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Background: One of the most common types of neurodegenerative diseases (NDDs) is Lewy body disease (LBD), which is characterized by excessive accumulation of α-synuclein (α-syn) in the neurons and affects around 6 million individuals globally. In recent years, due to the environmental factors that can affect the development of this condition, such as exposure to herbicides and pesticides, so it has become a younger disease. Currently, the vast majority of studies on the neurotoxic effects of paraquat (PQ) focus on the late mechanisms of neuronal-glial network regulation, and little is known about the early origins of this environmental factor leading to LBD. Objective: To observe the effect of PQ exposure on intestinal function and to explore the key components of communicating the gut-brain axis by establishing a mouse model. Methods and results: In this study, C57BL/6J mice were treated by intraperitoneal injection of 15 mg/kg PQ to construct an LBD time-series model, and confirmed by neurobehavioral testing and pathological examination. After PQ exposure, on the one hand, we found that fecal particle counts and moisture content were abnormal. on the other hand, we found that the expression levels of colonic tight junction proteins decreased, the expression levels of inflammatory markers increased, and the diversity and abundance of gut microbiota altered. In addition, pathological aggregation of α-syn was consistent in the colon and midbrain, and the metabolism and utilization of short-chain fatty acids (SCFAs) were also markedly altered. This suggests that pathological α-syn and SCFAs form the gut may be key components of the communicating gut-brain axis. Conclusion: In this PQ-induced mouse model, gut microbiota disruption, intestinal epithelial barrier damage, and inflammatory responses may be the main causes of gut dysfunction, and pathological α-syn and SCFAs in the gut may be key components of the communicating gut-brain axis.

The automobile tire antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its quinone metabolite 6PPDQ have recently received much attention for their acute aquatic toxicity. The present study investigated the mechanistic developmental toxicity of 6PPD and 6PPDQ in embryonic zebrafish. Neither compound induced significant mortality but significantly decreased spontaneous embryo movement and heart rate. Both compounds induced malformations with different phenotypes; the 6PPD-exposed larvae manifested a myopia-like phenotype with a convex eyeball and fusion vessels, while the 6PPDQ-exposed embryonic zebrafish manifested enlarged intestine and blood-coagulated gut, activated neutrophils, and overexpressed enteric neurons. mRNA-Seq and quantitative real-time PCR assays showed that 6PPD- and 6PPDQ-induced distinct differential gene expression aligned with their toxic phenotype. 6PPD activated the retinoic acid metabolic gene cyp26a, but 6PPDQ activated adaptive cellular response to xenobiotics gene cyp1a. 6PPD suppressed the gene expression of the eye involved in retinoic acid metabolism, phototransduction, photoreceptor function and visual perception. In contrast, 6PPDQ perturbed genes involved in inward rectifier K + and voltage-gated ion channels activities, K + import across the plasma membrane, iron ion binding, and intestinal immune network for IgA production. The current study advances the present understanding the reason of why many fish species are so adversely impacted by 6PPD and 6PPDQ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Deoxynivalenol (DON) is a major mycotoxin present in staple foods (particularly in cereal products) that induces intestinal inflammation and disrupts intestinal integrity. Lactoferrin (LF) is a multifunctional protein that contributes to maintaining intestinal homeostasis and improving host health. However, the protective effects of LF on DON-induced intestinal dysfunction remain unclear., Objectives: This study aimed to investigate the effects of LF on DON-induced intestinal dysfunction in mice, and its underlying protective mechanism., Methods: Male BALB/c mice (5 wk old) with similar body weights were divided into 4 groups (n = 6/group) and treated as follows for 5 wk: Veh [peroral vehicle daily, commercial (C) diet]; LF (peroral 10 mg LF/d, C diet); DON (Veh, C diet containing 12 mg DON/kg); and LF + DON (peroral 10 mg LF/d, DON diet). Intestinal morphology, tight junction proteins, cytokines, and microbial community were determined. Data were analyzed by 2-factor ANOVA or Kruskal-Wallis test., Results: The DON group exhibited lower final body weight (-12%), jejunal villus height (VH; -41%), and jejunal occludin expression (-36%), and higher plasma IL-1β concentration (+85%) and jejunal Il1b mRNA expression (+98%) compared with the Veh group (P < 0.05). In contrast, final body weight (+19%), jejunal VH (+49%), jejunal occludin (+53%), and intelectin 1 protein expression (+159%) were greater in LF + DON compared with DON (P < 0.05). Additionally, jejunal Il1b mRNA expression (-31%) and phosphorylation of p38 and extracellular signal regulated kinase 1/2 (-40% and - 38%) were lower in LF + DON compared with DON (P < 0.05). Furthermore, the relative abundance of Clostridium XIVa (+181%) and colonic butyrate concentration (+53%) were greater in LF + DON compared with DON (P < 0.05)., Conclusions: Our study highlights a promising antimycotoxin approach using LF to alleviate DON-induced intestinal dysfunction by modulating the mitogen-activated protein kinase pathway and gut microbial community in mice., (Copyright © 2022 American Society for Nutrition.)

Recently, an unexpected connection between necroptosis and members of the a disintegrin and metalloproteinase (ADAM) protease family has been reported. Necroptosis represents an important cell death routine which helps to protect from viral, bacterial, fungal and parasitic infections, maintains adult T cell homeostasis and contributes to the elimination of potentially defective organisms before parturition. Equally important for organismal homeostasis, ADAM proteases control cellular processes such as development and differentiation, immune responses or tissue regeneration. Notably, necroptosis as well as ADAM proteases have been implicated in the control of inflammatory responses in the intestine. In this review, we therefore provide an overview of the physiology and pathophysiology of necroptosis, ADAM proteases and intestinal (dys)function, discuss the contribution of necroptosis and ADAMs to intestinal (dys)function, and review the current knowledge on the role of ADAMs in necroptotic signaling., Competing Interests: Conflict of interest M.H and D.A. declare no competing interests. S.R.-J. has acted as a consultant and speaker for AbbVie, Chugai, Genentech Roche, Pfizer, Sanofi, Eli Lilly and Boehringer Ingelheim. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein Olamkicept together with the company I-Mab. S.R.-J. has stock ownership in CONARIS., (© 2020 Elsevier Inc. All rights reserved.)

As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions., (Copyright © 2017 Elsevier Inc. All rights reserved.)