knowledge, this is the first study to report the direct analysis of lipid C═C isomers in tissues using AMS. Our results demonstrated that this method can serve as a rapid analytical approach for the profiling of unsaturated lipid C═C isomers in biological tissues and should contribute to functional lipidomics and clinical diagnosis.

Differences in postinjury auditory system pathophysiology after mild blast and nonblast acute acoustic trauma.

Hearing difficulties are the most commonly reported disabilities among veterans. Blast exposures during explosive events likely play a role, given their propensity to directly damage both peripheral (PAS) and central auditory system (CAS) components. Postblast PAS pathophysiology has been well documented in both clinical case reports and laboratory investigations. In contrast, blast-induced CAS dysfunction remains understudied but has been hypothesized to contribute to an array of common veteran behavioral complaints, including learning, memory, communication, and emotional regulation. This investigation compared the effects of acute blast and nonblast acoustic impulse trauma in adult male Sprague-Dawley rats. An array of audiometric tests were utilized, including distortion product otoacoustic emissions (DPOAE), auditory brain stem responses (ABR), middle latency responses (MLR), and envelope following responses (EFRs). Generally, more severe and persistent postinjury central auditory processing (CAP) deficits were observed in blast-exposed animals throughout the auditory neuraxis, spanning from the cochlea to the cortex. DPOAE and ABR results captured cochlear and auditory nerve/brain stem deficits, respectively. EFRs demonstrated temporal processing impairments suggestive of functional damage to regions in the auditory brain stem and the inferior colliculus. MLRs captured thalamocortical transmission and cortical activation impairments. Taken together, the results suggest blast-induced CAS dysfunction may play a complementary pathophysiological role to maladaptive neuroplasticity of PAS origin. Even mild blasts can produce lasting hearing impairments that can be assessed with noninvasive electrophysiology, allowing these measurements to serve as simple, effective diagnostics.NEW & NOTEWORTHY Blasts exposures often produce hearing difficulties. Although cochlear damage typically occurs, the downstream effects on central auditory processing are less clear. Moreover, outcomes were compared between individuals exposed to the blast pressure wave vs. those who experienced the blast noise without the pressure wave. It was found that a single blast exposure produced changes at all stages of the ascending auditory path at least 4 wk postblast, whereas blast noise alone produced largely transient changes.

Dimercaprol is an acrolein scavenger that mitigates acrolein-mediated PC-12 cells toxicity and reduces acrolein in rat following spinal cord injury.

Acrolein is one of the most toxic byproducts of lipid peroxidation, and it has been shown to be associated with multiple pathological processes in trauma and diseases, including spinal cord injury, multiple sclerosis, and Alzheimer's disease. Therefore, suppressing acrolein using acrolein scavengers has been suggested as a novel strategy of neuroprotection. In an effort to identify effective acrolein scavengers, we have confirmed that dimercaprol, which possesses thiol functional groups, could bind and trap acrolein. We demonstrated the reaction between acrolein and dimercaprol in an abiotic condition by nuclear magnetic resonance spectroscopy. Specifically, dimercaprol is able to bind to both the carbon double bond and aldehyde group of acrolein. Its acrolein scavenging capability was further demonstrated by in vitro results that showed that dimercaprol could significantly protect PC-12 cells from acrolein-mediated cell death in a dose-dependent manner. Furthermore, dimercaprol, when applied systemically through intraperitoneal injection, could significantly reduce acrolein contents in spinal cord tissue following a spinal cord contusion injury in rats, a condition known to have elevated acrolein concentration. Taken together, dimercaprol may be an effective acrolein scavenger and a viable candidate for acrolein detoxification.

Acrolein-mediated conduction loss is partially restored by K⁺ channel blockers.

Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure and activation of juxtaparanodal voltage-gated K(+) channels due to myelin damage leads to conduction block, and K(+) channel blockers have long been studied as a means for restoring axonal conduction in spinal cord injury (SCI) and multiple sclerosis (MS). In this study, we have found that 100 µM K(+) channel blockers 4-aminopyridine-3-methanol (4-AP-3-MeOH), and to a lesser degree 4-aminopyridine (4-AP), can significantly restore compound action potential (CAP) conduction in spinal cord tissue following acrolein-mediated myelin damage using a well-established ex vivo SCI model. In addition, 4-AP-3-MeOH can effectively restore CAP conduction in acrolein-damaged axons with a range of concentrations from 0.1 to 100 µM. We have also shown that while both compounds at 100 µM showed no preference of small- and large-caliber axons when restoring CAP conduction, 4-AP-3-MeOH, unlike 4-AP, is able to augment CAP amplitude while causing little change in axonal responsiveness measured in refractory periods and response to repetitive stimuli. In a prior study, we show that 4-AP-3-MeOH was able to functionally rescue mechanically injured axons. In this investigation, we conclude that 4-AP-3-MeOH is an effective K(+) channel blocker in restoring axonal conduction following both primary (physical) and secondary (chemical) insults. These findings also suggest that 4-AP-3-MeOH is a viable alternative of 4-AP for treating myelin damage and improving function following central nervous system trauma and neurodegenerative diseases.