Markers of intestinal barrier damage in patients with chronic insomnia disorder
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ABSTRACT:
SUBMITTER: Cai Y
PROVIDER: S-EPMC11007705 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:The ascending arousal system plays a crucial role in individuals' consciousness. Recently, advanced functional magnetic resonance imaging (fMRI) has made it possible to investigate the ascending arousal network (AAN) in vivo. However, the role of AAN in the neuropathology of human insomnia remains unclear. Our study aimed to explore alterations in AAN and its connections with cortical networks in chronic insomnia disorder (CID). Resting-state fMRI data were acquired from 60 patients with CID and 60 good sleeper controls (GSCs). Changes in the brain's functional connectivity (FC) between the AAN and eight cortical networks were detected in patients with CID and GSCs. Multivariate pattern analysis (MVPA) was employed to differentiate CID patients from GSCs and predict clinical symptoms in patients with CID. Finally, these MVPA findings were further verified using an external data set (32 patients with CID and 33 GSCs). Compared to GSCs, patients with CID exhibited increased FC within the AAN, as well as increased FC between the AAN and default mode, cerebellar, sensorimotor, and dorsal attention networks. These AAN-related FC patterns and the MVPA classification model could be used to differentiate CID patients from GSCs with 88% accuracy in the first cohort and 77% accuracy in the validation cohort. Moreover, the MVPA prediction models could separately predict insomnia (data set 1, R2 = .34; data set 2, R2 = .15) and anxiety symptoms (data set 1, R2 = .35; data set 2, R2 = .34) in the two independent cohorts of patients. Our findings indicated that AAN contributed to the neurobiological mechanism of insomnia and highlighted that fMRI-based markers and machine learning techniques might facilitate the evaluation of insomnia and its comorbid mental symptoms.
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Project description:The kidneys are key contributors to body homeostasis, by virtue of controlled excretion of excessive fluid, electrolytes, and toxic waste products. The syndrome of uremia equals the altered physiology due to irreversible loss of kidney function that is left uncorrected for, despite therapeutic intervention(s). The intestines and its microbial content are prime contributors to this syndrome. The intestinal barrier separates the self (or the so-called "milieu intérior") from the environment. In the large intestine, the intestinal barrier keeps apart human physiology and the microbiota. The enterocytes and the extracellular mucin layer functions form a complex multilayered structure, facilitating complex bidirectional metabolic and immunological crosstalk. The current review focuses on the intestinal barrier in chronic kidney disease (CKD). Loss of kidney function results in structural and functional alterations of the intestinal barrier, contribution to the syndrome of uremia.
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Project description:BackgroundChronic intestinal pseudo-obstruction (CIPO) is a rare condition due to severe impairment of gut motility responsible for recurrent subocclusive episodes. Although neuromuscular-glial-ICC abnormalities represent the main pathogenetic mechanism, the pathophysiology of CIPO remains poorly understood. Intestinal epithelial and vascular endothelial barrier (IEVB) abnormalities can contribute to neuroepithelial changes by allowing passage of harmful substances.MethodsTo test retrospectively whether IEVB defects occur in patients with CIPO, we measured the jejunal protein expression of the major tight junction (TJ) components. CIPO patients were subdivided according to gut neuromuscular histopathology: apparently normal (AN); with inflammation (INF); or with degenerative alterations (DEG). The presence of occludin/claudin oligomers (index of TJ assembly), the amount of occludin, claudin-4, and zonula occludens-1 (ZO-1), and the expression of vasoactive intestinal polypeptide (VIP) and glial fibrillary acidic protein (GFAP) immunoreactivities were evaluated on jejunal full-thickness biopsies using Western blot.Key resultsOligomers were absent in the 73% of CIPO. Total occludin decreased in CIPO with AN and INF changes. Claudin-4 was upregulated in CIPO with INF and DEG features. ZO-1 and VIP expression decreased selectively in DEG group. GFAP increased in CIPO regardless the histopathological phenotype.Conclusions & inferencesThe absence of oligomers demonstrated in our study suggests that IEBV is altered in CIPO. The mechanism leading to oligomerization is occludin-dependent in AN and INF, whereas is ZO-1-dependent in DEG. Our study provides support to IEVB abnormalities contributing to CIPO clinical and histopathological features.
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Project description:Impaired sympathetic response is frequently observed in neurodegenerative diseases, such as Alzheimer's disease (AD). On the other hand, chronic insomnia disorder (CID) is also often accompanied by activation of sympathetic nerves. Considering that cutaneous microcirculation reflects sympathetic tone, we hypothesized that baseline cutaneous microcirculation in fingers, as detected by laser Doppler flowmetry (LDF), differs among patients with mild cognitive impairment (MCI), AD, and CID. As light therapy is one of the adjunctive treatments for AD and CID, we designed a randomized controlled cross-over trial of light therapy through eyes for 12 weeks with red light as treatment and green light as control limb, and examined if light therapy has an impact on cutaneous microcirculation. Before light therapy, patients with AD had significantly lower baseline cutaneous perfusion than those with CID in left and right first to fourth fingers. After red light therapy, however, cutaneous perfusion of fingers in CID patients significantly decreased (right fingers, before vs. after = 227.25 ± 62.00 vs. 162.00 ± 49.34, p = 0.007; left fingers, before vs. after = 228.99 ± 58.80 vs. 177.41 ± 59.41, p = 0.003) while cutaneous perfusion of fingers in CID patients did not significantly change after green light therapy. Light therapy with red light also significantly increased cutaneous finger perfusion in patients with AD (right fingers, before vs. after = 130.13 ± 49.82 vs. 172.38 ± 38.32, p = 0.043). Our results suggest that cutaneous perfusion is a useful tool to detect sympathetic dysfunction in patients with CID and AD, and that light therapy with red light is a potential therapeutic intervention to reverse impaired sympathetic function in patients with CID and patients with AD.
| S-EPMC8703751 | biostudies-literature
Project description:Mycophenolic acid (MPA) may cause gastrointestinal adverse effects by damaging the intestinal epithelial barrier, the underlying mechanisms remain elusive. Studies have demonstrated that oxidative stress caused by reactive oxygen species (ROS) is linked to tight junction (TJ) proteins and apoptosis, both of which cause abnormalities in intestinal barrier function. Mitochondria, one of the main sources of ROS and abnormally high levels of ROS are linked to mitochondrial dysfunction. The aim of this study was to investigate whether MPA induces intestinal barrier dysfunction through regulation of the mitochondrial ROS. MPA-induced intestinal injury model in Kunming mice and Caco-2 cells. The effect of MPA on Caco-2 cell viability was measured by MTT; tissue diamine oxidase and endotoxin expression were determined by ELISA; expression of total proteins of ZO-1, occludin, Bax, Bcl-2, and mitochondrial proteins of Cytochrome C and Bax was measured by Western blot; and the localization of Cytochrome C with MitoTraker was observed by immunofluorescence staining. Caco-2 cell apoptosis, ROS levels, and mitochondrial membrane potential were detected by flow cytometry, while intramitochondrial ROS levels were observed by MitoSOX fluorescence staining. The results showed that MPA increased intracellular and mitochondrial ROS production to promote oxidative stress and the antioxidant NAC effectively restored ZO-1 and occludin expressions, reduced apoptosis in intestinal epithelial cells. Furthermore, we found that low concentrations of MPA caused mitochondrial damage, induced hyperpolarization of the mitochondrial membrane potential and the translocation of Cytochrome C and Bax proteins from the cytoplasm to the mitochondria. The mitochondrial protectant SS-31 reduces intracellular and intramitochondrial ROS, upregulates TJ, and reduces apoptosis. Our studies suggest that MPA-induced intestinal barrier dysfunction in vivo and in vitro is mediated, at least in part, by impairing mitochondrial function and promoting oxidative stress.
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Project description:ObjectiveIntestinal ischemia-reperfusion (II/R) is a common pathological injury in clinic, and the systemic inflammatory response it causes will lead to multiple organ damage and functional failure. miR-185-5p has been reported to be a regulator of inflammatory response and autophagy, but whether it participates in the regulation of autophagy in II/R is still unclear. Therefore, we aimed to explore the mechanism of miR-185-5p regulating intestinal barrier injury in (II/R).MethodsCaco-2 cells was induced by oxygen-glucose deprivation/reoxygenation (OGD/R) to establish II/R model. The superior mesenteric artery of C57BL/6 mice was clamped for 45 min and then subjected to reperfusion for 4 h for the establishment of II/R mice model. miR-185-5p mimic, miR-185-5p inhibitor, pcDNA-autophagy-related 101 (ATG101) were respectively transfected into Caco-2 cells. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to assess miR-185-5p expression. Western blot detected the level of ATG101 and tight junction-associated proteins ZO1, Occludin, E-cadherin, β-catenin, as well as autophagy markers ATG5, ATG12, LC3Ⅰ/Ⅱ, Beclin1 and SQSTM1. Transepithelial electrical resistance (TEER) values was detected by a resistance meter. FITC-Dextran was performed to measure cell permeability. 5-ethynyl-2'-deoxyuridine (EDU) staining measured cell proliferation. Transmission electron microscope was conducted to observe autophagosomes. Hematoxylin & eosin (H&E) staining observed the damage of mice intestinal. Immunohistochemistry (IHC) measured the percentage of ki67 positive cells. TdT-mediated dUTP nick-end labeling (TUNEL) assay assessed cell apoptosis in intestinal tissues of II/R. Dual-luciferase assay verified the targeting relationship between miR-185-5p and ATG101.Results miR-185-5p was overexpressed in OGD/R-induced Caco-2 cells and intestinal tissues of II/R mice. Knocking down miR-185-5p markedly promoted autophagy and TEER values, reduced cell permeability, and alleviated intestinal barrier damage. ATG101 was a target of miR-185-5p, and overexpression of ATG101 promoted autophagy and dampened OGD/R-induced intestinal barrier damage. Overexpression of miR-185-5p reversed the effect of overexpressed ATG101 on OGD/R-induced Caco-2 cells.ConclusionKnockdown of miR-185-5p enhanced autophagy and alleviated II/R intestinal barrier damage by targeting ATG101.
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Project description:IntroductionThe intestinal mucosal barrier is an important line of defense for the body, protecting it from intestinal bacteria, endotoxins, and antigens. Cisplatin, a clinical important chemotherapy medicine, is found the side effect with impairing intestinal epithelial cells' structure and function, even causes intestinal mucositis which causes patients immense suffering and hinders the process of cancer treatment. Chlorogenic acid, as the component only second to caffeine in coffee, has been proved the contribution on cardiovascular and gastrointestinal benefits. So, we investigate the protective effect of chlorogenic acid on cisplatin induced intestinal barrier structure and function injury in mice from the perspective of gut microbiota.MethodsC57BL/6J mice were divided into 4 groups, including the control group, a cisplatin group, a chlorogenic acid treatment group receiving intraperitoneal injections alongside cisplatin (Cis + CGA1), and the last group pre-treated with chlorogenic acid before cisplatin administration (Cis + CGA2). The inflammation factor of IL-6, IL-1β, and TNF-α in colonic tissue and serum were detected, respectively. To explore the protection of chlorogenic acid on mucosal barrier's integrity, we also detected the fecal LPS and the expression of occludin and ZO-1 proteins in colon tissue. And H&E staining was used to study the histopathological conditions of the colon tissue. Moreover, this article also utilized16S rDNA sequencing to analyze the gut microbiota of feces.ResultsChlorogenic acid administration reduced IL-6, IL-1β, and TNF-α level in both colon tissue and serum compared to the cisplatin alone treatment group. Furthermore, chlorogenic acid pretreatment notably improved intestinal barrier integrity by enhancing the expression of occludin and ZO-1 proteins in colon tissues. Moreover, 16S rDNA sequencing showed that compared with the control group, cisplatin group showed a reduced microbiota diversity, elevating abundance of Proteobacteria and pro-inflammatory environment of the increased Firmicutes/Bacteroidetes (F/B) ratio. However, chlorogenic acid treatment especially the pretreatment reversed the reduced microbiota diversity, elevating abundance of Proteobacteria and F/B ratio.DiscussionMicrobiota diversity and all results suggest that chlorogenic acid treatment was able to mitigate these intestinal microbiota disorder and diversity reduction induced by cisplatin, effectively offer a protective effect against the inflammatory response and destruction of the mucosal barrier in the intestines caused by cisplatin.
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Project description: Not available
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Project description:Weaning of piglets is accompanied by intestinal inflammation, impaired intestinal barrier function, and intestinal microflora disorder. Regulating intestinal microflora structure can directly or indirectly affect intestinal health and host growth and development. However, whether dietary fiber (DF) affects the inflammatory response and barrier function by affecting the intestinal microflora and its metabolites is unclear. In this study, we investigated the role of intestinal microflora in relieving immune stress and maintaining homeostasis using piglets with lipopolysaccharide (LPS)-induced intestinal injury as a model. DF improved intestinal morphology and barrier function, inhibited the expression of inflammatory signal pathways (Toll-like receptor 2 [TLR2], TLR4, and NF-κB) and proinflammatory cytokines (interleukin 1β [IL-1β], IL-6, and tumor necrosis factor alpha [TNF-α]), and upregulated the expression of barrier-related genes (encoding claudin-1, occludin, and ZO-1). The contents of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and the activity of diamine oxidase in plasma were decreased. Meanwhile, DF had a strong effect on the composition and function of intestinal microflora at different taxonomic levels, the relative abundances of cellulolytic bacteria and anti-inflammatory bacteria were increased, and the concentrations of propionate, butyrate, and total short-chain fatty acids (SCFAs) in intestinal contents were increased. In addition, the correlation analysis also revealed the potential relationship between metabolites and certain intestinal microflora, as well as the relationship between metabolites and intestinal morphology, intestinal gene expression, and plasma cytokine levels. These results indicate that DF improves intestinal barrier function, in part, by altering intestinal microbiota composition and increasing the synthesis of SCFAs, which subsequently alleviate local and systemic inflammation.IMPORTANCE Adding DF to the diet of LPS-challenged piglets alleviated intestinal and systemic inflammation, improved intestinal barrier function, and ultimately alleviated the growth retardation of piglets. In addition, the addition of DF significantly increased the relative abundance of SCFA-producing bacteria and the production of SCFAs. We believe that the improvement of growth performance of piglets with LPS-induced injury can be attributed to the beneficial effects of DF on intestinal microflora and SCFAs, which reduced the inflammatory response in piglets, improving intestinal barrier function and enhancing body health. These research results provide a theoretical basis and guidance for the use of specific fiber sources in the diet to improve intestinal health and growth performance of piglets and thus alleviate weaning stress. Our data also provide insights for studying the role of DF in regulating gastrointestinal function in human infants.
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