Intestinal Reactive Oxygen Species Research Articles

Paeoniflorin alleviates toxicity and accumulation of 6-PPD quinone by activating ACS-22 in Caenorhabditis elegans

6-PPD quinone (6-PPDQ) is extensively existed in various environments. In Caenorhabditis elegans, exposure to 6-PPDQ could cause multiple toxic effects. In the current study, we further used C. elegans to investigate the effect of paeoniflorin (PF) treatment on 6-PPDQ toxicity and accumulation and the underlying mechanism. Treatment with PF (25–100 mg/L) inhibited 6-PPDQ toxicity on reproduction capacity and locomotion behavior and in inducing reactive oxygen species (ROS) production. Additionally, PF (25–100 mg/L) alleviated the dysregulation in expression of genes governing oxidative stress caused by 6-PPDQ exposure. Moreover, PF (25–100 mg/L) inhibited the enhancement in intestinal permeability caused by 6-PPDQ exposure and the accumulation of 6-PPDQ in the body of nematodes. In 6-PPDQ exposed nematodes, PF (25–100 mg/L) increased expression of acs-22 encoding a fatty acid transporter. RNAi of acs-22 could inhibit the beneficial effect of PF against 6-PPDQ toxicity in decreasing reproductive capacity and locomotion behavior, in inducing intestinal ROS production, and in enhancing intestinal permeability. RNAi of acs-22 could also suppress the PF beneficial effect against 6-PPDQ accumulation in the body of nematodes. Therefore, our results demonstrate the function of PF treatment against 6-PPDQ toxicity and accumulation in nematodes by activating the ACS-22.

Effects of Beraprost on Intestinal Microcirculation and Barrier Function in a Mouse Model of Renal Failure.

Endothelial dysfunction plays an important role in the pathogenesis of chronic kidney disease. Prostacyclin (PGI2), an endothelial cell-produced endogenous prostaglandin, plays a crucial role in maintaining endothelial function. However, its effects on intestinal microcirculation and barrier function are not fully understood. We hypothesized that PGI2 improves intestinal microcirculation and barrier function via endothelial protective effects. ICR and ICGN (a spontaneous nephrotic model) mice were used in this study. Intestinal microcirculation was visualized invivo to investigate PGI2 effects. Beraprost served as PGI2. PGI2 administration spanned 4 weeks, following which we assessed its influence on intestinal endothelial, intestinal barrier, and renal functions. We visualized intestinal microcirculation and endothelial glycocalyx in the intestinal blood vessels. Beraprost administration induced a 1.2-fold dilatation of the vascular diameter of the small intestine. Intestinal blood flow in ICGN mice was significantly reduced compared that in ICR mice but improved with beraprost administration. ICGN mice exhibited reduced serum albumin levels, decreased ambulation, an imbalance in intestinal reactive oxygen species (ROS)/nitric oxide (NO), and impaired tight junctions; all were ameliorated by beraprost administration. Beraprost improves intestinal microcirculation and barrier function by ameliorating ROS/NO imbalances, thereby reducing physical inactivity during renal failure.

Establishing the link between D-mannose and juvenile grass carp (Ctenopharyngodon idella): Improved growth and intestinal structure associated with endoplasmic reticulum stress, mitophagy, and apical junctional complexes

D-mannose, essential for protein glycosylation, has been reported to have immunomodulatory effects and to maintain intestinal flora homeostasis. In addition to evaluating growth performance, we examined the impact of D-mannose on the structure of epithelial cells and apical junction complexes in the animal intestine. All 1800 grass carp (16.20 ± 0.01 g) were randomly divided into six treatments with six replicates of 50 fish each and fed with six different levels of D-mannose (0.52, 1.75, 3.02, 4.28, 5.50 and 6.78 g/kg diet) for 70 d. The study revealed that D-mannose increased feed intake (P < 0.001) but did not affect the percent weight gain (PWG), special growth rate, and feed conversion ratio (P > 0.05). D-mannose supplementation at 1.75 g/kg increased crude protein content in fish and lipid production value (P < 0.05). D-mannose supplementation at 4.28 g/kg increased intestinal length, intestinal weight and fold height of grass carp compared to the control group (P < 0.05). This improvement may be attributed to the phosphomannose isomerase (PMI)-mediated enhancement of glycolysis. This study found that D-mannose supplementation at 4.28 or 3.02 g/kg reduced serum diamine oxidase activity or D-lactate content (P < 0.05) and improved cellular and intercellular structures for the first time. The improvement of cellular redox homeostasis involves alleviating endoplasmic reticulum (ER) stress through the inositol-requiring enzyme 1 (IRE1), RNA-dependent protein kinase-like ER kinase (PERK), and activating transcription factor 6 (ATF6) signaling pathways. The alleviation of ER stress may be linked to the phosphomannomutase (PMM)-mediated enhancement of protein glycosylation. In addition, ubiquitin-dependent [PTEN-induced putative kinase 1 (PINK1)/Parkin] and ubiquitin-independent [BCL2-interacting protein 3-like (BNIP3L), BCL2-interacting protein 3 (BNIP3), and FUN14 domain containing 1 (FUNDC1)] mitophagy may play a role in maintaining cellular redox homeostasis. The enhancement of intercellular structures includes enhancing tight junction and adherent junction structures, which may be closely associated with the small Rho GTPase protein (RhoA)/the Rho-associated protein kinase (ROCK) signaling pathway. In conclusion, D-mannose improved intestinal cellular redox homeostasis associated with ER stress and mitophagy pathways, and enhanced intercellular structures related to tight junctions and adherent junctions. Furthermore, quadratic regression analysis of the PWG and intestinal reactive oxygen species content indicated that the optimal addition level of D-mannose for juvenile grass carp was 4.61 and 4.59 g/kg, respectively.

Effects of florfenicol on the midgut physiological function of Bombyx mori, based on the diversity of intestinal microbiota

AbstractFlorfenicol (FF) is a new antibiotic commonly used in sericulture. This study aimed to examine the effects of low (LC: 0.06 g/L), medium (MC: 0.12 g/L), and high (HC: 1.2 g/L) concentrations of FF on the midgut physiological functions of the silkworm, Bombyx mori (L.) (Lepidoptera: Bombycidae). The results showed that the body weight and the whole cocoon weight of silkworms decreased and the development duration of the fifth instar was prolonged in the HC group. The structure of intestinal microbiota of silkworm larvae was changed by high FF exposure. Specifically, the abundance of conditional pathogens (Curtobacterium, Sanguibater, etc.) was significantly increased, whereas the abundance of Pseudomonas and Pedobacter was decreased significantly. Additionally, the intestinal reactive oxygen species level at 72 h was significantly elevated, and the muscle layer had become loose, together with the appearance of gut goblet cell atrophy. We observed that the increase in Lactobacillus abundance led to a reduction in intestinal fluid pH, resulting in decreased α‐amylase and protease activities, whereas lipase activity exhibited an elevation. The results demonstrated that the accumulation of peroxides induced by exposure to 1.2 g/L FF caused intestinal damage, and the decrease in pH resulting from alterations in microbial composition and structure affected digestive enzyme activity, collectively leading to physiological impairment of the silkworm midgut. These findings provide a valuable reference for the safe use of FF in sericulture.

Environmentally persistent free radicals on photoaging microplastics shortens longevity via inducing oxidative stress in Caenorhabditis elegans

Microplastics (MPs) are ubiquitous environmental contaminants that exert multiple toxicological effects. Current studies have mainly focused on modeled or unaged MPs, which lack environmental relevance. The generation and toxicity of environmentally persistent free radicals (EPFRs) on photoaging polystyrene (PS) have not been well studied, and the role of EPFRs on the toxic effects of photoaged PS is easily ignored. Photoaging primarily produces EPFRs, followed by an increase in reactive oxygen species (ROS) content and oxidative potential, which alter the physicochemical properties of photoaged PS. The mean lifespan and lipofuscin content were significantly altered after acute exposure to photoaged PS for 45 d (PS-45) and 60 d (PS-60) in Caenorhabditis elegans. Intestinal ROS and gst-4::GFP expression were enhanced, concomitant with the upregulation of associated genes. Treatment with N-acetyl-l-cysteine by radical quenching test significantly decreased EPFRs levels on the aged PS and inhibited the acceleration of the aging and oxidative stress response in nematodes. Pearson's correlation analysis also indicated that the EPFRs levels were significantly associated with these factors. Thus, the EPFRs generated on photoaged PS contribute to the acceleration of aging by oxidative stress. This study provides new insights into the potential toxicity and highlights the need to consider the role of EPFRs in the toxicity assessment of photoaged PS.

Orostachys malacophylla (pall.) fisch extracts alleviate intestinal inflammation in Drosophila

Ethnopharmacological relevanceOrostachys malacophylla (Pall.) Fisch (O. malacophylla) is a succulent herbaceous plant that is the Orostachys genus of Crassulaceae family. O. malacophylla has been widely used as a traditional Chinese medicine with antioxidant, anti-inflammatory, anti-febrile, antidote, anti-Toxoplasma gondii properties. However, the biological function of alleviating intestinal inflammation and key bioactive compounds were still unknown. Aim of the studyWe used a Drosophila model to study the protective effects and bioactive compounds of O. malacophylla water extract (OMWE) and butanol extract (OMBE) on intestinal inflammation. Materials and methodsDrosophila intestinal inflammation was induced by oral invasion of dextran sodium sulfate (DSS) or Erwinia carotovora carotovora 15 (Ecc15). We revealed the protective effects of two extracts by determining intestinal reactive oxygen species (ROS) and antimicrobial peptide (AMP) levels and intestinal integrity, and using network pharmacology analysis to identify bioactive compounds. ResultsWe demonstrated that both OMWE and OMBE could ameliorate the detrimental effects of DSS, including a decreased survival rate, elevated ROS levels, increased cell death, excessive proliferation of ISCs, acid-base imbalance, and disruption of intestinal integrity. Moreover, the overabundance of lipid droplets (LDs) and AMPs by Ecc15 infection is mitigated by these extracts, thereby enhancing the flies' resistance to adverse stimuli. In addition, we used widely targeted metabolomics and network pharmacology analysis to identify bioactive compounds associated with IBD healing that are present in OMWE and OMBE. ConclusionsIn summary, our research indicates that OMWE and OMBE significantly mitigate intestinal inflammation and have the potential to be effective therapeutic agents for IBD in humans.

Fucoxanthin alleviates lipopolysaccharide-induced intestinal barrier injury in mice.

The aim of this study was to evaluate the preventive role and underlying mechanisms of fucoxanthin (Fx) on lipopolysaccharide (LPS)-induced intestinal barrier injury in mice. Our results demonstrated that the oral administration of Fx (50 and 200 mg per kg body weight per day) for consecutive 7 days significantly alleviated the severity of LPS-induced intestinal barrier injury in mice, as evidenced by attenuating body weight loss, improving intestinal permeability, and ameliorating intestinal morphological damage such as reduction in the ratio of the villus length to the crypt depth (V/C), intestinal epithelium distortion, goblet cell depletion, and low mucin 2 (MUC2) expression. Fx also significantly mitigated LPS-induced excessive apoptosis of intestinal epithelial cells (IECs) and curbed the decrease of tight junction proteins including claudin-1, occludin, and zonula occludens-1 in the ileum and colon. Additionally, Fx effectively alleviated LPS-induced extensive infiltration of macrophages and neutrophils into the intestinal mucosa, the overproduction of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1beta (IL-1β) and IL-6, and gasdermin D (GSDMD)-mediated pyroptosis of IECs. The underlying mechanisms might be associated with inhibiting the activation of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs) and nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathways. Moreover, Fx also notably restrained intestinal reactive oxygen species (ROS), malondialdehyde and protein carbonylation levels in LPS-treated mice, and it might be mediated by activating the nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway. Overall, these findings indicated that Fx might be developed as a potential effective dietary supplement to prevent intestinal barrier injury.

Prebiotic Mannan Oligosaccharide Attenuates Cognitive and Behavioral Disorders in HIV-1 gp120 Transgenic Mouse Via the Microbiota-Gut-Brain Axis

Background The prevalence of HIV-associated neurocognitive disorders (HAND) remains high among HIV-1 infected patients, despite significant advances in antiretroviral therapy (HAART). HAND is characterized by clinical symptoms such as motor and attention deficits, impaired learning and memory, and in severe cases, dementia. The HIV-1 envelope protein gp120 is believed to have a crucial role in the development of these disorders HIV-1-related neurocognitive dysfunction is strongly linked to the host inflammatory regulator α7 nicotinic acetylcholine receptor (A7R) and the signaling of highly reactive oxygen species (ROS). A7R plays a crucial role in regulating calcium ion exchange in nerve cells, immune cells, and endothelial cells. In the brain, antioxidants are present to control and prevent the formation of harmful ROS, which further contribute to the severity of neurodegeneration. Assessing ROS can help predict oxidative tissue damage, including modifications in proteins, lipids, or DNA. ROS tend to accumulate in the small and large intestines, leading to oxidative stress and affecting cognitive function. The prebiotic mangan oligosaccharide (MOS) has been reported to reshape the gut microbiome and increase short-chain fatty acid (SCFAs) production. This, in turn, alters neuronal redox status through the gut-brain axis. There may be a critical role for HIV-1 gp120 (Gp120) protein in these disorders. The microbiota-gut-brain (MGB) axis is bidirectional, and gut microbiota influence brain disorders including HAND, which could be targeted by nutritional interventions. Methods: The HIV-1 gp120 transgenic mice (Gp120 transgenic mice), and wild-type (WT) mice were randomly divided into 4 groups (9 months old, n=6 per group): WT group, WT+MOS group, Gp120 transgenic group, Gp120 transgenic + MOS group. All MOS group mice were administered the prebiotic MOS (0.12% w/v in the drinking water).The drinking water added MOS or was replaced twice a week for 8 weeks and recorded water intake. In the in vitro cell experiment, the cortex of neonatal Sprague-Dawley (SD) rats (1-3 days) was dissected to prepare astrocytes. Cells were identified using Cy3-conjugated GFAP immunostaining. Cultured astrocytes were treated with 300 pM Gp120 protein for 24 hours, and then 0.2, 2, 20 or 200 μM MOS was applied for 24 hours, and different proteins level of expression were detected by Western blot. The ROS level were then analyzed on FACS Calibur-Tangerine flow cytometry in 502 nm. The alteration in mitochondrial membrane potential in astrocytes was assessed through the utilization of the JC-1 Assay Kit in mPMs. Results: As a result of treatment with MOS, the redox status of the brain and the neuroinflammatory responses were significantly balanced. Through correlation analysis, it was observed that a modified gut microbiome and increased butyrate production had a significant impact on behavioral changes and brain oxidative status. Our findings suggest that MOS could mitigate cognitive and behavioral disorders in the Gp120 transgenic mouse. MOS achieves this by suppressing Gp120-induced chronic inflammation and dysregulated production of reactive oxygen species (ROS), thereby improving HIV-1-related neurocognitive dysfunction. This is achieved by targeting A7R and intestinal ROS signaling. Additionally, our results indicate that SCFA supplementation in the brain of HAND mice alleviated behavioral disorders and balanced the HPA-axis and redox status. Conclusion: Overall, the present study demonstrated that MOS significantly reduced cognitive and mental deficits in Gp120 transgenic mice. As prebiotics, MOS could be translated into novel microbiota-targeted approaches to manage metabolic and neurodegenerative diseases. ( Acknowledgements: Natural Science Foundation of Guangdong Province, No. 208059478058 to H.C.; Corresponding author: Hong Cao, gzhcao@smu.edu.cn ) Keywords：HIV-1 gp120, mangan oligosaccharide, α7nAChR, reactive oxygen species

Epithelial Dual Oxidase 2 Shapes the Mucosal Microbiome and Contributes to Inflammatory Susceptibility.

Reactive oxygen species (ROS) are highly reactive molecules formed from diatomic oxygen. They act as cellular signals, exert antibiotic activity towards invading microorganisms, but can also damage host cells. Dual oxidase 2 (DUOX2) is the main ROS-producing enzyme in the intestine, regulated by cues of the commensal microbiota and functions in pathogen defense. DUOX2 plays multiple roles in different organs and cell types, complicating the functional analysis using systemic deletion models. Here, we interrogate the precise role of epithelial DUOX2 for intestinal homeostasis and host-microbiome interactions. Conditional Duox2∆IEC mice lacking DUOX2, specifically in intestinal epithelial cells, were generated, and their intestinal mucosal immune phenotype and microbiome were analyzed. Inflammatory susceptibility was evaluated by challenging Duox2∆IEC mice in the dextran sodium sulfate (DSS) colitis model. DUOX2-microbiome interactions in humans were investigated by paired analyses of mucosal DUOX2 expression and fecal microbiome data in patients with intestinal inflammation. Under unchallenged conditions, we did not observe any obvious phenotype of Duox2∆IEC mice, although intestinal epithelial ROS production was drastically decreased, and the mucosal microbiome composition was altered. When challenged with DSS, Duox2∆IEC mice were protected from colitis, possibly by inhibiting ROS-mediated damage and fostering epithelial regenerative responses. Finally, in patients with intestinal inflammation, DUOX2 expression was increased in inflamed tissue, and high DUOX2 levels were linked to a dysbiotic microbiome. Our findings demonstrate that bidirectional DUOX2-microbiome interactions contribute to mucosal homeostasis, and their dysregulation may drive disease development, thus highlighting this axis as a therapeutic target to treat intestinal inflammation.

Silibinin alleviates intestinal inflammation via inhibiting JNK signaling in Drosophila.

Inflammatory bowel diseases (IBDs) are characterized by chronic relapsing intestinal inflammation that causes digestive system dysfunction. For years, researchers have been working to find more effective and safer therapeutic strategies to treat these diseases. Silibinin (SIL), a flavonoid compound extracted from the seeds of milk thistle plants, possesses multiple biological activities and is traditionally applied to treat liver diseases. SIL is also widely used in the treatment of a variety of inflammatory diseases attributed to its excellent antioxidant and anti-inflammatory effects. However, the efficacy of SIL against IBDs and its mechanisms remain unclear. In this study, using Drosophila melanogaster as a model organism, we found that SIL can effectively relieve intestinal inflammation caused by dextran sulfate sodium (DSS). Our results suggested that SIL supplementation can inhibit the overproliferation of intestinal stem cells (ISCs) induced by DSS, protect intestinal barrier function, acid-base balance, and intestinal excretion function, reduce intestinal reactive oxygen species (ROS) levels and inflammatory stress, and extend the lifespan of Drosophila. Furthermore, our study demonstrated that SIL ameliorates intestinal inflammation via modulating the c-Jun N-terminal kinase (JNK) signaling pathway in Drosophila. Our research aims to provide new insight into the treatment of IBDs.

Design of Antioxidant Nanoparticle, which Selectively Locates and Scavenges Reactive Oxygen Species in the Gastrointestinal Tract, Increasing The Running Time of Mice.

Excess reactive oxygen species (ROS) produced during strong or unfamiliar exercise cause exercise-induced gastrointestinal syndrome (EIGS), leading to poor health and decreased exercise performance. The application of conventional antioxidants can neither ameliorate EIGS nor improve exercise performance because of their rapid elimination and severe side effects on the mitochondria. Hence, a self-assembling nanoparticle-type antioxidant (RNPO ) that is selectively located in the gastrointestinal (GI) tract for an extended time after oral administration is developed. Interestingly, orally administered RNPO significantly enhances the running time until exhaustion in mice with increasing dosage, whereas conventional antioxidants (TEMPOL) tends to reduce the running time with increasing dosage. The running (control) and TEMPOL groups show severe damage in the GI tract and increased plasma lipopolysaccharide (LPS) levels after 80 min of running, resulting in fewer red blood cells (RBCs) and severe damage to the skeletal muscles and liver. However, the RNPO group is protected against GI tract damage and elevation of plasma LPS levels, similar to the nonrunning (sedentary) group, which prevents damage to the whole body, unlike in the control and TEMPOL groups. Based on these results, it is concluded that continuous scavenging of excessive intestinal ROS protects against gut damage and further improves exercise performance.

Homeostatic control of an iron repressor in a GI tract resident.

The transition metal iron plays a crucial role in living cells. However, high levels of iron are potentially toxic through the production of reactive oxygen species (ROS), serving as a deterrent to the commensal fungus Candida albicans for colonization in the iron-rich gastrointestinal tract. We observe that the mutant lacking an iron-responsive transcription factor Hap43 is hyper-fit for colonization in murine gut. We demonstrate that high iron specifically triggers multiple post-translational modifications and proteasomal degradation of Hap43, a vital process guaranteeing the precision of intestinal ROS detoxification. Reduced levels of Hap43 de-repress the expression of antioxidant genes and therefore alleviate the deleterious ROS derived from iron metabolism. Our data reveal that Hap43 functions as a negative regulator for oxidative stress adaptation of C. albicans to gut colonization and thereby provide a new insight into understanding the interplay between iron homeostasis and fungal commensalism.

Microbiota-driven changes in colitis susceptibility in CGD mice are associated with alterations in intestinal epithelial reactive oxygen species production and NADPH oxidase subunit gene expression

BackgroundChronic granulomatous disease (CGD) is an inborn error of immunity caused by defects in any one of the 6 subunits (gp91phox, p47phox, p22phox, p67phox, p40phox or chaperone EROS) forming the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) complex 2 (NOX2) resulting in defective phagocyte-derived reactive oxygen species (ROS) production. Almost 50% of patients with CGD suffer from inflammatory bowel disease (IBD). While ROS plays an important role in intestinal homeostasis, the impact of NOX2 defects on intestinal barrier ROS levels is unknown. We previously demonstrated that the intestinal microbiome is a critical driver of colitis susceptibility in mice with CGD. Given the importance of ROS at the intestinal barrier, we hypothesize that the microbiota drives intestinal inflammation by modulating NOX-derived intestinal epithelial ROS production. ObjectiveTo determine whether microbiota-driven changes in colitis susceptibility in mice with CGD are associated with alterations in intestinal epithelial ROS production and NOX gene expression. MethodSusceptibility to dextran sodium sulfate (DSS) colitis was evaluated in CGD mice with distinct microbiota: 1) gp91phox-/- -mice from NIH (non-colitogenic microbiota), 2) gp91phox-/- -mice from IRCM (colitogenic microbiota), 3) p47phox-/- -mice from NIH and IRCM (colitogenic microbiota) and wild type (WT) mice cross-fostered with p47phox-/- -mice (i.e. WT mice colonized with the colitogenic p47phox-/-microbiota). ROS production and NOX (i.e. NOX1, NOX4, NOX2, DUOX2) gene expression was measured in colon epithelial cells isolated from mice used in the aforementioned colitis experiments. ResultsNIH gp91phox-/- -mice did not have increased colitis susceptibility compared to WT mice whereas IRCM gp91phox-/- -mice, p47phox-/- -mice from both facilities and cross-fostered WT mice had increased susceptibility to DSS colitis. Intestinal epithelial cells sorted from mice with increased colitis susceptibility produced more ROS and were associated with distinct patterns of NOX subunit gene expression. ConclusionOur data suggest the microbiota may drive intestinal inflammation in mice with CGD by increasing NOX-derived ROS production in the intestinal epithelium. These findings bring forward a possible mechanism by which the microbiota contributes to the pathogenesis of CGD-associated IBD.

Direct evidence for the involvement of intestinal reactive oxygen species in the progress of depression via the gut-brain axis

Depression is a serious global social problem. Various therapeutic drugs have been developed based on the monoamine hypothesis; however, treatment-resistant depression is a common clinical issue. Recently, the gut-brain axis, which is associated with the hypothesis that the intestinal environment affects the brain, has garnered significant interest, and several studies have attempted to treat brain disorders based on this axis. These attempts include fecal transplantation, probiotics and prebiotics. In this study, we focused on intestinal reactive oxygen species (ROS) because excessive ROS levels disturb the intestinal environment. To elucidate the impact of scavenging intestinal ROS on depression treatment via the gut-brain axis, a novel polymer-based antioxidant (siSMAPoTN), which was distributed only in the intestine and did not diffuse into the whole body after oral administration, was used. siSMAPoTN selectively scavenged intestinal ROS and protected the intestinal environment from damage caused by chronic restraint stress (CRS). In addition, siSMAPoTN suppressed physiological and behavioral depression-related symptoms in the CRS mouse model.

Raspberry polyphenols alleviate neurodegenerative diseases: through gut microbiota and ROS signals.

Neurodegenerative diseases are neurological disorders that become more prevalent with age, usually caused by damage or loss of neurons or their myelin sheaths, such as Alzheimer's disease and epilepsy. Reactive oxygen species (ROS) are important triggers for neurodegenerative disease development, and mitigation of oxidative stress caused by ROS imbalance in the human body is important for the treatment of these diseases. As a widespread delicious fruit, the raspberry is widely used in the field of food and medicine because of its abundant polyphenols and other bioactive substances. Polyphenols from a wide variety of raspberry sources could alleviate neurodegenerative diseases. This review aims to summarize the current roles of these polyphenols in maintaining neurological stability by regulating the composition and metabolism of the intestinal flora and the gut-brain axis signal transmission. Especially, we discuss the therapeutic effects on neurodegenerative diseases of raspberry polyphenols through intestinal microorganisms and ROS signals, by means of summary and analysis. Finally, methods of improving the digestibility and utilization of raspberry polyphenols are proposed, which will provide a potential way for raspberry polyphenols to guarantee the health of the human nervous system.

Long-term exposure to tire-derived 6-PPD quinone causes intestinal toxicity by affecting functional state of intestinal barrier in Caenorhabditis elegans

2-((4-Methylpentan-2-yl)amino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione (6-PPDQ) is the ozonation product of 6-PPD, a commonly used tire preservative. Although the 6-PPDQ has been frequently detected in different environmental ecosystems, its long-term effects on organisms remain still largely unknown. We here used Caenorhabditis elegans as an experimental animal to investigate the toxic effect of prolonged exposure to 6-PPDQ (0.1–100 μg/L). After the exposure, we found that 100 μg/L 6-PPDQ caused the lethality. We further selected concentrations of 0.1–10 μg/L to examine the possible intestinal toxicity induced by 6-PPDQ. Although 0.1–10 μg/L 6-PPDQ could not influence intestinal morphology, the intestinal permeability was significantly enhanced by 1–10 μg/L 6-PPDQ as indicated by erioglaucine disodium staining. In addition, the expression of intestinal fatty acid transporter ACS-22 governing functional state of intestinal barrier was decreased by exposure to 1–10 μg/L 6-PPDQ. Meanwhile, intestinal reactive oxygen species (ROS) production was induced by 0.1–10 μg/L 6-PPDQ and lipofuscin accumulation reflected by intestinal autofluorescence was activated by 1–10 μg/L 6-PPDQ. Accompanied with activation of intestinal oxidative stress, expressions of some anti-oxidation related genes (ctl-2, sod-2, sod-3, and sod-4) were significantly increased by 0.1–10 μg/L 6-PPDQ. Moreover, intestinal RNAi of acs-22 strengthened the susceptibility of nematodes to intestinal toxicity of 6-PPDQ. Therefore, considering that the environmentally relevant concentrations of 6-PPDQ were ≤10 μg/L, our data suggested that long-term exposure to 6-PPDQ at environmentally relevant concentrations potentially results in intestinal toxicity by disrupting functional state of intestinal barrier in organisms.

NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures

ObjectiveLoss-of-function mutations in genes generating reactive oxygen species (ROS), such as NOX1, are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined.DesignROS measurements and single-cell transcriptomics...

The use of different sublethal endpoints to monitor atrazine toxicity in nematode Caenorhabditis elegans

In this work, Caenorhabditis elegans was employed as an in vivo model to determine the toxic effects of atrazine at different concentrations. After the exposure period from the larval stage L1 to adulthood day 1, atrazine (10 mg/L) significantly decreased the body length and lifespan of nematodes. In addition, exposure to ≥0.01 mg/L atrazine remarkably increased the intestinal reactive oxygen species (ROS) levels and reduced locomotion behavior of nematodes, while exposure to ≥ 1 mg/L atrazine decreased the brood size of nematodes. Moreover, atrazine (0.001–0.1 mg/L) upregulated the expression levels of hsp-6::GFP and hsp-6/60 in nematodes, indicating the activation of mitochondrial unfolded protein response (mtUPR). On the contrary, atrazine (1–10 mg/L) downregulated the expression levels of hsp-6::GFP and hsp-6/60 in nematodes. Furthermore, mtUPR induction governed by the RNAi knockdown of atfs-1 could increase the vulnerability of nematodes against atrazine toxicity. Overall, our findings highlighted the dynamic responses of nematodes toward different concentrations of atrazine, which could be monitored using different sublethal endpoints as bioindicators.

Multigenerational effects of polyethylene terephthalate microfibers in Caenorhabditis elegans

Microfibers (MFs) have recently become an increasingly prevalent pollutant in ecosystems and pose a direct threat to organisms and an indirect threat via adsorption of other pollutants. Here, we used Caenorhabditis elegans to study multigenerational effects of polyethylene terephthalate (PET) MFs (diameter 17.4 μm) by observing the maternal generation (P0) to the seventh offspring generation (F7) with continuous MF exposure. Exposure to 250-μm PET MFs decreased locomotion behavior and induced intestinal reactive oxygen species (ROS) in the P0 generation compared with other PET MF sizes. Moreover, no notably negative effects on survival were observed in any generation during continuous exposure to 250-μm PET MFs. However, the reproduction rate clearly decreased in the F2 and F3 generations but gradually recovered in the F4–F7 generations. Developmental abnormalities showed a close relationship with body length. Although some recovery was confirmed, there were significant decreases in body length in the F2–F5 generations. Interestingly, growth inhibition was also observed in the F6 generation without MF exposure. ROS production and dermal damage in the P0–F5 generations might have resulted in the toxicological responses. To the best of our knowledge, this is the first study to provide evidence of multigenerational toxicity of MFs in C. elegans.

Proanthocyanidin-Rich Grape Seed Extract Reduces Inflammation and Oxidative Stress and Restores Tight Junction Barrier Function in Caco-2 Colon Cells.

Grape polyphenols have previously been shown to improve gut health and attenuate the symptoms of metabolic syndrome; however, the mechanism of these beneficial effects is still debated. In this study, we investigated the protective effect of proanthocyanidin-rich grape seed extract (GSE) on bacterial lipopolysaccharide (LPS)-induced oxidative stress, inflammation, and barrier integrity of human Caco-2 colon cells. GSE significantly reduced the LPS-induced intracellular reactive oxygen species (ROS) production and mitochondrial superoxide production, and upregulated the expression of antioxidant enzyme genes. GSE also restored the LPS-damaged mitochondrial function by increasing mitochondrial membrane potential. In addition, GSE increased the expression of tight junction proteins in the LPS-treated Caco-2 cells, increased the expression of anti-inflammatory cytokines, and decreased pro-inflammatory cytokine gene expression. Our findings suggest that GSE exerts its beneficial effects on metabolic syndrome by scavenging intestinal ROS, thus reducing oxidative stress, increasing epithelial barrier integrity, and decreasing intestinal inflammation.