Intestinal Disorder in Zebrafish Larvae (Danio rerio): The Protective Action of N-Palmitoylethanolamide-oxazoline

IBD (Inflammatory Bowel Disease) is an inflammatory disease affecting the gastrointestinal tract that is common in both humans and veterinarians. Several studies have revealed the pharmacological properties of the oxazoline of palmitoylethanolamide (PEAOXA). Zebrafish larvae were exposed to sodium dextran sulphate (DSS) to induce enterocolitis and study the protective action of PEAOXA. After repetitive exposure with 0.25% DSS, larvae presented gut alteration with an increase in mucus production. Furthermore, DSS exposure induced an increase in the inflammatory pathway in the intestine, related to an increase in the Endoplasmic-reticulum (ER) stress genes. PEAOXA exposure at a concentration of 10 mg/L decreased the DSS-induced gut damage and mucus production, as well as being able to reduce the inflammatory and ER stress-related genes expression. In conclusion, our results demonstrate that the alterations induced by repeated exposure to DSS were counteracted by PEAOXA action that was able to inhibit the increase in inflammation and ER stress involved in the progression of enterocolitis.

Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia

Mycobacterium tuberculosis (Mtb) infection is difficult to treat because Mtb spends the majority of its life cycle in a nonreplicating (NR) state. Since NR Mtb is highly tolerant to antibiotic effects and can mutate to become drug resistant (DR), our conventional tuberculosis (TB) treatment is not effective. Thus, a novel strategy to kill NR Mtb is required. Accumulating evidence has shown that repetitive exposure to sublethal doses of antibiotics enhances the level of drug tolerance, implying that NR Mtb is formed by adaptive metabolic remodeling. As such, metabolic modulation strategies to block the metabolic remodeling needed to form NR Mtb have emerged as new therapeutic options. Here, we modeled in vitro NR Mtb using hypoxia, applied isotope metabolomics, and revealed that phosphoenolpyruvate (PEP) is nearly completely depleted in NR Mtb. This near loss of PEP reduces PEP-carbon flux toward multiple pathways essential for replication and drug sensitivity. Inversely, supplementing with PEP restored the carbon flux and the activities of the foregoing pathways, resulting in growth and heightened drug susceptibility of NR Mtb, which ultimately prevented the development of DR. Taken together, PEP depletion in NR Mtb is associated with the acquisition of drug tolerance and subsequent emergence of DR, demonstrating that PEP treatment is a possible metabolic modulation strategy to resensitize NR Mtb to conventional TB treatment and prevent the emergence of DR.

A single exposure to altered auditory feedback causes observable sensorimotor adaptation in speech

Sensory errors caused by perturbations to movement-related feedback induce two types of behavioral changes that oppose the perturbation: rapid compensation within a movement, as well as longer-term adaptation of subsequent movements. Although adaptation is hypothesized to occur whenever a sensory error is perceived (including after a single exposure to altered feedback), adaptation of articulatory movements in speech has only been observed after repetitive exposure to auditory perturbations, questioning both current theories of speech sensorimotor adaptation as well as the universality of more general theories of adaptation. Thus, positive evidence for the hypothesized single-exposure or 'one-shot' learning would provide critical support for current theories of speech sensorimotor learning and control and align adaptation in speech more closely with other motor domains. We measured one-shot learning in a large dataset in which participants were exposed to intermittent, unpredictable auditory perturbations to their vowel formants (the resonant frequencies of the vocal tract that distinguish between different vowels). On each trial, participants spoke a word out loud while their first formant was shifted up, shifted down, or remained unshifted. We examined whether the perturbation on a given trial affected speech on the subsequent, unperturbed trial. We found that participants adjusted their first formant in the opposite direction of the preceding shift, demonstrating that learning occurs even after a single auditory perturbation as predicted by current theories of sensorimotor adaptation. While adaptation and the preceding compensation responses were correlated, this was largely due to differences across individuals rather than within-participant variation from trial to trial. These findings are more consistent with theories that hypothesize adaptation is driven directly by updates to internal control models than those that suggest adaptation results from incorporation of feedback responses from previous productions.

The Changes in Expression of NaV1.7 and NaV1.8 and the Effects of the Inhalation of Their Blockers in Healthy and Ovalbumin-Sensitized Guinea Pig Airways

Background: The presented study evaluated the suppositional changes in the airway expression of Nav1.8 and Nav1.7 and their role in the airway defense mechanisms in healthy animals and in an experimental asthma model. Methods: The effects of the blockers inhalation on the reactivity of guinea pig airways, number of citric-acid-induced coughs and ciliary beating frequency (CBF) were tested in vivo. Chronic inflammation simulating asthma was induced by repetitive exposure to ovalbumin. The expression of Nav1.7 and Nav1.8 was examined by ELISA. Results: The Nav 1.8 blocker showed complex antitussive and bronchodilatory effects and significantly regulated the CBF in healthy and sensitized animals. The Nav1.7 blockers significantly inhibited coughing and participated in CBF control in the ovalbumin-sensitized animals. The increased expression of the respective ion channels in the sensitized animals corresponded to changes in CBF regulation. The therapeutic potency of the Nav1.8 blocker was evidenced in combinations with classic bronchodilators. Conclusion: The allergic-inflammation-upregulated expression of Nav1.7 and Nav1.8 and corresponding effects of blocker inhalation on airway defense mechanisms, along with the Nav1.8 blocker’s compatibility with classic antiasthmatic drugs, bring novel possibilities for the treatment of various respiratory diseases. However, the influence of the Nav1.8 blocker on CBF requires further investigation.

The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma

Repetitive exposure of Rag1−/− mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3–15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma. ATAC-seq demonstrated a distinct epigenetic landscape of memory ILC2s and identified Bach2 and AP1 (JunD and Fosl2) motifs as major drivers of altered gene accessibility. scRNA-seq, gene knockout, and signaling studies suggest that repetitive allergenic stress induces a gene repression program involving Nr4a2, Zeb1, Bach2, and JunD and a preparedness program involving Fhl2, FosB, Stat6, Srebf2, and MPP7 in memory ILC2s. A mutually regulated balance between these two programs establishes and maintains memory. The preparedness program (e.g., Fhl2) can be activated with a subthreshold cognate stimulation, which down-regulates repressors and activates effector pathways to elicit the memory-driven phenotype.

Hypersensitivity pneumonitis – acceptance of the diagnosis

Hypersensitivity pneumonia (HP) is an inflammatory lung syndrome due to repetitive exposure to small organic particles. The etiological agents of the disease are diverse and can be represented by fungi, bacteria, small molecule chemical compounds, as well as proteins from animals or insects. We present the case of a 25-year-old male, who was admitted to our Pulmonology Clinic for the following symptoms: morning cough with mucosal sputum for about 2 years, moderate exertional dyspnea (mMRC 3) started for 2 months, weight loss of about 6 kg in the past 5 months and fatigue. Clinical examination revealed bilateral mid- basal crackling rales. Chest high-resolution computed tomography (HRCT) (multiple micronodular opacities, diffuse contoured, bilaterally disseminated), lung function tests (restrictive ventilatory dysfunction with decreased carbon monoxide diffusing capacity), bronchoalveolar lavage (BAL) (lymphocyte alveolitis) and serological tests (positive antibodies for pigeon heathers and dejections) pointed to the diagnosis of hypersensitivity pneumonitis. It was recommended to avoid exposure to pigeons, as the patient was a pigeon breeder. Prednisone treatment was initiated. The general condition of the patient 1 month after diagnosis had improved, the evolution being good under treatment.

Neural Correlates of Auditory Pattern Learning in the Auditory Cortex

Learning of new auditory stimuli often requires repetitive exposure to the stimulus. Fast and implicit learning of sounds presented at random times enables efficient auditory perception. However, it is unclear how such sensory encoding is processed on a neural level. We investigated neural responses that are developed from a passive, repetitive exposure to a specific sound in the auditory cortex of anesthetized rats, using electrocorticography. We presented a series of random sequences that are generated afresh each time, except for a specific reference sequence that remains constant and re-appears at random times across trials. We compared induced activity amplitudes between reference and fresh sequences. Neural responses from both primary and non-primary auditory cortical regions showed significantly decreased induced activity amplitudes for reference sequences compared to fresh sequences, especially in the beta band. This is the first study showing that neural correlates of auditory pattern learning can be evoked even in anesthetized, passive listening animal models.

Lung Inflammation from Single and Repetitive Exposure to Glyphosate

Background: Glyphosate is an active ingredient in herbicides used in agriculture worldwide. Exposure to glyphosate has been associated with respiratory dysfunctions in agricultural workers. However, the ability of glyphosate to induce inflammation in the lung is not well studied. Therefore, we evaluated lung inflammatory response to glyphosate at agricultural relevant dose for single and repetitive exposures. Methods: Male C57BL/6 mice were intranasally exposed to glyphosate (1 μg/40 μl) for 1-day or once daily for 5-days, and 10-days. After the exposure periods, mice were euthanized to collect the bronchoalveolar lavage (BAL) fluid and lung tissue. Results: Repetitive exposure to glyphosate for 5-days and 10-days showed an increase of neutrophils in BAL fluid and eosinophil peroxidase levels in lungs, a marker for eosinophils. Leukocyte infiltration in lungs was further confirmed through lung histology. Th2 cytokines including IL-5 and IL-13 were increased in BAL fluid after 10-days of glyphosate exposure whereas IL-4 was not increased. Lung sections from all glyphosate groups showed higher expression for ICAM-1, VCAM-1, and vWF adhesion molecules. TLR-4 and TLR-2 expression was increased in lungs after repetitive exposure to glyphosate. Conclusions: We conclude that repetitive exposure to glyphosate induces migration of neutrophils and eosinophils and release of Th2 cytokines. This study, for the first time, provides evidence for the role of ICAM-1, VCAM-1 and vWF in lungs of glyphosate-treated animals.