Inulin alleviates perfluorooctanoic acid-induced intestinal injury in mice by modulating the PI3K/AKT/mTOR signaling pathway.

Perfluorooctanoic acid (PFOA) is a widely used industrial compound that has been found to induce intestinal toxicity. However, the underlying mechanisms have not been fully clarified and effective interventions are rarely developed. Inulin, a prebiotic, has been used as a supplement in human daily life as well as in gastrointestinal diseases and metabolic disorders. In this study, male mice were exposed to PFOA with or without inulin supplementation to investigate the enterotoxicity and potential intervention effects of inulin. Mice were administered PFOA at 1 mg/kg/day, PFOA with inulin at 5 g/kg/day, or Milli-Q water for 12 weeks. Histopathological analysis showed that PFOA caused colon shortening, goblet cell reduction, and inflammatory cell infiltration. The expression of the tight junction proteins ZO-1, occludin and claudin5 significantly decreased, indicating impaired barrier function. According to the RNA-sequencing analysis, PFOA exposure resulted in 917 differentially expressed genes, involving 39 significant pathways, such as TNF signaling and cell cycle pathways. In addition, the protein expression of TNF-α, IRG-47, cyclinB1, and cyclinB2 increased, while Gadd45γ, Lzip, and Jam2 decreased, suggesting the involvement of the TNF signaling pathway, cell cycle, and cell adhesion molecules in PFOA-associated intestinal injury. Inulin intervention alleviated PFOA-induced enterotoxicity by activating the PI3K/AKT/mTOR signaling pathway and increasing the protein expression of Wnt1, ß-catenin, PI3K, Akt3, and p62, while suppressing MAP LC3ß, TNF-α, and CyclinE expression. These findings suggested that PFOA-induced intestinal injury, including inflammation and tight junction disruption, was mitigated by inulin through modifying the PI3K/AKT/mTOR signaling pathways. Our study provides valuable insights into the enterotoxic effects of PFOA and highlights the potential therapeutic role of inulin.

New R2-CHA2DS2-VASc score predicts no-reflow phenomenon and long-term prognosis in patients with ST-segment elevation myocardial infarction after primary percutaneous coronary intervention.

Aims: Evaluating the prognostic validity of new R2-CHA2DS2-VASc score for no-reflow phenomena and long-term prognosis in patients following primary percutaneous coronary intervention (PCI) with ST-elevation myocardial infarction (STEMI). Materials and methods: From January 2017 to December 2018, a total of 401 patients with STEMI were continuously enrolled. According to the cut-off value, the patients were separated into two groups: R2-CHA2DS2-VASc < 3 group (n = 275) and R2-CHA2DS2-VASc ≥ 3 group (n = 126). Results: With a sensitivity of 52.6% and a specificity of 73.1%, the optimal cut-off value for predicting no-reflow is R2-CHA2DS2-VASc ≥ 3. R2-CHA2DS2-VASc ≥ 3 as the ideal cut-off value for predicting major adverse cardiovascular events (MACE) with an area under the curve (AUC) of 0.781 [95% Confidence interval (CI): 0.738-0.801, P 0.001], a sensitivity of 50%, and a specificity of 91.1%. The incidence of MACE, death from all causes, and worsening heart failure was greater in the R2-CHA2DS2-VASc ≥ 3 group, although there was no significant difference in the incidence of repeated revascularisation procedures following PCI between the two groups. R2-CHA2DS2-VASc ≥ 3 was also an independent predictor of MACE (hazard ratio = 2.48, 95% confidence interval CI: 1.33-4.62, P = 0.04). Moreover, this score has a greater sensitivity (66.7%) and specificity (88.7%) for predicting the progression of heart failure. Conclusion: R2-CHA2DS2-VASc ≥ 3 was independently associated with no-reflow phenomenon and poor clinical outcomes for patients in STEMI after primary PCI.

Gestational PCB52 exposure induces hepatotoxicity and intestinal injury by activating inflammation in dam and offspring mice: A maternal and progeny study.

Although Polychlorinated biphenyl (PCB) levels are decreased in the environment, the adverse effects of gestational exposure on the mother and offspring cannot be ignored due to the vulnerability of the fetus. In the present study, pregnant Balb/c mice were administered PCB52 (1 mg/kg BW/day) or corn oil vehicle by gavage until parturition. In the dams, PCB52 caused histopathological changes in the liver, higher serum levels of aminotransferase and alanine aminotransferase, and activated apoptosis and autophagy, suggesting hepatotoxicity. Overexpressed indicators of TLR4 pathway were observed in the liver of PCB52-exposed dams, indicated hepatic inflammation. Moreover, PCB52 exposure weakened the intestinal barrier and triggered inflammatory response, which might contribute to the hepatic inflammation by gut-liver axis. In the pups, prenatal PCB52 exposure affected the sex ratio at birth and reduced birth length and weights. Similar to the dams, prenatal PCB52 exposure induced hepatotoxicity in the pups without gender difference. Consistent with the alteration of gut microbiota, intestinal inflammation was confirmed, accompanying the disruption in the intestinal barrier and the activation of apoptosis and autophagy in the PCB52-exposed pups. Intestinal injury might be responsible for hepatotoxicity at least in part. Taken together, these findings suggested that gestational PCB52 exposure induced hepatic and intestinal injury in both maternal and offspring mice by arousing inflammation.

Gut microbiota mediates methamphetamine-induced hepatic inflammation via the impairment of bile acid homeostasis.

Methamphetamine (Meth), an addictive psychostimulant of abuse worldwide, has been a common cause of acute toxic hepatitis in adults. Gut microbiota has emerged as a modulator of host immunity via metabolic pathways. However, the microbial mechanism of Meth-induced hepatic inflammation and effective therapeutic strategies remain unknown. Here, mice were intraperitoneally (i.p.) injected with Meth to induce hepatotoxicity. Cecal microbiome and bile acids (BAs) composition were analyzed after Meth administration. Fecal microbiota transplantation (FMT) technology was utilized to investigate the role of microbiota. Additionally, the protective effects of obeticholic acid (OCA), an agonist of farnesoid X receptor (FXR), were evaluated. Results indicated that Meth administration induced hepatic cholestasis, dysfunction and aroused hepatic inflammation by stimulating the TLR4/MyD88/NF-κB pathway in mice. Meanwhile, Meth disturbed the cecal microbiome and impaired the homeostasis of BAs. Interestingly, FMT from Meth administered mice resulted in serum and hepatic BA accumulation and transferred similar phenotypic changes into the healthy recipient mice. Finally, OCA normalized Meth-induced BA accumulation in both serum and the liver, and effectively protected against Meth-induced hepatic dysfunction and inflammation by suppressing the TLR4/MyD88/NF-κB pathway. This study established the importance of microbial mechanism and its inhibition as a potential therapeutic target to treat Meth-related hepatotoxicity.

Methamphetamine induces intestinal injury by altering gut microbiota and promoting inflammation in mice.

Methamphetamine (METH) is a psychostimulant abused worldwide. Its abuse induces intestinal toxicity. Moreover, the gut microbiota is altered by drugs, which induces intestinal injury. Whether gut microbiota mediates METH-induced intestinal toxicity remains to be validated. In the present study, wild-type and TLR4-/- mice were treated with METH. Gut microbiota was determined using 16S rRNA gene sequencing. Transcriptomics of the intestinal mucosa was performed by RNA-Sequencing. Blood levels of pro-inflammatory cytokines and lipopolysaccharide (LPS), the intestinal barrier, and inflammation were also assessed. METH treatment weakened the intestinal barrier and increased pro-inflammatory cytokines and LPS levels in the blood. Moreover, METH treatment significantly decreased the diversity of probiotics but increased the abundance of pathogenic gut microbiota, contributing to the over-production of LPS and disruption of intestinal barrier. Inflammatory pathways were enriched in the intestinal mucosa of METH-treated mice by KEGG analysis. Consistently, activation of the TLR4 pathway was determined in METH-treated mice, which confirmed intestinal inflammation. However, pretreatment with antibiotics or Tlr4 silencing significantly alleviated METH-induced gut microbiota dysbiosis, LPS over-production, intestinal inflammation, and disruption of the intestinal barrier. These findings suggested that the gut microbiota and LPS-mediated inflammation took an important role in METH-induced intestinal injury. Taken together, these findings suggest that METH-induced intestinal injury is mediated by gut microbiota dysbiosis and LPS-associated inflammation.

Gestational exposure to GenX induces hepatic alterations by the gut-liver axis in maternal mice: A similar mechanism as PFOA.

GenX is an alternative to perfluorooctanoic acid (PFOA) and was included in the accession list of Substances of Very High Concern in 2019. Gestational GenX exposure induces maternal hepatotoxicity in animals. However, the mechanisms of GenX toxicity have not been explored. In the present study, pregnant Balb/c mice were administered with PFOA (1 mg/kg BW/day), GenX (2 mg/kg BW/day), or Milli-Q water by gavage during gestation. Similar hepatic pathological changes, including enlargement of hepatocytes, cytoplasm loss, nucleus migration, inflammatory cell infiltration, and reduction of glycogen storage, were observed in PFOA and GenX groups. Increased expression levels of indicators of the TLR4 pathway indicated activation of inflammation in the liver of maternal mice after exposure to PFOA or GenX, consistent with the pathological changes. Overexpression of cleaved PARP-1, cleaved caspase 3, Bax and decreased Bcl-2 proteins indicated activation of apoptosis, whereas overexpression of ULK-1, p62, beclin-1, LC3-II proteins and downregulation of p-mTOR implied that PFOA and GenX exposure initiated autophagy. Decreased secretion of mucus, reduced expression levels of tight junction proteins, and higher serum levels of lipopolysaccharide indicated disruption of the intestinal barrier. Translocation of lipopolysaccharide may be recognized by TLR4, thus triggering inflammatory pathway in the maternal liver. In summary, gestational exposure to PFOA or GenX induced maternal hepatic alterations through the gut-liver axis.

Antibiotics Attenuate Methamphetamine-Induced Hepatotoxicity by Regulating Oxidative Stress and TLR4/MyD88/Traf6 Axis.

Methamphetamine (METH) is a major psychostimulant drug of abuse worldwide, and its neurotoxicity has been studied extensively. In addition to neurotoxicity, METH can also induce hepatotoxicity. The underlying mechanism of intestinal microorganisms in METH-induced hepatotoxicity remains unclear. In this study, mice have received antibiotics intragastrically or PBS once each day for 1 week, followed by METH or saline. The antibiotics attenuated METH-induced hepatotoxicity as evidenced by histopathological observation and biochemical analysis; furthermore, they alleviated METH-induced oxidative stress. The effect of antibiotics on METH-induced hepatotoxicity was investigated using RNA-sequencing (RNA-seq). The RNA-seq results demonstrated that antibiotics could regulate 580 differentially expressed genes (DEGs), of which 319 were upregulated after METH treatment and then downregulated with antibiotic pretreatment and 237 were first downregulated after METH administration and then upregulated after antibiotic pretreatment, in addition to 11 upregulated and 13 downregulated ones simultaneously in METH and antibiotic-pretreated groups. RNA-seq analyses revealed that TLR4 is one of the hub genes. Western blot analysis indicated that antibiotics inhibited the increase of TLR4, MyD88 and Traf6 induced by METH. This research suggests that antibiotics may play an important role in preventing METH-induced liver injury by regulating oxidative stress and TLR4/MyD88/Traf6 axis, though further investigation is required.

Association of Soluble Suppression of Tumorigenicity with No-Reflow Phenomenon and Long-Term Prognosis in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome after Percutaneous Coronary Intervention.

AIMS: Soluble suppression of tumorigenicity 2 (sST2) was validated to independently predict prognosis for heart failure (HF) and ST-segment elevation myocardial infarction (STEMI). In this study, we aimed to evaluate the relation between sST2 and coronary artery stenosis, and no-reflow phenomenon and one-year prognosis in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). METHODS: This prospective study consecutively enrolled 205 patients who were diagnosed with NSTE-ACS and underwent percutaneous coronary intervention (PCI). sST2 was measured for all patients during admission. Patients were divided into two groups based on the optimal cutoff value: sST2 ＞34.2 ng/ml and sST2 ≤ 34.2 ng/ml groups. RESULTS: Patients in the sST2 ＞34.2 ng/ml group was associated with higher Gensini scores and multivessel disease. sST2 had weak predictive value for no-reflow phenomenon (area under the curve [AUC], 0.662; 95% confidence interval [CI], 0.53-0.79; P=0.015) with 66.7% sensitivity and 65.2% specificity, and it also had independent predictive value of no-reflow phenomenon after adjusting for confounding factors (odds ratio [OR], 3.802; 95% CI, 1.03-14.11; P=0.046). sST2 ＞34.2 ng/ml had a commendable predictive value for the one-year prognosis (AUC, 0.84; 95% CI, 0.75-0.93; P＜0.001) with 72% sensitivity and 84% specificity, and it independently predicted one-year major cardiovascular and cerebrovascular events (MACCE) (hazard ratio [HR], 10.22; 95% CI, 4.05-25.7; P＜0.001). CONCLUSION: The sST2 concentration on admission is correlated with the degree of coronary artery stenosis. sST2 can predict both no-reflow and MACCE in patients with NSTE-ACS after PCI and was an independent predictor of MACCE and no-reflow phenomenon.

New CHA2DS2-VASc-HSF score predicts the no-reflow phenomenon after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction.

BACKGROUND: The no-reflow phenomenon (NRP) is a serious complication of primary percutaneous coronary intervention (PPCI) and is an independent predictor of poor prognosis. We aimed to find a simple but effective risk stratification method for the prediction of NRP. METHODS: This retrospective single-center study included 454 consecutive patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI) and treated by PPCI, who were admitted to our emergency department between January 2017 and March 2019. The patients were divided according to the post-PPCI thrombolysis in the myocardial infarction flow rate: the NRP group and the control group. The CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc-HSF scores were calculated for all the patients in this study, and multivariable regression and receiver operating characteristic curve analyses were conducted to determine the independent predictors of NRP and the predictive value of the three scores. RESULTS: A total of 454 patients were analyzed in this study: 80 in the no-reflow group and 374 in the control group. The incidence of NRP was 17.6%. Creatine kinase-myocardial band, Killip class, stent length, and multivessel disease also independently predicted NRP. The CHA2DS2-VASc-HSF score had a higher predictive value than the other two scores, and a CHA2DS2-VASc-HSF score of ≥4 predicted NRP with a sensitivity of 72.5% and specificity of 66.5% (area under the curve: 0.755, 95% confidence interval [0.702-0.808]). CONCLUSION: Although the CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc-HSF scores can all be used as simple tools to predict NRP, our findings show that the CHA2DS2-VASc-HSF score had the highest predictive value. Thus, the CHA2DS2-VASc-HSF score may be an optimal tool for predicting high-risk patients.

Clinical Application of the FICE Technique for Biopsy of Bronchial Mucosal Lesions.

OBJECTIVE: To determine the diagnostic accuracy of flexile spectral imaging color enhancement (FICE) of abnormal morphologic changes in bronchial mucosal lesions. STUDY DESIGN: Descriptive, analytical study. PLACE AND DURATION OF STUDY: Department of endoscopy, the 10th People's Hospital of Shenyang, China, from January 2015 to April 2016. METHODOLOGY: Patients aged 17-71 years, who presented with abnormal lesions of lung and bronchus, were included. Patients with severe heart disease, arrhythmias, aneurysm of aorta, blood pressure >160/100 mmHg, allergic to anaesthetic drugs, and unwilling to undergo endoscopy were excluded. The bronchoscopic FICE technique was used to observe abnormal bronchial mucosa in 85 patients. Targeted brushings, lavage, and tissue biopsies were performed under the FICE mode. RESULTS: With routine pathological results under white light as a reference, high definition electronic bronchoscopy combined with FICE biopsy yielded a positive rate for bronchial mucosal lesions and bronchial tumors in up to (73 87%) of cases. CONCLUSION: The FICE technique showed significant enhancement of bronchial mucosal lesion diagnosis, which can help endoscopists in the early and accurate diagnosis. Key Words: FICE, Bronchial mucosal lesions, Biopsy, Diagnostic accuracy.

The combination of neutrophil-to-lymphocyte ratio and platelet correlation parameters in predicting the no-reflow phenomenon after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction.

OBJECTIVE: To evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), and platelet distribution width (PDW) for the no-reflow phenomenon in patients with ST-segment elevation myocardial infarction. Methods: Patients who underwent primary percutaneous coronary intervention from January 2017 to April 2019 were consecutively enrolled in this study and were split into the control and no-reflow groups. Logistic regression analysis was used to determine the independent predictors. Receiver operating characteristic curves were carried out to evaluate the predictive value. Results: A total of 455 patients were included and the incidence of the no-reflow was 19.6%. After the adjustment of confounding factors, logistic regression analyses showed that the NLR (odds ratio [OR] per unit increase: 1.107, 95% confidence interval [CI]: 1.044-1.172, p = .001), MPV (OR: 1.398, 95% CI: 1.010-1.937, p = .044), and PDW (OR: 1.392, 95% CI: 1.012-1.914, p = .042) were all independent predictors. In the prediction of the no-reflow, the NLR had the largest area under the curve of 0.650 (95% CI: 0.593-0.708) with 90% sensitivity and 36% specificity. The area under the curve of the combination of NLR + MPV was 0.676 and that of NLR + PDW was 0.654. Conclusions: The NLR, MPV and PDW are all associated with the no-reflow. However, there is no significant difference in the predictive value of these indicators. The combinations of NLR and platelet-associated parameters also do not show a better predictive value than NLR alone.