Microbiota-derived metabolite Indoles induced aryl hydrocarbon receptor activation and inhibited neuroinflammation in APP/PS1 mice.

Gut microbiota alterations might affect the development of Alzheimer's disease (AD) through microbiota-derived metabolites. For example, microbiota-derived Indoles via tryptophan metabolism prevented Aß accumulation and Tau hyperphosphorylation, restored synaptic plasticity, and then promoted the cognitive and behavioral ability of APP/PS1 mice. The imbalanced compositions of Indoles-producing bacteria with tryptophan deficiency were found in male APP/PS1 mice, but the molecular mechanisms remained unclear. Our current study revealed that Indoles (including indole, indole-3-acetic acid and indole-3-propionic acid) upregulated the production of aryl hydrocarbon receptor (AhR), inhibited the activation of the NF-κB signal pathway as well as the formation of the NLRP3 inflammasome, reduced the release of inflammatory cytokines, including TNF-α, IL-6, IL-1ß and IL-18, alleviating the inflammatory response of APP/PS1 mice. These findings demonstrated the roles of Indoles-producing bacteria in activating the AhR pathway to regulate neuroinflammation of AD through gut microbiota-derived Indoles, which implied a novel way for AD treatment.

Fish oil alleviates LPS-induced inflammation and depressive-like behavior in mice via restoration of metabolic impairments.

Our previous study revealed that fish oil (FO) pre-treatment could improve the lipopolysaccharides (LPS)-induced depressive-like behavior in mice but did not alter the expression of stress hormones associated with the hypothalamic-pituitary-adrenal (HPA) axis. The exact mechanisms underlying the protective effects of FO remain elusive. Here we applied the metabolomic technique to investigate the potential involvement of FO metabolites in ameliorating depressive-like behaviors in LPS-injected mice. It revealed that LPS-injection stimulated systemic inflammation, exhausted the nicotinamide adenine dinucleotide (NAD) level in the brain, decreased energy metabolism and impaired neuronal function, which collectively contributed to depressive-like behaviors in mice. FO treatment enhanced the production of neuroprotective metabolites including taurine, hypotaurine and tyramine, decreased the generation of neurotoxic agents such as ADPR, glutamate accumulation and oxidized glutathione, and prevented the NAD exhaustion in the brain, which might underlie the beneficial effects of FO against LPS-induced inflammation and depressive-like behaviors.

IFN-ß is a macrophage-derived effector cytokine facilitating the resolution of bacterial inflammation.

The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation. High-burden uptake of apoptotic cells is associated with loss of phagocytosis in resolution phase macrophages. Here, using a transcriptomic analysis of macrophage subsets, we show that non-phagocytic resolution phase macrophages express a distinct IFN-ß-related gene signature in mice. We also report elevated levels of IFN-ß in peritoneal and broncho-alveolar exudates in mice during the resolution of peritonitis and pneumonia, respectively. Elimination of endogenous IFN-ß impairs, whereas treatment with exogenous IFN-ß enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. STAT3 signalling in response to IFN-ß promotes apoptosis of human PMNs. Finally, uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo. Collectively, these results identify IFN-ß produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation.

Eicosapentaenoic and docosahexaenoic acids have different effects on peripheral phospholipase A2 gene expressions in acute depressed patients.

INTRODUCTION: Omega-3 polyunsaturated fatty acids (PUFAs) have been proven critical in the development and management of major depressive disorder (MDD) by a number of epidemiological, clinical and preclinical studies, but the molecular mechanisms underlying this therapeutic action are yet to be understood. Although eicosapentaenoic acid (EPA) seems to be the active component of omega-3 PUFAs' antidepressant effects, the biological research about the difference of specific genetic regulations between EPA and docosahexaenoic acid (DHA), the two main components of omega-3 PUFAs, is still lacking in human subjects. METHODS: We conducted a 12-week randomized-controlled trial comparing the effects of EPA and DHA on gene expressions of phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX2), serotonin transporter (5HTT), and Tryptophan hydroxylase 2 (TPH-2) in 27 MDD patients. In addition, the erythrocyte PUFA compositions and the candidate gene expressions were also compared between these 27 MDD patients and 22 healthy controls. RESULTS: EPA was associated with a significant decrease in HAM-D scores (CI: -13 to -21, p<0.001) and significant increases in erythrocyte levels of EPA (CI: +1.0% to +2.9%, p=0.001) and DHA (CI: +2.9% to +5.6%, p=0.007). DHA treatment was associated with a significant decrease in HAM-D scores (CI: -6 to -14, p<0.001) and a significant increase in DHA levels (CI: +0.2% to +2.3%, p=0.047), but not of EPA levels. The cPLA2 gene expression levels were significantly increased in patients received EPA (1.9 folds, p=0.038), but not DHA (1.08 folds, p=0.92). There was a tendency for both EPA and DHA groups to decrease COX-2 gene expressions. The gene expressions of COX-2, cPLA2, TPH-2 and 5-HTT did not differ between MDD cases and healthy controls. CONCLUSIONS: EPA differentiates from DHA in clinical antidepressant efficacy and in upregulating cPLA2 gene regulations, which supports the clinical observation showing the superiority of EPA's antidepressant effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02615405.

Benzo(a)pyrene-induced a mitochondria-independent apoptosis of liver in juvenile Chinese rare minnows (Gobiocypris rarus).

To examine the effects of BaP on tissue apoptosis, laboratory studies were conducted using juvenile Chinese rare minnows (Gobiocypris rarus) exposed to 1, 5, 20, and 80 µg/L of BaP for 28 days. The post-treatment pathological findings in the liver were associated with hepatocyte swelling, karyopyknosis, and karyorrhexis. Moreover, an increase in the goblet cells in the intestine, epithelial hyperplasia of the gills and fusion of gill lamellae were observed. Significant increases in hepatocyte apoptosis using the TUNEL stain were observed in the liver tissue but not in the intestine and gills. In addition, BaP exposure significantly up-regulated the mRNA levels of cyp1a1, p53, bax, bcl-2, and caspase-9 in the liver following the 5, 20, and 80 µg/L treatments, whereas the apaf-1 was significantly down-regulated following all treatments. Moreover, the activities of caspase 3 and caspase 8 were markedly elevated, whereas the protein expression levels of Apaf-1 were down-regulated following the 20 and 80 µg/L treatments. Taken together, our results suggested that BaP strongly induces tissue-specific apoptosis in vivo, leading to significant pathological changes. The responsiveness of apoptotic-related genes demonstrates that BaP induced apoptosis in the liver may be through a mitochondria-independent pathway.

Toxicity of Moringa oleifera seed extract on some hematological and biochemical profiles in a freshwater fish, Cyprinus carpio.

The study was carried out to investigate the acute and sublethal toxicity of Moringa oleifera seed extract on hematological and biochemical variables of a freshwater fish Cyprinus carpio under laboratory conditions. The 96 h LC50 value of M. oleifera seed extract to the fish C. carpio was estimated by probit analysis method and was found to be 124.0 mg/L (with 95% confidence limits). For sublethal studies a non lethal dose of 1/10th of 96 h LC50 value (12.40 mg/L) was taken. During acute treatment (96 h), hematological variables like red blood cell count (RBC), hemoglobin (Hb), hematocrit (Hct), and mean corpuscular hemoglobin concentration (MCHC) were significantly (P<0.05) decreased in fish exposed to seed extract. However a significant (P<0.05) increase in white blood cell count (WBC), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) value was observed in the exposed fish during above treatment period when compared to that of the control groups. Biochemical parameters such as plasma protein and glucose levels significantly declined in fish exposed to seed extract while a significant (P<0.05) increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activity was observed. During sublethal treatment (12.40 mg/L), WBC count, MCV, MCH, plasma glucose, AST, ALT and ALP activities were gradually elevated (P<0.05) at the end of 7, 14, 21, 28 and 35th days in seed extract exposed fish, whereas plasma protein level declined. However, a biphasic trend was noticed in Hb, Hct, RBC and MCHC levels. This study may provide baseline information about the toxicity of M. oleifera seed extract to C. carpio and to establish safer limit in water purification.

Derivation of aquatic predicted no-effect concentration (PNEC) for 2,4-dichlorophenol: comparing native species data with non-native species data.

2,4-Dichlorophenol (2,4-DCP) is known as an important chemical intermediate and an environmental endocrine disruptor. There is no paper dealing with the predicted no-effect concentration (PNEC) of 2,4-DCP, mainly due to shortage of chronic and site-specific toxicity data. In the present study, toxicity data was obtained from the tests using six Chinese native aquatic species. The HC(5) (hazardous concentration for 5% of species) was derived based on the constructed species sensitivity distribution (SSD), which was compared with that derived from literature toxicity data of non-native species. For invertebrates, the survival no-observed effect concentrations (NOECs) were 0.05 and 1.00 mg L(-1) for Macrobrachium superbum and Corbicula fluminea, respectively. NOECs based on fishes' growth were 0.10, 0.20 and 0.40 mg L(-1) for Mylopharyngodon piceus, Plagiognathops microlepis and Erythroculter ilishaeformis, respectively. For aquatic plant Soirodela polyrhiza, NOEC based on concentration of chlorophyll was 1.00 mg L(-1). A final PNEC calculated using the SSD approach with a 50% certainty based on different taxa ranged between 0.008 and 0.045 mg L(-1). There is no significant difference between HC(5) derived from native and that from non-native taxa.