Developmental toxicity and estrogenic activity of antimicrobial phenolic-branched fatty acids using in silico simulations and in vivo and in vitro bioassay.

Due to the growing safety and environmental concerns associated with biocides, phenolic-soy branched chain fatty acids (phenolic-soy BCFAs) are synthesized as new bio-based antimicrobial agents. Safety evaluation is essential before the wide adoption of these new antimicrobial products. This study was initiated to evaluate the safety of four phenolic-soy BCFAs (with phenol, thymol, carvacrol, or creosote branches). Methyl-branched iso-oleic acid, phenol, and creosote were included in the study as controls. In silico toxicity simulation tools predicted that the phenolic BCFAs had much higher toxicities to aquatic organisms than free phenolics did, while the opposite was predicted for rats. The developmental toxicity of four phenolic-soy BCFAs was assessed using an in vivo chicken embryonic assay. Results showed that creosote-soy BCFA had much lower mortality rates than creosote at the same dosages. Additionally, creosote-soy BCFA and methyl-branched iso-oleic acid induced minimal estrogenic activity in the concentration range of 10 nM - 1 µM. Carvacrol-soy BCFA treatments significantly increased (p < 0.05) oxidative stress levels with higher thiobarbituric acid reactive substances in the livers of chicken embryos. Altogether, the phenolic-soy BCFAs, especially creosote-soy BCFA, reported in this study are potentially promising and safer bio-based antimicrobial products.

Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer's Disease and Diabetes-Related Dementia Rat Models.

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Correction: Novel aerosol treatment of airway hyper-reactivity and inflammation in a murine model of asthma with a soluble epoxide hydrolase inhibitor.

[This corrects the article DOI: 10.1371/journal.pone.0266608.].

The role of recurrent trauma on post-traumatic stress disorder symptoms and substance use among trauma exposed youth.

Comorbidity between post-traumatic stress disorder (PTSD) and substance use disorder may be explained by a prospective trauma risk conferred by both conditions. The current study modeled concurrent and prospective associations of trauma, PTSD symptoms, and substance use (SU) behavior among trauma exposed youth (ages 8-20). Clinical interviews assessed trauma exposure, PTSD symptom severity, and SU behavior at baseline and at six- and 12-month follow up study visits (N = 2,069). Structural equation models assessed the associations of trauma, PTSD symptoms, and SU behavior. Lifetime trauma was associated with more severe PTSD symptoms and SU behaviors, whereas trauma exposure during the study was only associated with PTSD symptoms. PTSD symptom severity was prospectively associated with trauma exposure. PTSD symptom severity and SU behavior at follow-up study visits were prospectively associated. These results highlight the dynamic interplay between trauma, PTSD symptoms, and SU behavior during youth, a developmental period during which complex psychiatric presentations can have longstanding consequences for health.

Comparing diagnostic criteria for posttraumatic stress disorder in a diverse sample of trauma-exposed youth.

Divergent conceptualization of posttraumatic stress disorder (PTSD) within the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) and International Statistical Classification of Diseases and Related Health Problems (11th ed..; ICD-11) significantly confounds both research and practice. Using a diverse sample of trauma-exposed youth (N = 1,542, age range: 8-20 years), we compared these two diagnostic approaches along with an expanded version of the ICD-11 PTSD criteria that included three additional reexperiencing symptoms (ICD-11+). Within the sample, PTSD was more prevalent using the DSM-5 criteria (25.7%) compared to the ICD-11 criteria (16.0%), with moderate agreement between these diagnostic systems, κ = .57. The inclusion of additional reexperiencing symptoms (i.e., ICD-11+) reduced this discrepancy in prevalence (24.7%) and increased concordance with DSM-5 criteria, κ = .73. All three PTSD classification systems exhibited similar comorbidity rates with major depressive episode (MDE) or generalized anxiety disorder (GAD; 78.0%-83.6%). Most youths who met the DSM-5 PTSD criteria also met the criteria for ICD-11 PTSD, MDE, or GAD (88.4%), and this proportion increased when applying the ICD-11+ criteria (95.5%). Symptom-level analyses identified reexperiencing/intrusions and negative alterations in cognition and mood symptoms as primary sources of discrepancy between the DSM-5 and ICD-11 PTSD diagnostic systems. Overall, these results challenge assertions that nonspecific distress and diagnostically overlapping symptoms within DSM-5 PTSD inflate comorbidity with depressive and anxiety disorders. Further, they support the argument that the DSM-5 PTSD criteria can be refined and simplified without reducing the overall prevalence of psychiatric diagnoses in youth.

The role of resilience in the development of depression, anxiety, and post-traumatic stress disorder after trauma in children and adolescents.

This investigation, conducted within the Texas Childhood Trauma Research Network, investigated the prospective relationships between resiliency and emergent internalizing symptoms among trauma-exposed youth. The cohort encompassed 1262 youth, aged 8-20, from twelve health-related institutions across Texas, who completed assessments at baseline and one- and six-month follow-ups for resiliency, symptoms of depression, generalized anxiety, posttraumatic stress disorder (PTSD), and other demographic and clinical characteristics. At baseline, greater resilience was positively associated with older age, male (vs female) sex assigned at birth, and history of mental health treatment. Unadjusted for covariates, higher baseline resilience was associated with greater prospective depression and PTSD symptoms but not anxiety symptoms. Upon adjusting for demographic and clinical factors, higher baseline resilience was no longer associated with depression, PTSD, or anxiety symptoms. Our analyses demonstrate that the predictive value of resilience on psychopathology is relatively small compared to more readily observable clinical and demographic factors. These data suggest a relatively minor prospective role of resilience in protecting against internalizing symptoms among trauma-exposed youth and highlight the importance of controlling for relevant youth characteristics when investigating a protective effect of resilience on internalizing symptoms.

An Occupational Perspective on Psychedelic Therapy: A Scoping Review.

Background. Interest in the use of psychedelics for mental health therapy is burgeoning. Qualitative research methods are increasingly used to understand patient's experiences; however, there is a lack of literature that explores psychedelic use from an occupational perspective. Purpose. To conduct a scoping review of qualitative literature on the experiences of psychedelic use for the purpose of mental health therapy, through an occupational lens. Key Issues. Wilcock's occupational perspective of health was employed to analyze the use of psychedelics in mental health from an occupational perspective. Despite heterogeneous therapy contexts and substances used, patients reported comparable benefits regarding occupational engagement, such as increased mindfulness and autonomy in doing, a renewed sense of being, greater motivation to grow and become, and an improved sense of connection and belonging. Implications. This review demonstrates how psychedelic use in the context of mental health support can be experienced as a meaningful occupation and may contribute to overall health. In turn, this review highlights the utility of an occupational perspective for "non-sanctioned" or stigmatized occupations like psychedelic use, as well as the need for more research on psychedelic use from an occupational perspective. Using an occupational perspective of health can help to de-stigmatize psychedelic use as a meaningful occupation, rather than a deviant one, and shed light on how psychedelics may also positively impact one's participation in everyday life and overall health.

Characterizing patterns of substance use in trauma exposed youth.

OBJECTIVE: Previous work investigating the impact of childhood trauma on substance use and co-occurring psychiatric disorders has primarily been conducted in adults or on specific trauma types. This limits understanding of traumas impact in childhood and how different types of traumas play a role. We sought to characterize substance use in a sample of trauma-exposed youth in the context of psychiatric comorbidities. METHOD: 1152 youth from the Texas Childhood Trauma Research Network (TX-CTRN) that were exposed to at least one trauma meeting DSM-5 Criterion A were assessed for current substance use and psychiatric diagnoses. Latent class analysis was used to identify patterns of substance use. To characterize these patterns, we examined if demographics, number of trauma types experienced, or childhood psychiatric disorders predicted class membership. RESULTS: We identified four primary patterns of substance use: Non-use (66.1%), predominantly alcohol use (19.7%), predominantly cannabis use (4.5%), and polysubstance use (9.7%). Compared to the non-users, polysubstance users tended to be older, Non-Hispanic White, have experienced more types of trauma. They were also more likely to have fulfilled diagnostic criteria for suicidality and ADHD. Comparisons among the substance using classes were more nuanced. CONCLUSION: The findings highlight the need for universal assessments of trauma, substance misuse, and mental health symptoms in youth as the presence or absence of their co-occurrence has implications for treatment.

Aflatoxin B1 Increases Soluble Epoxide Hydrolase in the Brain and Induces Neuroinflammation and Dopaminergic Neurotoxicity.

Parkinson's disease (PD) is an increasingly common neurodegenerative movement disorder with contributing factors that are still largely unexplored and currently no effective intervention strategy. Epidemiological and pre-clinical studies support the close association between environmental toxicant exposure and PD incidence. Aflatoxin B1 (AFB1), a hazardous mycotoxin commonly present in food and environment, is alarmingly high in many areas of the world. Previous evidence suggests that chronic exposure to AFB1 leads to neurological disorders as well as cancer. However, whether and how aflatoxin B1 contributes to the pathogenesis of PD is poorly understood. Here, oral exposure to AFB1 is shown to induce neuroinflammation, trigger the α-synuclein pathology, and cause dopaminergic neurotoxicity. This was accompanied by the increased expression and enzymatic activity of soluble epoxide hydrolase (sEH) in the mouse brain. Importantly, genetic deletion or pharmacological inhibition of sEH alleviated the AFB1-induced neuroinflammation by reducing microglia activation and suppressing pro-inflammatory factors in the brain. Furthermore, blocking the action of sEH attenuated dopaminergic neuron dysfunction caused by AFB1 in vivo and in vitro. Together, our findings suggest a contributing role of AFB1 to PD etiology and highlight sEH as a potential pharmacological target for alleviating PD-related neuronal disorders caused by AFB1 exposure.

MCK2-mediated MCMV infection of macrophages and virus dissemination to the salivary gland depends on MHC class I molecules.

Murine cytomegalovirus (MCMV) infection of macrophages relies on MCMV-encoded chemokine 2 (MCK2), while infection of fibroblasts occurs independently of MCK2. Recently, MCMV infection of both cell types was found to be dependent on cell-expressed neuropilin 1. Using a CRISPR screen, we now identify that MCK2-dependent infection requires MHC class Ia/ß-2-microglobulin (B2m) expression. Further analyses reveal that macrophages expressing MHC class Ia haplotypes H-2b and H-2d, but not H-2k, are susceptible to MCK2-dependent infection with MCMV. The importance of MHC class I expression for MCK2-dependent primary infection and viral dissemination is highlighted by experiments with B2m-deficient mice, which lack surface expression of MHC class I molecules. In those mice, intranasally administered MCK2-proficient MCMV mimics infection patterns of MCK2-deficient MCMV in wild-type mice: it does not infect alveolar macrophages and subsequently fails to disseminate into the salivary glands. Together, these data provide essential knowledge for understanding MCMV-induced pathogenesis, tissue targeting, and virus dissemination.

Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon.

Aging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed pathological mechanisms and endogenous regulators underlying colon aging are still largely unknown. Here, we report that the expression and activity of the soluble epoxide hydrolase (sEH) enzyme are increased in the colon of aged mice. Importantly, genetic knockout of sEH attenuated the age-related upregulation of senescent markers p21, p16, Tp53, and ß-galactosidase in the colon. Moreover, sEH deficiency alleviated aging-associated endoplasmic reticulum (ER) stress in the colon by reducing both the upstream regulators Perk and Ire1 as well as the downstream pro-apoptotic effectors Chop and Gadd34. Furthermore, treatment with sEH-derived linoleic acid metabolites, dihydroxy-octadecenoic acids (DiHOMEs), decreased cell viability and increased ER stress in human colon CCD-18Co cells in vitro. Together, these results support that the sEH is a key regulator of the aging colon, which highlights its potential application as a therapeutic target for reducing or treating age-related diseases in the colon.

Establishing a training plan and estimating inter-rater reliability across the multi-site Texas childhood trauma research network.

OBJECTIVE: Minimal guidance is available in the literature to develop protocols for training non-clinician raters to administer semi-structured psychiatric interviews in large, multi-site studies. Previous work has not produced standardized methods for maintaining rater quality control or estimating interrater reliability (IRR) in such studies. Our objective is to describe the multi-site Texas Childhood Trauma Research Network (TX-CTRN) rater training protocol and activities used to maintain rater calibration and evaluate protocol effectiveness. METHODS: Rater training utilized synchronous and asynchronous didactic learning modules, and certification involved critique of videotaped mock scale administration. Certified raters attended monthly review meetings and completed ongoing scoring exercises for quality assurance purposes. Training protocol effectiveness was evaluated using individual measure and pooled estimated IRRs for three key study measures (TESI-C, CAPS-CA-5, MINI-KID [Major Depressive Episodes - MDE & Posttraumatic Stress Disorder - PTSD modules]). A random selection of video-recorded administrations of these measures was evaluated by three certified raters to estimate agreement statistics, with jackknife (on the videos) used for confidence interval estimation. Kappa, weighted kappa and intraclass correlations were calculated for study measure ratings. RESULTS: IRR agreement across all measures was strong (TESI-C median kappa 0.79, lower 95% CB 0.66; CAPS-CA-5 median weighted kappa 0.71 (0.62), MINI-MDE median kappa 0.71 (0.62), MINI-PTSD median kappa 0.91 (0.9). The combined estimated ICC was ≥0.86 (lower CBs ≥0.69). CONCLUSIONS: The protocol developed by TX-CTRN may serve as a model for other multi-site studies that require comprehensive non-clinician rater training, quality assurance guidelines, and a system for assessing and estimating IRR.

Inhibition of soluble epoxide hydrolase reduces paraquat neurotoxicity in rodents.

Given the paucity of research surrounding the effect of chronic paraquat on striatal neurotoxicity, there is a need for further investigation into the neurotoxic effects of paraquat in mouse striatum. Furthermore, while previous studies have shown that inhibiting soluble epoxide hydrolase mitigates MPTP-mediated endoplasmic reticulum stress in mouse striatum, its effect on paraquat toxicity is still unknown. Thus, this study attempts to observe changes in inflammatory and endoplasmic reticulum stress markers in mouse striatum following chronic paraquat administration to determine whether inhibiting soluble epoxide hydrolase mitigates paraquat-induced neurotoxicity and whether it can reduce TLR4-mediated inflammation in primary astrocytes and microglia. Our results show that while the pro-inflammatory effect of chronic paraquat is small, there is a significant induction of inflammatory and cellular stress markers, such as COX2 and CHOP, that can be mitigated through a prophylactic administration of a soluble epoxide hydrolase inhibitor.

Aflatoxin B1 exposure disrupts the intestinal immune function via a soluble epoxide hydrolase-mediated manner.

Aflatoxin B1 (AFB1) contamination in food and feed leads to severe global health problems. Acting as the frontier immunological barrier, the intestinal mucosa is constantly challenged by exposure to foodborne toxins such as AFB1 via contaminated diets, but the detailed toxic mechanism and endogenous regulators of AFB1 toxicity are still unclear. Here, we showed that AFB1 disrupted intestinal immune function by suppressing macrophages, especially M2 macrophages, and antimicrobial peptide-secreting Paneth cells. Using an oxylipinomics approach, we identified that AFB1 immunotoxicity is associated with decreased epoxy fatty acids, notably epoxyeicosatrienoic acids, and increased soluble epoxide hydrolase (sEH) levels in the intestine. Furthermore, sEH deficiency or inhibition rescued the AFB1-compromised intestinal immunity by restoring M2 macrophages as well as Paneth cells and their-derived lysozyme and α-defensin-3 in mice. Altogether, our study demonstrates that AFB1 exposure impairs intestinal immunity, at least in part, in a sEH-mediated way. Moreover, the present study supports the potential application of pharmacological intervention by inhibiting the sEH enzyme in alleviating intestinal immunotoxicity and associated complications caused by AFB1 global contamination.

Computational design of peptides to target NaV1.7 channel with high potency and selectivity for the treatment of pain.

The voltage-gated sodium NaV1.7 channel plays a key role as a mediator of action potential propagation in C-fiber nociceptors and is an established molecular target for pain therapy. ProTx-II is a potent and moderately selective peptide toxin from tarantula venom that inhibits human NaV1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human NaV1.7 channels. Functional testing of designed peptides using electrophysiology identified the PTx2-3127 and PTx2-3258 peptides with IC50s of 7 nM and 4 nM for hNaV1.7 and more than 1000-fold selectivity over human NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.8, and NaV1.9 channels. PTx2-3127 inhibits NaV1.7 currents in mouse and human sensory neurons and shows efficacy in rat models of chronic and thermal pain when administered intrathecally. Rationally designed peptide inhibitors of human NaV1.7 channels have transformative potential to define a new class of biologics to treat pain.

A Unique Role of the Human Cytomegalovirus Small Capsid Protein in Capsid Assembly.

Morphogenesis of herpesvirus particles is highly conserved; however, the capsid assembly and genome packaging of human cytomegalovirus (HCMV) exhibit unique features. Examples of these include the essential role of the small capsid protein (SCP) and the existence of the ß-herpesvirus-specific capsid-associated protein pp150. SCP and pp150, as well as the UL77 and UL93 proteins, are important capsid constituents, yet their precise mechanism of action is elusive. Here, we analyzed how deletion of the open reading frames (ORFs) encoding pUL77, pUL93, pp150, or SCP affects the protein composition of nuclear capsids. This was achieved by generating HCMV genomes lacking the respective genes, combined with a highly efficient transfection technique that allowed us to directly analyze these mutants in transfected cells. While no obvious effects were observed when pUL77, pUL93, or pp150 was missing, the absence of SCP impeded capsid assembly due to strongly reduced amounts of major capsid protein (MCP). Vice versa, when MCP was lacking, SCP became undetectable, indicating a mutual dependence of SCP and MCP for establishing appropriate protein levels. The SCP domain mediating stable MCP levels could be narrowed down to a C-terminal helix known to convey MCP binding. Interestingly, an SCP-EGFP (enhanced green fluorescent protein) fusion protein which also impaired the production of infectious progeny acted in a different manner, as capsid assembly was not abolished; however, SCP-EGFP-harboring capsids were devoid of DNA and trapped in paracrystalline nuclear structures. These results indicate that SCP is essential in HCMV because of its impact on MCP levels and reveal SCP as a potential target for antiviral inhibitors. IMPORTANCE Human cytomegalovirus (HCMV) is a ubiquitous pathogen causing life-threatening disease in immunocompromised individuals. Virus-specific processes such as capsid assembly and genome packaging can be exploited to design new antiviral strategies. Here, we report on a novel function of the HCMV small capsid protein (SCP), namely, ensuring stable levels of major capsid protein (MCP), thereby governing capsid assembly. Furthermore, we discovered a mutual dependence of the small and major capsid proteins to guarantee appropriate levels of the other respective protein and were able to pin down the SCP domain responsible for this effect to a region previously shown to mediate binding to the major capsid protein. In summary, our data contribute to the understanding of how SCP plays an essential part in the HCMV infection cycle. Moreover, disrupting the SCP-MCP interface may provide a starting point for the development of novel antiviral drugs.

In Vivo Imaging of Retinal and Choroidal Morphology and Vascular Plexuses of Vertebrates Using Swept-Source Optical Coherence Tomography.

Purpose: To perform in vivo evaluation of the structural morphology and vascular plexuses of the neurosensory retina and choroid across vertebrate species using swept-source optical coherence tomography (SS-OCT) and SS-OCT angiography (SS-OCTA) imaging. Methods: A custom-built SS-OCT system with an incorporated flexible imaging arm was used to acquire the three-dimensional (3D) retinal OCT and vascular OCTA data of five different vertebrates: a mouse (C57BL/6J), a rat (Long Evans), a gray short-tailed opossum (Monodelphis domestica), a white sturgeon (Acipenser transmontanus), and a great horned owl (Bubo virginianus). Results: In vivo structural morphology of the retina and choroid, as well as en face OCTA images of retinal and choroidal vasculature of all species were generated. The retinal morphology and vascular plexuses were similar between rat and mouse, whereas distinct choroidal and paired superficial vessels were observed in the opossum retina. The retinal and vascular structure of the sturgeon, as well as the pecten oculi and overlying the avascular and choroidal vasculature in the owl retina are reported in vivo. Conclusions: A high-quality two-dimensional and 3D in vivo visualization of the retinal structures and en face visualization of the retina and choroidal vascular plexus of vertebrates was possible. Our studies affirm that SS-OCT and SS-OCTA are viable methods for evaluating the in vivo retinal and choroidal structure across terrestrial, aquatic, and aerial vertebrates. Translational Relevance: In vivo characterization of retinal morphology and vasculature plexus of multiple species using SS-OCT and SS-OCTA imaging can increase the pool of species available as models of human retinal diseases.

Novel aerosol treatment of airway hyper-reactivity and inflammation in a murine model of asthma with a soluble epoxide hydrolase inhibitor.

Asthma currently affects more than 339 million people worldwide. In the present preliminary study, we examined the efficacy of a new, inhalable soluble epoxide hydrolase inhibitor (sEHI), 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), to attenuate airway inflammation, mucin secretion, and hyper-responsiveness (AHR) in an ovalbumin (OVA)-sensitized murine model. Male BALB/c mice were divided into phosphate-buffered saline (PBS), OVA, and OVA+TPPU (2- or 6-h) exposure groups. On days 0 and 14, the mice were administered PBS or sensitized to OVA in PBS. From days 26-38, seven challenge exposures were performed with 30 min inhalation of filtered air or OVA alone. In the OVA+TPPU groups, a 2- or 6-h TPPU inhalation preceded each 30-min OVA exposure. On day 39, pulmonary function tests (PFTs) were performed, and biological samples were collected. Lung tissues were used to semi-quantitatively evaluate the severity of inflammation and airway constriction and the volume of stored intracellular mucosubstances. Bronchoalveolar lavage (BAL) and blood samples were used to analyze regulatory lipid mediator profiles. Significantly (p < 0.05) attenuated alveolar, bronchiolar, and pleural inflammation; airway resistance and constriction; mucosubstance volume; and inflammatory lipid mediator levels were observed with OVA+TPPU relative to OVA alone. Cumulative findings indicated TPPU inhalation effectively inhibited inflammation, suppressed AHR, and prevented mucosubstance accumulation in the murine asthmatic model. Future studies should determine the pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion) and pharmacodynamics (i.e., concentration/dose responses) of inhaled TPPU to explore its potential as an asthma-preventative or -rescue treatment.

Soluble epoxide hydrolase inhibition alleviates chemotherapy induced neuropathic pain.

Chemotherapy induced peripheral neuropathy (CIPN) is a particularly pernicious form of neuropathy and the associated pain is the primary dose-limiting factor of life-prolonging chemotherapy treatment. The prevalence of CIPN is high and can last long after treatment has been stopped. Currently, late in the COVID-19 pandemic, there are still increased psychological pressures on cancer patients as well as additional challenges in providing analgesia for them. These include the risks of nonsteroidal anti-inflammatory drug (NSAID) analgesics potentially masking early infection symptoms and the immunosuppression of steroidal and opiate based approaches. Even without these concerns, CIPN is often inadequately treated with few therapies that offer significant pain relief. The experiments we report use soluble epoxide hydrolase inhibitors (sEHI) which relieved this intractable pain in preclinical models. Doses of EC5026, an IND candidate intended to treat neuropathic pain, elicited dose dependent analgesic responses in multiple models including platinum-based, taxane, and vinca alkaloid-based CIPN pain in Sprague Dawley rats. At the same time as a class, the sEHI are known to result in fewer debilitating side effects of other analgesics, likely due to their novel mechanism of action. Overall, the observed dose-dependent analgesia in both male and female rats across multiple models of chemotherapy induced neuropathic pain holds promise as a useful tool when translated to the clinic.