Pyroptosis: a new insight into intestinal inflammation and cancer.

Pyroptosis is an innate immune response triggered by the activation of inflammasomes by various influencing factors, characterized by cell destruction. It impacts the immune system and cancer immunotherapy. In recent years, the roles of pyroptosis and inflammasomes in intestinal inflammation and cancer have been continuously confirmed. This article reviews the latest progress in pyroptosis mechanisms, new discoveries of inflammasomes, mutual regulation between inflammasomes, and their applications in intestinal diseases. Additionally, potential synergistic treatment mechanisms of intestinal diseases with pyroptosis are summarized, and challenges and future directions are discussed, providing new ideas for pyroptosis therapy.

Polyphenol Rich Forsythia suspensa Extract Alleviates DSS-Induced Ulcerative Colitis in Mice through the Nrf2-NLRP3 Pathway.

This study systematically evaluated the effect of Forsythia suspensa extract on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) and determined its mechanism of action. The results showed that Forsythia suspensa extract significantly inhibited DSS-induced UC in mice. In vivo mechanistic studies revealed that Forsythia suspensa extract relieved the symptoms of colitis by enhancing antioxidant activity and inhibiting pyroptosis. Further in vitro experiments on the mechanism of Forsythia suspensa showed that it reduced the level of reactive oxygen species (ROS) in J774A.1 cells. We found that Forsythia suspensa extract enhanced cellular antioxidation activity and inhibited pyroptosis. After silencing NLRP3, it was found to play an important role in pyroptosis. In addition, after Nrf2 was silenced, the inhibitory effect of Forsythia suspensa extract on cell pyroptosis was eliminated, indicating an interaction between Nrf2 and NLRP3. Metabonomics revealed that Forsythia suspensa extract significantly improved metabolic function in colitis mice by reversing the abnormal changes in the levels of 9 metabolites. The main metabolic pathways involved were glutathione metabolism, aminoacyl-tRNA biosynthesis and linoleic acid metabolism. In conclusion, we found that Forsythia suspensa extract significantly alleviated DSS-induced UC injury through the Nrf2-NLRP3 pathway and relieved metabolic dysfunction.

Comparative Evaluation of Forsythiae Fructus From Different Harvest Seasons and Regions by HPLC/NIR Analysis and Anti-inflammatory and Antioxidant Assays.

Forsythiae Fructus (FF), the dry fruit of Forsythia suspensa (Thunb.) Vahl, has a long history of use in traditional Chinese Medicine for its heat-clearing and detoxifying properties. It possesses clinical therapeutic effects and biological functions showing efficacy in handling different diseases. To investigate the FF differences in Henan, Shanxi, and Shaanxi in August and October, the surface morphology, mid-infrared and near-infrared spectrums, and HPLC were analyzed. Concurrently, the anti-inflammatory and antioxidant effects on LPS-induced J774A.1 cells were evaluated by western blot and RT-qPCR. The results showed that FF from different Harvest Seasons and Regions are provided with different microstructures and mid-infrared and near-infrared spectrums, and the levels of forsythiaside A and phillyrin of FF from Shanxi in August and phillygenin of FF from Shaanxi in August were the highest. Meanwhile, FF from Shanxi and Shaanxi in August markedly reduced the levels of inflammatory cytokines and mediators (TNF-α, IL-1ß, NF-κB, and iNOS) and the protein expression levels of phosphorylated total IKKα/ß and nuclear NF-κB. In August, SXFF and SAXFF also promoted the mRNA expression levels of HO-1 and NQO1 and the protein expression levels of HO-1 and nuclear Nrf2 and suppressed the protein expression levels of KEAP1. Spearman correlation analysis showed that phillygenin had a strong correlation with the protein expression on LPS-induced J774A.1 cells. In summary, our results showed that FF from harvest seasons and regions contributed to the distinct differences in microstructure, the mid-infrared and near-infrared spectrums, and compound content. More importantly, FF from Shanxi and Shaanxi in August showed marked anti-inflammatory and antioxidant activities, but with some differences, which may be because of different contents of phillygenin and phillyrin of lignans in FF.

Melatonin Alleviates Neuroinflammation and Metabolic Disorder in DSS-Induced Depression Rats.

There is a bidirectional relationship between inflammatory bowel disease (IBD) and depression/anxiety. Emerging evidences indicate that the liver may be involved in microbiota-gut-brain axis. This experiment focused on the role of melatonin in regulating the gut microbiota and explores its mechanism on dextran sulphate sodium- (DSS-) induced neuroinflammation and liver injury. Long-term DSS-treatment increased lipopolysaccharide (LPS), proinflammation cytokines IL-1ß and TNF-α, and gut leak in rats, breaking blood-brain barrier and overactivated astrocytes and microglia. Ultimately, the rats showed depression-like behavior, including reduction of sucrose preference and central time in open field test and elevation of immobility time in a forced swimming test. Oral administration with melatonin alleviated neuroinflammation and depression-like behaviors. However, melatonin supplementation did not decrease the level of LPS but increase short-chain fatty acid (SCFA) production to protect DSS-induced neuroinflammation. Additionally, western blotting analysis suggested that signaling pathways farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF 15) in gut and apoptosis signal-regulating kinase 1 (ASK1) in the liver overactivated in DSS-treated rats, indicating liver metabolic disorder. Supplementation with melatonin markedly inhibited the activation of these two signaling pathways and its downstream p38. As for the gut microbiota, we found that immune response- and SCFA production-related microbiota, like Lactobacillus and Clostridium significantly increased, while bile salt hydrolase activity-related microbiota, like Streptococcus and Enterococcus, significantly decreased after melatonin supplementation. These altered microbiota were consistent with the alleviation of neuroinflammation and metabolic disorder. Taken together, our findings suggest melatonin contributes to reshape gut microbiota and improves inflammatory processes in the hippocampus (HPC) and metabolic disorders in the liver of DSS rats.

Shen-Ling-Bai-Zhu-San Improves Dextran Sodium Sulfate-Induced Colitis by Inhibiting Caspase-1/Caspase-11-Mediated Pyroptosis.

The traditional Chinese medicine Shen-ling-bai-zhu-san (SLBZS) is described in "Tai Ping Hui Min He Ji Ju Fang." SLBZS has been shown to be effective against many gastrointestinal diseases. The present study aimed to investigate the effect of SLBZS on experimental colitis in mice and to define the potential mechanisms. Our data suggest that compared to the model group, SLBZS treatment increases mouse body weight and colon length, decreases the DAI score, and improves colonic injury. SLBZS reduces the production of cytokines (IL-1ß, IL-18, and TNF-α) in colon tissue and mouse colonic mucosal epithelial (MCME) cells. Mechanistically, SLBZS inhibits inflammation by inhibiting the MAPK and NF-κB signaling pathways. Further mechanistic analyses showed that SLBZS attenuates the expression levels of pyroptosis-related genes, including NLRP3, ASC, and GSDMD-N in the colons of mice. In addition, SLBZS restores the levels of the colon tight junction proteins ZO-1 and occludin, suggesting that it protects colonic barrier integrity and ameliorates the progression of colitis. In this paper, we demonstrate that SLBZS attenuates DSS-induced ulcerative colitis injury in mice via the MAPK/NF-κB and pyroptosis signaling pathway. These results indicate that SLBZS is a potential drug for the treatment of UC.

Effects of Probiotics on Depressive or Anxiety Variables in Healthy Participants Under Stress Conditions or With a Depressive or Anxiety Diagnosis: A Meta-Analysis of Randomized Controlled Trials.

Background: Probiotics have been associated with the treatment of depression and anxiety. However, the results reported in the literature have been inconsistent, and no meta-analysis specifically reported probiotics used on participants with varying levels of emotional state. Methods: This meta-analysis aimed to study the effectiveness of probiotics on anxious or depressive symptomatology for participants under stress conditions or with a depressive or anxiety disorder diagnosis. Medline, PubMed, EMBASE, and the Cochrane Library were searched through December 2019 for randomized controlled trials (RCTs). The primary outcomes were depression and anxiety scores. Main inclusion criteria: RCTs of probiotics for participants with a mood or emotional disorder diagnosis or under stress situations; and all participants were adults (age ≥16 years); Assessed by the modified Jadad assessment scale found seven high-quality studies and three low-quality studies. Results: Ten clinical trials (n = 685 total participants) were included based on the inclusion and exclusion criteria. All studies were assessed as low or moderate risk of bias. The meta-analysis showed that probiotics could significantly reduce the depression scale for patients with anxiety and depression, and healthy participants under stress. However, there was no significant difference between the probiotics and placebo groups in the reduction of patient anxiety scores, even if they are depressive or anxious patients or healthy participants under stress. Subgroup analysis revealed that probiotics had significant effect on depressive symptoms just in patients with depression, and no significant change in anxiety in patients, and no improvement in participant performance under stress. Conclusions: Probiotics could alleviate depressive symptoms in patients with a depression diagnosis or depression scores also in anxiety disorder diagnosis, and suggesting that probiotics may be adjunct therapies for mood or emotional disorders. Therefore, it is essential that probiotics could be more involved in the treatment of patients with depression in the future. The evidence of probiotics successfully treating depression is still insufficient, and more high-quality studies on patients with depression are still needed.

The Gut Microbiome Modulates the Changes in Liver Metabolism and in Inflammatory Processes in the Brain of Chronic Unpredictable Mild Stress Rats.

Generally, depression is the result of complex gene-environment interactions. Recent studies have showed that the gut microbiota can affect brain function through the microbiota-gut-brain axis. However, the underlying mechanism of the microbiota and potential influence of depression remain elusive. We aimed to determine how gut microbiome contributes to the process of depression and further influences the host. Chronic unpredictable mild stress (CUMS) is used to establish a depression model. Fecal microbiota transplant (FMT) is applied to illustrate that depression can be transmitted via microbiota, and metabolism of liver analysis is applied to demonstrate further influence to the liver. We also analyzed the astrocyte activation in the brain by immunofluorescence (IF). Here, we show that the structure of the gut microbiome changes markedly after rats undergo CUMS. Notably, we found that the ratio of Lactobacillus to Clostridium can be a vital index for the development of depression. Depression-like behavior can be duplicated through FMT. Moreover, increased zonulin and fatty acid binding protein-2 indicates that gut barrier integrity is broken after FMT. Subsequently, metabolomics shows that liver metabolic disorder occurs and leads to liver coagulative necrosis. In addition, increased inflammatory cytokine expression and higher astrocyte activation indicate an inflammatory process in the brain. These findings suggest that dysbiosis gut microbiome contributes to development of depression and further causes liver metabolic disorders in a way that may be relevant to the Lactobacillus to Clostridium ratio.

Characterization of the cellular effects and mechanism of arsenic trioxide-induced hepatotoxicity in broiler chickens.

To characterize the cellular effects and mechanism of arsenic trioxide (ATO)-induced hepatotoxicity in broiler chickens, increasing concentrations of ATO (0, 0.6, 1.2, 2.4, and 4.8 µM) were added to chicken hepatocyte cultures in vitro. The changes in hepatocyte morphology, oxidative stress and apoptosis were evaluated using fluorescence microscopy and flow cytometry. The effects of ATO on mRNA or protein expression of antioxidant enzymes, especially methionine sulfoxide reductase (Msr), were analyzed using qRT-PCR and western blotting assays. Increased apoptosis were concomitant with increased reactive oxygen species (ROS) accumulation and upregulation of antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) with increasing ATO concentrations. Moreover, G1 phase arrest and dysregulation of the balance between antiapoptotic versus proapoptotic factors were noted. Furthermore, upregulation of HO-1, SOD-1, and TRX in the ATO groups were consistent with ATO-induced oxidative damage. High Msr, SOD-1, TRX, Bak1, Bax, and p53 protein levels in the ATO groups indicate that these proteins may have accumulated to counter ATO-induced oxidative stress. ROS scavenger N-acetyl-l-cysteine (NAC) could reverse ATO-induced oxidative damage and restore hepatocyte viability, even with compromised Msr function. Our findings suggest that Msr can protect broiler hepatocytes against ATO-induced oxidative stress. Furthermore, NAC-mediated reversal of oxidative damage may represent a strategy to mitigate potential economic losses associated with arsenic poisoning in the poultry industry.

Systems Pharmacology and Microbiome Dissection of Shen Ling Bai Zhu San Reveal Multiscale Treatment Strategy for IBD.

Generally, inflammatory bowel disease (IBD) can be caused by psychology, genes, environment, and gut microbiota. Therefore, IBD therapy should be improved to utilize multiple strategies. Shen Ling Bai Zhu San (SLBZS) adheres to the aim of combating complex diseases from an integrative and holistic perspective, which is effective for IBD therapy. Herein, a systems pharmacology and microbiota approach was developed for these molecular mechanisms exemplified by SLBZS. First, by systematic absorption-distribution-metabolism-excretion (ADME) analysis, potential active compounds and their corresponding direct targets were retrieved. Then, the network relationships among the active compounds, targets, and disease were built to deduce the pharmacological actions of the drug. Finally, an "IBD pathway" consisting of several regulatory modules was proposed to dissect the therapeutic effects of SLBZS. In addition, the effects of SLBZS on gut microbiota were evaluated through analysis of the V3-V4 region and multivariate statistical methods. SLBZS significantly shifted the gut microbiota structure in a rat model. Taken together, we found that SLBZS has multidimensionality in the regulation of IBD-related physiological processes, which provides new sights into herbal medicine for the treatment of IBD.

Structural Modulation of Gut Microbiota during Alleviation of Suckling Piglets Diarrhoea with Herbal Formula.

To determine whether the traditional Chinese herbal formula of Shen Ling Baizhu (SLB) could modulate the composition of the gut microbiota and alleviate diarrhoea in suckling piglets, twenty-four newly born piglets (Large White × Landrace × Duroc) were selected and allocated to 4 groups (control group and experimental groups I, II, and III) randomly. Faecal microbiome composition was assessed by 16S rRNA gene 454-pyrosequencing. The result indicated that experimental groups I and II exhibited significantly different gut microbiota from the control group. Most notably, the genera Lactobacillus and Bifidobacterium were significantly elevated in experimental group II compared with the control group (P < 0.05). Collinsella and Faecalibacterium were also enhanced in experimental group II compared with the control group (P < 0.05). The results showed that SLB treatment could modulate the gut microbiota composition of suckling piglets, enriching the amount of beneficial bacteria in particular. The observed changes in the gut microbiota could provide the basis for further research on the pharmacological mechanism of the tested Chinese herbal formula.

Fabrication of CH3NH3PbI3/PVP Composite Fibers via Electrospinning and Deposition.

In our study, one-dimensional PbI2/polyvinylpyrrolidone (PVP) composition fibers have been prepared by using PbI2 and PVP as precursors dissolved in N,N-dimethylformamide via a electrospinning process. Dipping the fibers into CH3NH3I solution changed its color, indicating the formation of CH3NH3PbI3, to obtain CH3NH3PbI3/PVP composite fibers. The structure, morphology and composition of the all as-prepared fibers were characterized by using X-ray diffraction and scanning electron microscopy.