Stress-induced Inflammatory Response Research Articles

Laquinimod attenuates oxidative stress-induced mitochondrial injury and alleviates intervertebral disc degeneration by inhibiting the NF-κB signaling pathway

BackgroundLow back pain (LBP) caused by intervertebral disc degeneration (IVDD) is a significant global health concern. It is necessary to investigate the underlying pathological mechanisms leading to IVDD and develop precise treatment strategies for this condition. Considering the well-established anti-inflammatory properties and ability to reduce oxidative stress in various diseases, for the first time we aim to explore the potential of Laquinimod in alleviating IVDD. MethodsWe used hydrogen peroxide (H2O2) to simulate the oxidative stress microenvironment in IVDD, and Laquinimod for intervention purposes. Western blot analysis, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence assay were used to measure the expression levels of inflammatory cytokines, catabolic enzymes, and markers of extracellular matrix (ECM) synthesis in nucleus pulposus (NP) cells. In addition, dichlorofluorescin-diacetate (DCFH-DA) and JC-1 fluorescent probes, flow cytometry analysis, and qRT-PCR were used to measure mitochondrial function and apoptosis in NP cells under conditions of oxidative stress. An acupuncture-induced rat model of IVDD was established to further evaluate the efficacy of Laquinimod in alleviating IVDD in vivo. ResultsOur findings showed that Laquinimod significantly reduced the oxidative stress-induced inflammatory response in NP cells, downregulated the expression of catabolic enzymes, and markedly enhanced ECM degradation by inhibiting the NF-κB signaling pathway. The administration of Laquinimod concurrently improved the mitochondrial functional state and reduced apoptosis in NP cells. Additionally, in vivo experiments in rats showed that Laquinimod significantly alleviated acupuncture-induced IVDD. ConclusionsCollectively, the findings of this study provide new insights into the therapeutic potential of Laquinimod as a treatment for oxidative stress-induced IVDD.

Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats

BackgroundMajor depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signalling during inflammation, is dysregulated in many chronic inflammatory disorders; however, its role in depression and the associated sex differences have yet to be explored. Here, we investigated the sex-specific antidepressant and cognitive effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles.MethodsMale and female rats were treated with vehicle or DMF (25 mg/kg) whilst subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Sex differences in hippocampal (HIP) gene expression responses were also evaluated.ResultsDMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, and DMF treatment rescued these deficits. Further, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, most of the differentially expressed genes in males normalized by DMF were related to antioxidant, inflammatory or immune responses.ConclusionsCollectively, these findings may support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression.

Sodium butyrate alleviates heat stress-induced damage to morphology, anti-oxidant status, inflammatory response and barrier integrity in jejunum of broilers

To evaluate the protective effects of sodium butyrate (SB) on intestinal morphology, anti-oxidant status, inflammatory response and barrier integrity in male broilers under heat stress. A total of 180 21-d-old male Arbour Acres broilers with similar body weight were used for this 21-d experiment. Broilers were randomly allocated to three groups: CON group, basal diet and raised under 24 °C; HS group, basal diet and raised under heat stress condition (34 °C from 10:00 to 18:00 and 24 °C for the rest time); HS-SB group, basal diet with 1200 mg/kg SB and raised under heat stress condition. Compared to the HS group, SB supplementation increased average daily gain (ADG), villus height: crypt depth ratio (VH: CD), VH, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity, and interleukin-10 (IL-10) level, decreased feed conversion ratio (FCR), CD, reactive oxygen species (ROS), IL-1β and tumour necrosis factor-alpha (TNF-α) level, up-regulated the mRNA expression of nuclear factor erythroid 2-related factor 2, haem oxygenase 1, GSH 1 (GPX1), SOD and CAT, down-regulated the mRNA expression of toll-like receptor 4 (TLR4), nuclear transcription factors, IL-1β, and TNF-α in jejunum of heat-stressed broilers. Furthermore, SB supplementation up-regulated the mRNA expression of occluding, claudin-1 and zona occludens-1 (ZO-1) in jejunum of heat-stressed broilers, accompanied with decreasing serum endotoxin and D-lactic acid concentration, and diamine oxidase (DAO) activity. There results suggested that SB supplementation could alleviate heat stress-induced jejunal tight junction structure dysfunction by up-regulated the expression of occluding, claudin-1 and ZO-1, presumably through alleviating oxidative stress and inflammatory response. HIGHLIGHTS Sodium butyrate alleviated heat stress-induced jejunal morphology damage. Sodium butyrate alleviated heat stress-induced jejunal oxidative damage. Sodium butyrate alleviated heat stress-induced jejunal inflammatory response. Sodium butyrate alleviated heat stress-induced tight junction structure dysfunction.

ER stress mediated inflammation in cancer pathogenesis

Inflammation is a complex process which is associated with the initiation and progression of cancer. Prolonged Endoplasmic Reticulum (ER) stress triggers inflammation which is a key factor associated with cancer pathogenesis. ER stress also contributes to immune suppression in inflammatory and tumor microenvironment. It stimulates the production of pro-inflammatory cytokines by regulating the activation of various transcription factors and inflammatory signalling pathways. Targeting ER stress is an exciting possibility that can be used as a therapeutic strategy for cancer treatment. This mini review focuses on the emerging link between ER stress-induced inflammatory responses in cancer development.

Ginsenoside Rg1 ameliorates depressive-like behavior by inhibiting NLRP3 inflammasome activation in mice exposed to chronic stress

Microglia-mediated inflammatory process is recognized as a target in the treatment of depression. Ginsenoside Rg1 (GRg1), the active ingredient of traditional ginseng, regulates microglial phenotypes to resist stress-induced inflammatory responses. Here we used a mouse model of stress-induced depression to investigate the involvement of microglial Nod-like receptor protein 3 (NLRP3) in the antidepressant effects of GRg1. Male C57BL/6J mice were exposed to chronic mild stress (CMS) for three weeks, followed by intraperitoneal injection of GRg1 (20 mg/kg) or the antidepressant imipramine (20 mg/kg) for another three weeks. Depressive-like behaviors were assessed by sucrose preference test, forced swimming test, and tail suspension test. Microglial phenotypes were assessed in terms of morphological features and cytokine profiles; inflammasome activity, in terms of levels of complexes containing NLRP3, apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1; and neurogenesis, in terms of numbers of proliferating, differentiating, and mature neurons identified by immunostaining. GRg1 reduced abnormal animal behaviors caused by CMS, such as anhedonia and desperate behaviors, without affecting locomotor behaviors. GRg1 also reduced the number of ASC-specks, implying inhibition of inflammasome activation, which was associated with weaker activation of pro-inflammatory microglia. At the same time, GRg1 rescued impairment of hippocampal neurogenesis in vivo and in vitro, which correlated with modulation of microglial phenotypes. GRg1 exert antidepressant effects by preventing stress from activating the NLRP3 inflammasome in microglia, promoting a proneurogenic phenotype and allowing adult hippocampal neurogenesis.

The iron-dopamine D1 coupling modulates neural signatures of working memory across adult lifespan

Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.

Pre-operative exercise therapy suppresses colorectal liver metastases by triggering anti-tumor trained immunity of Kupffer cells

Abstract Hepatic recurrence after surgical resection of colorectal liver metastasis is the major cause of treatment failure. Pre-operative exercise therapy (PEx) has been shown to improve outcomes from major abdominal surgeries. We demonstrate that PEx significantly attenuates liver ischemia/reperfusion (I/R) injury by inducing an anti-inflammatory phenotype in Kupffer cells (KCs). However, the mechanisms by which PEx prevents surgery-induced hepatic recurrence remain unclear. Results: Four weeks of treadmill running significantly reduces I/R-induced hepatic metastatic tumor growth in mice compared to sedentary controls. Depletion of KCs substantially decreases I/R-induced tumor progression, indicating a pro-tumor role of KCs. Our scRNA-seq data reveal that PEx causes dramatic transcriptomic changes in KCs. A clear induction of trained immunity with noticeably higher levels of anti-tumor cytokines IFN-γ and TNF-α is observed in PEx-KCs. With scATAC-seq, we find that PEx triggers the chromatin accessibilities profile changes in KCs, which is associated with the metabolic reprogramming of itaconate/IRG1 pathway. Furthermore, PEx significantly changes the transcriptomic profile of polymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs) in the tumor microenvironment (TME) and decreases them from forming neutrophil extracellular traps (NETs), which promote tumor progression. We identify the cell-cell interaction between KCs and PMN-MDSCs in the TME is significantly enriched after PEx, suggesting that PEx may facilitate KCs to modulate PMN-MDSCs. In summary, PEx ameliorates surgical stress-induced pro-tumorigenic inflammatory responses and sustains an anti-tumor immune microenvironment in the liver. Supported by grants from NIH (R01GM137203 for Hai Huang, R01CA214865 for Allan Tsung)

The role of inflammation in acute psychosocial stress-induced modulation of reward processing in healthy female adults

BackgroundAnhedonia, or loss of interest and pleasure, is a pernicious symptom of depression that involves deficits in reward processing. Stress-induced inflammation is a plausible biopsychosocial mechanism of reward deficits, but little is known whether stress-induced inflammation alters reward behavior. The present study (a secondary analysis of a completed randomized controlled trial) tested whether acute stress activated a key pro-inflammatory transcription control pathway, NF-κB, and whether this activation was associated with acute stress-induced modulation of reward processing. MethodsHealthy female adults (age 18–25) were randomized to undergo an acute psychosocial stressor (Trier Social Stress Test; n = 36) or a no-stress active control (n = 16). The Probabilistic Reward Task (PRT) (n = 30 stress; n = 12 control) was administered at baseline and at 90 min post-stress, coinciding with the peak of the stress-induced inflammatory response. Genome-wide expression profiling and bioinformatics analyses of NF-kB transcription factor activity were used to assess pro-inflammatory gene regulation. ResultsRelative to the control condition, stress increased bioinformatic measures of NF-κB transcription factor activity (p = .01) and increased reward response bias scores on the PRT (p = .03). Within the stress condition, greater NF-κB activity was associated with greater increases in PRT scores (p = .01), whereas in the control condition greater NF-κB activity was associated with decreases in PRT scores (p = .002). ConclusionsAcute stress increases inflammatory signaling, and this effect is associated with increased reward processing. This demonstrates the reward system to be highly sensitive to inflammatory signaling, including the relatively mild alterations that occur following a single episode of acute psychosocial stress.

Acceleration of Oral Wound Healing under Diabetes Mellitus Conditions Using Bioadhesive Hydrogel

Oral wounds under diabetic conditions display a significant delay during the healing process, mainly due to oxidative stress-induced inflammatory status and abnormal immune responses. Besides, the wet and complicated dynamic environment of the oral cavity impedes stable treatment of oral wounds. To overcome these, a biomimetic hydrogel adhesive was innovatively developed based on a mussel-inspired multifunctional structure. The adhesive displays efficient adhesion and mechanical harmony on the oral mucosa through enhanced bonding in an acidic proinflammatory environment. The bioadhesive hydrogel exhibits excellent antioxidative properties by mimicking antioxidative enzymatic activities to reverse reactive oxygen species (ROS)-mediated immune disorders. Experiments on oral wounds of diabetic rats showed that this hydrogel adhesive could effectively protect against mucosal wounds and obviously shorten the inflammatory phase, thus promoting the wound-healing process. Therefore, this study offers a promising therapeutic choice with the potential to advance the clinical treatment of diabetic oral wounds.

Award for Distinguished Scientific Early Career Contributions to Psychology: Keely A. Muscatell.

The Early Career Awards, given for the first time in 1974, recognize the large number of excellent early career psychologists. Recipients of this award may not have held a doctoral degree for more than nine years. For sweepingly integrative approaches to understanding how social experiences contribute to health and illness. Keely A. Muscatell expertly weaves theory and methods from experimental social psychology, cognitive and affective neuroscience, psychoneuroimmunology, physiology, pharmacology, and population health to fundamentally reshape multiple areas of health psychology. Her work offers groundbreaking insights into the pernicious biological consequences wrought by entrenched lack of privilege, the neural and molecular mechanisms that underlie stress-induced inflammatory responses, and the bidirectional links between inflammation and social psychological processes. In combination, her scientific creativity, lucid writing, and unwavering commitment to ameliorating health disparities launched the interdisciplinary subfield of social psychoneuroimmunology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Impacts of stress-induced inflammation on feed intake of beef cattle

Livestock animals are often exposed to unavoidable stressful situations during their productive life that triggers stress-induced inflammatory responses, which are known to influence their nutrient requirements and feed intake. Decreased growth performance and immunocompetence of stressed livestock are often the main consequence of reduced feed intake. Because feed intake is usually reduced in animals experiencing stress conditions, concentrations of certain nutrients in the diets typically need to be increased to meet the requirements of the animals. Therefore, understanding the mechanisms that control feed intake in animals experiencing stress-induced inflammation is essential for increasing intake, milk or meat production, feed efficiency, and animal health. This review highlights the hormones regulating feed intake in ruminants and how stress-induced inflammation affect these hormones at local and systemic levels. The mechanism of feed intake regulation in ruminants is extremely complex and involves multiple controls. The liver is an important sensor of energy status in animals under homeostatic conditions, which transmits signals to brain feeding centers that modulate appetite. However, the physiologic consequences associated with different stressors will rearrange the hierarchy of mechanisms controlling feed intake compared to animals under homeostatic conditions, and other tissues (e.g., intestines), systems (e.g., endocrine and lymphatic) hormones (e.g., leptin and ghrelin) will directly affect intake regulation during stress and inflammatory conditions. It is suggested that the immune system can interact with the central nervous system to modulate feed intake. As example, stress events elicit numerous stressors that increase circulating proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-8, and acute-phase proteins (APP), and the magnitude of these responses are negatively correlated with feed intake. A direct effect of these cytokines on rumen microbial fermentation and intestinal barrier function was also reported and might indirectly affect intake regulation in ruminants. This review describes the main hormones and proinflammatory cytokines involved in stress-induced inflammation and how they can directly or indirectly affect intake regulation in ruminants. Understanding the mechanisms controlling feed intake in ruminants will help producers to implement management and feed strategies to optimize productivity and profitability in stressed livestock species.

Associations Between Direct and Indirect Forms of Racism Exposure and Stress-Induced Inflammatory Response and Health in Pregnancy.

Theory and research suggest chronic direct and indirect exposures to racism impact health, and stress-responsive inflammation may play a role in these paths. This study examines links between forms of racism-related stress, salivary markers of inflammation during acute psychosocial stress, and perinatal mental and physical health in a racially heterogenous sample. Pregnant people (n = 108, 27% non-white) self-reported personal and vicarious exposure to racism (racial microaggressions, online racism, overt racial/ethnic discrimination) and racial collective self-esteem, as well as affective symptoms and general physical health. Five saliva samples collected before and after the Trier Social Stress Test were assayed for pro-inflammatory cytokines and C-reactive protein. Results revealed associations between racism-related stress and greater inflammatory reactivity/delayed recovery to acute stress, between racial collective self-esteem and lower levels of inflammation, and between profiles of inflammatory responses to stress and mental and physical symptoms. We discuss implications for understanding perinatal health disparities.

Melatonin attenuates chronic stress-induced hippocampal inflammatory response and apoptosis by inhibiting ADAM17/TNF-α axis.

Melatonin, as a dietary supplement, has a potent neuroprotective effect and exerts a certain antidepressant effect. This study explored the molecular mechanisms and targets of melatonin on chronic stress-induced hippocampal damage from the perspective of inhibiting inflammatory cytokines release. Our results indicated that melatonin alleviated chronic restraint stress (CRS)-induced inflammatory response and apoptosis, thus improving hippocampal structural damage and subsequent depression-like behaviors in rats. The radar map displayed that the change of TNF-α content was the most significant. Meanwhile, correlation analysis showed that TNF-α content was highly positively correlated with apoptosis. Molecular autodocking studies suggested that TNF-α converting enzyme ADAM17 as a potential target has a priority in docking with melatonin. Molecular mechanism studies indicated that melatonin inhibited CRS-induced activation of the ADAM17/TNF-α axis and its downstream proteins p38 and p53 phosphorylation in the hippocampus. Analogously, Both ADAM17 inhibitor TMI-1 and TNF-α inhibitor thalidomide relieved the effects of CRS on ADAM17/TNF-α axis and its downstream proteins phosphorylation, hippocampal apoptosis, hippocampal inflammatory response, and depression-like behaviors in rats. Altogether, these findings reveal that melatonin relieves CRS-induced inflammatory response and apoptosis, and subsequent depression-like behaviors by inhibiting ADAM17/TNF-α axis.

New Insights into the Pivotal Role of the Amygdala in Inflammation-Related Depression and Anxiety Disorder.

Depression and anxiety disorders are the two most prevalent psychiatric diseases that affect hundreds of millions of individuals worldwide. Understanding the etiology and related mechanisms is of great importance and might yield new therapeutic strategies to treat these diseases effectively. During the past decades, a growing number of studies have pointed out the importance of the stress-induced inflammatory response in the amygdala, a kernel region for processing emotional stimuli, as a potentially critical contributor to the pathophysiology of depression and anxiety disorders. In this review, we first summarized the recent progress from both animal and human studies toward understanding the causal link between stress-induced inflammation and depression and anxiety disorders, with particular emphasis on findings showing the effect of inflammation on the functional changes in neurons in the amygdala, at levels ranging from molecular signaling, cellular function, synaptic plasticity, and the neural circuit to behavior, as well as their contributions to the pathology of inflammation-related depression and anxiety disorders. Finally, we concluded by discussing some of the difficulties surrounding the current research and propose some issues worth future study in this field.

Long-term environmental levels of microcystin-LR exposure induces colorectal chronic inflammation, fibrosis and barrier disruption via CSF1R/Rap1b signaling pathway

Microcystin-LR (MC-LR) is a very common toxic cyanotoxins threating ecosystems and the public health. This study aims to explore the long-term effects and potential toxicity mechanisms of MC-LR exposure at environmental levels on colorectal injury. We performed histopathological, biochemical indicator and multi-omics analyses in mice with low-dose MC-LR exposure for 12 months. Long-term environmental levels of MC-LR exposure caused epithelial barrier disruption, inflammatory cell infiltration and an increase of collagen fibers in mouse colorectum. Integrated proteotranscriptomics revealed differential expression of genes/proteins, including CSF1R, which were mainly involved in oxidative stress-induced premature senescence and inflammatory response. MC-LR induced chronic inflammation and fibrosis through oxidative stress and CSF1R/Rap1b signaling pathway were confirmed in cell models. We found for the first time that long-term environmental levels of MC-LR exposure caused colorectal chronic inflammation, fibrosis and barrier disruption via a novel CSF1R/Rap1b signaling pathway. Moreover, MC-LR changed the gut microbiota and microbial-related metabolites in a vicious cycle aggravating colorectal injury. These findings provide novel insights into the effects and toxic mechanisms of MC-LR and suggest strategies for the prevention and treatment of MC-caused intestinal diseases.

Potential Utility of Natural Products against Oxidative Stress in Animal Models of Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune-mediated degenerative disease of the central nervous system (CNS) characterized by immune cell infiltration, demyelination and axonal injury. Oxidative stress-induced inflammatory response, especially the destructive effect of immune cell-derived free radicals on neurons and oligodendrocytes, is crucial in the onset and progression of MS. Therefore, targeting oxidative stress-related processes may be a promising preventive and therapeutic strategy for MS. Animal models, especially rodent models, can be used to explore the in vivo molecular mechanisms of MS considering their similarity to the pathological processes and clinical signs of MS in humans and the significant oxidative damage observed within their CNS. Consequently, these models have been used widely in pre-clinical studies of oxidative stress in MS. To date, many natural products have been shown to exert antioxidant effects to attenuate the CNS damage in animal models of MS. This review summarized several common rodent models of MS and their association with oxidative stress. In addition, this review provides a comprehensive and concise overview of previously reported natural antioxidant products in inhibiting the progression of MS.

Seaweed-Derived Polysaccharides Attenuate Heat Stress-Induced Splenic Oxidative Stress and Inflammatory Response via Regulating Nrf2 and NF-κB Signaling Pathways.

With global warming, heat stress (HS) has become a worldwide concern in both humans and animals. The ameliorative effect of seaweed (Enteromorpha prolifera) derived polysaccharides (SDP) on HS-induced oxidative stress and the inflammatory response of an immune organ (spleen) was evaluated using an animal model (Gallus gallus domesticus). In total, 144 animals were used in this 4-week trial and randomly assigned to the following three groups: thermoneutral zone, HS, and HS group supplemented with 1000 mg/kg SDP. Dietary SDP improved the antioxidant capacity and reduced the malondialdehyde (MDA) of the spleen when exposed to HS, regulated via enhancing nuclear factor erythroid 2-related factor-2 (Nrf2) signaling. Furthermore, the inclusion of SDP reduced the levels of pro-inflammatory cytokines and alleviated HS-induced splenic inflammatory response by suppressing the nuclear factor-kappa B (NF-κB) p65 signaling. These findings suggest that the SDP from E. prolifera can be used as a functional food and/or feed supplement to attenuate HS-induced oxidative stress and inflammatory responses of the immune organs. Moreover, the results could contribute to the development of high-value marine products from seaweed for potential use in humans and animals, owing to their antioxidant and anti-inflammatory effects.

Gallnut Tannic Acid Exerts Anti-stress Effects on Stress-Induced Inflammatory Response, Dysbiotic Gut Microbiota, and Alterations of Serum Metabolic Profile in Beagle Dogs.

Stress exposure is a potential threat to humans who live or work in extreme environments, often leading to oxidative stress, inflammatory response, intestinal dysbiosis, and metabolic disorders. Gallnut tannic acid (TA), a naturally occurring polyphenolic compound, has become a compelling source due to its favorable anti-diarrheal, anti-oxidative, anti-inflammatory, and anti-microbial activities. Thus, this study aimed to evaluate the anti-stress effects of gallnut TA on the stress-induced inflammatory response, dysbiotic gut microbiota, and alterations of serum metabolic profile using beagle models. A total of 13 beagle dogs were randomly divided into the stress (ST) and ST + TA groups. Dietary supplementation with TA at 2.5 g/kg was individually fed to each dog in the ST + TA group for 14 consecutive days. On day 7, all dogs were transported for 3 h from a stressful environment (days 1–7) to a livable site (days 8–14). In our results, TA relieved environmental stress-induced diarrheal symptoms in dogs and were shown to protect from myocardial injury and help improve immunity by serum biochemistry and hematology analysis. Also, TA inhibited the secretion of serum hormones [cortisol (COR), glucocorticoid (GC), and adrenocorticotropic hormone (ACTH)] and the expression of heat shock protein (HSP) 70 to protect dogs from stress-induced injury, thereby relieving oxidative stress and inflammatory response. Fecal 16S rRNA gene sequencing revealed that TA stimulated the growth of beneficial bacteria (Allobaculum, Dubosiella, Coriobacteriaceae_UCG-002, and Faecalibaculum) and suppressed the growth of pathogenic bacteria (Escherichia-Shigella and Streptococcus), thereby increasing fecal butyrate levels. Serum metabolomics further showed that phytosphingosine, indoleacetic acid, arachidonic acid, and biotin, related to the metabolism of sphingolipid, tryptophan, arachidonic acid, and biotin, respectively, could serve as potential biomarkers of stress exposure. Furthermore, Spearman’s correlation analysis showed strong relationships between the four potential serum biomarkers and differential bacteria. Overall, gallnut TA may be a potential prebiotic for the prevention and treatment of stress-induced metabolic disorders by targeting intestinal microbiota.

Effect of Probiotic Bifidobacterium bifidum TMC3115 Supplementation on Psychosocial Stress Using a Sub-Chronic and Mild Social Defeat Stress in Mice.

With the accumulation of knowledge on the relation between psychological stress and gut microbiota, there is growing interest in controlling stress and/or mood disorders via probiotic supplementation. We aimed to examine the effect of probiotic Bifidobacterium bifidum TMC3115 (TMC3115) supplementation using a sub-chronic and mild social defeat stress murine model in this study. TM3115 supplementation maintained body weight gain and alleviated a polydipsia-like symptom induced by the stress. In the analyses of fecal and cecal bacterial profiles, expansions of Proteobacteria in stressed mice and increases in Actinobacteria and Bifidobacterium in mice supplemented with TMC3115 were observed. There was no marked difference in the diversity of cecal bacteria between the tested mice. Elevated serum levels of inflammatory markers such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 were observed in the stressed mice, while TMC3115 only reduced the IL-6 level. These findings suggest that TMC3115 supplementation confers tolerance to psychosocial stress in the host through modulation of the gut microbiota and alleviation of stress-induced inflammatory responses. Furthermore, it may be expected to exert prevention and treatment of disorders related to peripheral IL-6, including depression.

Maternal Benzophenone Exposure Impairs Hippocampus Development and Cognitive Function in Mouse Offspring.

Benzophenones are widely supplemented in personal care products, but little is known about its neurodevelopmental toxicity. The previous epidemiological study discovered a negative correlation between maternal exposure to a benzophenone metabolite 4‐hydroxybenzophenone (4HBP) and child's neurodevelopment, yet the causal relationship and detailed mechanism remain to be defined. Here, it is reported that prenatal, but not postnatal, exposure to environmentally relevant level of 4HBP impairs hippocampus development and causes cognitive dysfunction in offspring mice. Transcriptomic analyses reveal that 4HBP induces the endoplasmic reticulum stress‐induced apoptotic signaling and inflammatory response in hippocampal neural stem cells. Mechanistically, 4HBP exposure activates protein kinase R‐like ER kinase (PERK) signaling, which induces CHOP, inhibits IκB translation, and transactivates p65, thereby promoting inflammation and apoptosis on multiple levels. Importantly, genetic or pharmacological inhibition of PERK pathway significantly attenuates 4HBP‐induced NFκB signaling and neurodevelopmental abnormalities in mice and in a human brain organoid model. The study uncovers the neurodevelopmental toxicity of BP and cautions its exposure during pregnancy.