Solute trapping and non-equilibrium microstructure during rapid solidification of additive manufacturing.

Solute transport during rapid and repeated thermal cycle in additive manufacturing (AM) leading to non-equilibrium, non-uniform microstructure remains to be studied. Here, a fully-coupled fluid dynamics and microstructure modelling is developed to rationalise the dynamic solute transport process and elemental segregation in AM, and to gain better understanding of non-equilibrium nature of intercellular solute segregation and cellular structures at sub-grain scale during the melting-solidification of the laser powder bed fusion process. It reveals the solute transport induced by melt convection dilutes the partitioned solute at the solidification front and promotes solute trapping, and elucidates the mechanisms of the subsequent microstructural morphology transitions to ultra-fine cells and then to coarse cells. These suggest solute trapping effect could be made used for reducing crack susceptibility by accelerating the solidification process. The rapid solidification characteristics exhibit promising potential of additive manufacturing for hard-to-print superalloys and aid in alloy design for better printability.

Computer-aided diagnosis of early-stage colorectal cancer using nonmagnified endoscopic white-light images (with videos).

BACKGROUND AND AIMS: Differentiation of colorectal cancers (CRCs) with deep submucosal invasion (T1b) from CRCs with superficial invasion (T1a) or no invasion (Tis) is not straightforward. This study aimed to develop a computer-aided diagnosis (CADx) system to establish the diagnosis of early-stage cancers using nonmagnified endoscopic white-light images alone. METHODS: From 5108 images, 1513 lesions (Tis, 1074; T1a, 145; T1b, 294) were collected from 1470 patients at 10 academic hospitals and assigned to training and testing datasets (3:1). The ResNet-50 network was used as the backbone to extract features from images. Oversampling and focal loss were used to compensate class imbalance of the invasive stage. Diagnostic performance was assessed using the testing dataset including 403 CRCs with 1392 images. Two experts and 2 trainees read the identical testing dataset. RESULTS: At a 90% cutoff for the per-lesion score, CADx showed the highest specificity of 94.4% (95% confidence interval [CI], 91.3-96.6), with 59.8% (95% CI, 48.3-70.4) sensitivity and 87.3% (95% CI, 83.7-90.4) accuracy. The area under the characteristic curve was 85.1% (95% CI, 79.9-90.4) for CADx, 88.2% (95% CI, 83.7-92.8) for expert 1, 85.9% (95% CI, 80.9-90.9) for expert 2, 77.0% (95% CI, 71.5-82.4) for trainee 1 (vs CADx; P = .0076), and 66.2% (95% CI, 60.6-71.9) for trainee 2 (P < .0001). The function was also confirmed on 9 short videos. CONCLUSIONS: A CADx system developed with endoscopic white-light images showed excellent per-lesion specificity and accuracy for T1b lesion diagnosis, equivalent to experts and superior to trainees. (Clinical trial registration number: UMIN000037053.).

Digital Media Teaching and Effectiveness Evaluation Integrating Big Data and Artificial Intelligence.

With the development of digital media technology, its application in teaching and learning is becoming more widespread. Digital media technology helps present information in transmitting knowledge or skills, reduces cognitive load, and promotes understanding of knowledge. Evaluation of the effectiveness of digital media teaching has also become important. A scientific and reasonable evaluation of digital media teaching effectiveness can help teachers select digital media technology and grasp the amount, degree, and timing of digital media use to change teaching effectiveness. This paper proposed using a combination of big data and artificial intelligence methods to evaluate the effectiveness of digital media teaching methods using the RBF neural network model. The digital media teaching effectiveness evaluation was used as the input variable of RBF, the degree of digital media effectiveness was the output variable and the neural network was trained through the collected sample data. The research results showed that the RBF neural network model proposed in this paper has a strong generalization and extension ability in evaluating digital media teaching effectiveness, providing a new way to evaluate digital media teaching effectiveness.

Vaccinia virus BTB-Kelch proteins C2 and F3 inhibit NF-κB activation.

Vaccinia virus (VACV) encodes scores of proteins that suppress host innate immunity and many of these target intracellular signalling pathways leading to activation of inflammation. The transcription factor NF-κB plays a critical role in the host response to infection and is targeted by many viruses, including VACV that encodes 12 NF-κB inhibitors that interfere at different stages in this signalling pathway. Here we report that VACV proteins C2 and F3 are additional inhibitors of this pathway. C2 and F3 are BTB-Kelch proteins that are expressed early during infection, are non-essential for virus replication, but affect the outcome of infection in vivo. Using reporter gene assays, RT-qPCR analyses of endogenous gene expression, and ELISA, these BTB-Kelch proteins are shown here to diminish NF-κB activation by reducing translocation of p65 into the nucleus. C2 and F3 are the 13th and 14th NF-κB inhibitors encoded by VACV. Remarkably, in every case tested, these individual proteins affect virulence in vivo and therefore have non-redundant functions. Lastly, immunisation with a VACV strain lacking C2 induced a stronger CD8+ T cell response and better protection against virus challenge.

Computer-aided diagnosis of serrated colorectal lesions using non-magnified white-light endoscopic images.

PURPOSE: Computer-aided diagnosis systems for polyp characterization are commercially available but cannot recognize subtypes of sessile lesions. This study aimed to develop a computer-aided diagnosis system to characterize polyps using non-magnified white-light endoscopic images. METHODS: A total of 2249 non-magnified white-light images from 1030 lesions including 534 tubular adenomas, 225 sessile serrated adenoma/polyps, and 271 hyperplastic polyps in the proximal colon were consecutively extracted from an image library and divided into training and testing datasets (4:1), based on the date of colonoscopy. Using ResNet-50 networks, we developed a classifier (1) to differentiate adenomas from serrated lesions, and another classifier (2) to differentiate sessile serrated adenoma/polyps from hyperplastic polyps. Diagnostic performance was assessed using the testing dataset. The computer-aided diagnosis system generated a probability score for each image, and a probability score for each lesion was calculated as the weighted mean with a log10-transformation. Two experts (E1, E2) read the identical testing dataset with a probability score. RESULTS: The area under the curve of classifier (1) for adenomas was equivalent to E1 and superior to E2 (classifier 86%, E1 86%, E2 69%; classifier vs. E2, p < 0.001). In contrast, the area under the curve of classifier (2) for sessile serrated adenoma/polyps was inferior to both experts (classifier 55%, E1 68%, E2 79%; classifier vs. E2, p < 0.001). CONCLUSION: The classifier (1) developed using white-light images alone compares favorably with experts in differentiating adenomas from serrated lesions. However, the classifier (2) to identify sessile serrated adenoma/polyps is inferior to experts.

Effects of sialylated lactulose on the mouse intestinal microbiome using Illumina high-throughput sequencing.

Sialylated oligosaccharides are known to have beneficial effects, such as increasing the level of bifidobacteria, reducing the levels of blood endotoxin and blood ammonia, and enhancing the body's immune system. However, it is unknown whether sialylated lactuloses have modulatory effects on the intestinal microbiota. In this study, 60 healthy mice were randomly divided into six groups, namely, a normal control group, a lactulose group, a Kdn-α2,3-lactulose group, a Kdn-α2,6-lactulose group, a Neu5Ac-α2,3-lactulose group, and a Neu5Ac-α2,6-lactulose group. After 14 days of lactulose administration, the feces of three mice from each group were collected, and the intestinal microbiota were detected by Illumina MiSeq high-throughput sequencing targeting the V3-V4 region of the 16S rDNA gene. At the phylum level, the relative abundance of Firmicutes was increased in the sialylated lactulose groups, while the abundance of Bacteroidetes was decreased. At the family level, sialylated lactulose intervention decreased the relative abundance of Bacteroidales S24-7 group and Helicobacteraceae and enhanced the abundance of Lactobacillaceae, which reflects the modulatory effect of sialylated lactulose on intestinal microbiota. Diversity analysis indicated that the index of Chao was higher in the sialylated lactulose groups than in the normal control group, and the Shannon and Simpson diversity indices were higher in the Kdnα-2,6-lactulose group and the Neu5Ac-α2,3-lactulose group than in the normal control group. The results of the intestinal microbiota sample composition indicated that there were differences between the sialylated lactulose groups and the normal control group. Thus, sialylated lactulose could be used as a functional food component with potential therapeutic applications in manipulating intestinal microbiota to exert beneficial effects on the host's health.

Immunomodulatory influences of sialylated lactuloses in mice.

The aim of this study was to investigate the immune modulatory influences of sialylated lactuloses in mice. The effects of the four sialylated lactuloses by gavage methods on the weight gain rate, organ, serum and spleen immunoglobulin of mice were investigated. Neu5Ac-α2,3-lactulose group and Kdn-α2,3-lactulose group had significantly higher weight gain rate than control group. The weight gain rate, thymus index and spleen index of Kdn-α2,3-lactulose group were significantly higher than control group and lactulose group. Liver and small intestine of Neu5Ac-α2,3-lactulose group, Neu5Ac-α2,6-lactulose group and Kdn-α2,6-lactulose group showed different degree of damage. IgG levels of serum and spleen in Neu5Ac-α2,6-lactulose group and Kdn-α2,6-lactulose group were significantly higher than control group and lactulose group. The contents of IgG in serum and spleen of Kdn-α2,3-lactulose group were significantly lower than that of control group, while the contents of IgA and IgM in serum were significantly higher than those of control group. The IgA level increased by 12.23% and 58.77% comparing with lactulose group and control group, respectively. The IgM level in serum of Kdn-α2,3-lactulose group mice increased by 43.88% and 8.05% comparing with control group and lactulose group, respectively. The IgA level and IgM level in spleen of Kdn-α2,3-lactulose group mice increased by 49.05% and 47.25% comparing with control group. In short, Kdn-α2,3-lactulose is relatively safe and superior to use as a food supplement or potential drug candidate. Our results also indicate that some other sialylated oligosaccharides are potentially harmful to organisms, they may cause some side effects.

Vaccinia Virus BBK E3 Ligase Adaptor A55 Targets Importin-Dependent NF-κB Activation and Inhibits CD8+ T-Cell Memory.

Viral infection of cells is sensed by pathogen recognition receptors that trigger an antiviral innate immune response, and consequently viruses have evolved countermeasures. Vaccinia virus (VACV) evades the host immune response by expressing scores of immunomodulatory proteins. One family of VACV proteins are the BTB-BACK (broad-complex, tram-trac, and bric-a-brac [BTB] and C-terminal Kelch [BACK]) domain-containing, Kelch-like (BBK) family of predicted cullin-3 E3 ligase adaptors: A55, C2, and F3. Previous studies demonstrated that gene A55R encodes a protein that is nonessential for VACV replication yet affects viral virulence in vivo Here, we report that A55 is an NF-κB inhibitor acting downstream of IκBα degradation, preventing gene transcription and cytokine secretion in response to cytokine stimulation. A55 targets the host importin α1 (KPNA2), acting to reduce p65 binding and its nuclear translocation. Interestingly, while A55 was confirmed to coprecipitate with cullin-3 in a BTB-dependent manner, its NF-κB inhibitory activity mapped to the Kelch domain, which alone is sufficient to coprecipitate with KPNA2 and inhibit NF-κB signaling. Intradermal infection of mice with a virus lacking A55R (vΔA55) increased VACV-specific CD8+ T-cell proliferation, activation, and cytotoxicity in comparison to levels of the wild-type (WT) virus. Furthermore, immunization with vΔA55 induced increased protection to intranasal VACV challenge compared to the level with control viruses. In summary, this report describes the first target of a poxvirus-encoded BBK protein and a novel mechanism for DNA virus immune evasion, resulting in increased CD8+ T-cell memory and a more immunogenic vaccine.IMPORTANCE NF-κB is a critical transcription factor in the innate immune response to infection and in shaping adaptive immunity. The identification of host and virus proteins that modulate the induction of immunological memory is important for improving virus-based vaccine design and efficacy. In viruses, the expression of BTB-BACK Kelch-like (BBK) proteins is restricted to poxviruses and conserved within them, indicating the importance of these proteins for these medically important viruses. Using vaccinia virus (VACV), the smallpox vaccine, we report that the VACV BBK protein A55 dysregulates NF-κB signaling by disrupting the p65-importin interaction, thus preventing NF-κB translocation and blocking NF-κB-dependent gene transcription. Infection with VACV lacking A55 induces increased VACV-specific CD8+ T-cell memory and better protection against VACV challenge. Studying viral immunomodulators therefore expands not only our understanding of viral pathogenesis and immune evasion strategies but also of the immune signaling cascades controlling antiviral immunity and the development of immune memory.

Chemoenzymatic synthesis of sialylated lactuloses and their inhibitory effects on Staphylococcus aureus.

BACKGROUND: Sialylated glycoconjugates play important roles in physiological and pathological processes. However, available sialylated oligosaccharides source is limited which is a barrier to study their biological roles. This work reports an efficient approach to produce sialic acid-modified lactuloses and investigates their inhibitory effects on Staphylococcus aureus (S. aureus). METHODS: A one-pot two-enzyme (OPTE) sialylation system was used to efficiently synthesize sialylated lactuloses. Silica gel flash chromatography column was employed to purify the sialylated products. The purity and identity of the product structures were confirmed with mass spectrometry (MS) and nuclear magnetic resonance (NMR). The inhibitory effect of sialylated lactuloses against S. aureus was evaluated by using microplate assay, fluorescence microscopy, DAPI (4',6-diamidino-2-phenylindole) fluorescence staining and protein leakage quantification. RESULTS: Neu5Ac-containing sialylated lactuloses with either α2,3- or α2,6-linkages were efficiently synthesized via an efficient OPTE sialylation system using α-2,3-sialyltransferase or α-2,6-sialyltransferase, respectively. Neu5Ac-α2,3-lactulose and Neu5Ac-α2,6-lactulose significantly inhibited the growth of S. aureus. Fluorescence microscopy and DAPI fluorescence staining indicated that the sialylated lactuloses might disrupt nucleic acid synthesis of S. aureus. CONCLUSIONS: Neu5Ac-containing sialylated lactuloses had higher antibacterial activity against S. aureus than non-sialylated lactulose. The inhibitory effect of Neu5Ac-α2,3-lactulose was superior to that of Neu5Ac-α2,6-lactulose. The sialylated lactuloses might inhibit S. aureus by causing cell membrane leakage and disrupting nucleic acid synthesis.

5-HT Drives Mortality in Sepsis Induced by Cecal Ligation and Puncture in Mice.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection with a high mortality. 5-Hydroxytryptamine (5-HT) is an important regulatory factor in inflammation. The aim of this study is to investigate the role of 5-HT on cecal ligation and puncture- (CLP-) induced sepsis in the mouse model. CLP was performed on C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout (KO) mice. The results showed that the 5-HT-sufficient group mice had a significantly lower survival rate than the 5-HT-deficient group in CLP-induced sepsis and septic shock. The KO-CLP sepsis group received a lower clinical score than the WT-CLP sepsis group. Meanwhile, the body temperature of mice in the KO-CLP sepsis group was higher than that in the WT-CLP sepsis group and was much closer to the normal body temperature 24 hours after CLP. The tissue histopathology analysis revealed that 5-HT markedly exacerbated histological damages in the peritoneum, lung, liver, kidney, intestinal tissue, and heart in sepsis. Moreover, significant lower levels of TNF-α, IL-6, bacterial loads, MPO, and ROS were discovered in the KO-CLP sepsis group in contrast to the WT-CLP sepsis group. In conclusion, 5-HT drives mortality and exacerbates organ dysfunction by promoting serum cytokines and bacterial loads as well as facilitating oxidative stress in the process of sepsis.

XB130: A novel adaptor protein in cancer signal transduction.

Adaptor proteins are functional proteins that contain two or more protein-binding modules to link signaling proteins together, which affect cell growth and shape and have no enzymatic activity. The actin filament-associated protein (AFAP) family is an important member of the adaptor proteins, including AFAP1, AFAP1L1 and AFAP1L2/XB130. AFAP1 and AFAP1L1 share certain common characteristics and function as an actin-binding protein and a cSrc-activating protein. XB130 exhibits certain unique features in structure and function. The mRNA of XB130 is expressed in human spleen, thyroid, kidney, brain, lung, pancreas, liver, colon and stomach, and the most prominent disease associated with XB130 is cancer. XB130 has a controversial effect on cancer. Studies have shown that XB130 can promote cancer progression and downregulation of XB130-reduced growth of tumors derived from certain cell lines. A higher mRNA level of XB130 was shown to be associated with a better survival in non-small cell lung cancer. Previous studies have shown that XB130 can regulate cell growth, migration and invasion and possibly has the effect through the cAMP-cSrc-phosphoinositide 3-kinase/Akt pathway. Except for cancer, XB130 is also associated with other pathological or physiological procedures, such as airway repair and regeneration.

Exploring the diagnosis markers for gallbladder cancer based on clinical data.

Presently, no effective markers are available to facilitate gallbladder cancer (GBC) diagnosis. This study aims to explore available markers for GBC diagnosis. Clinical data of 144 GBC and 116 cholelithiasis patients were retrospectively reviewed. Logistic regression analysis was performed to evaluate GBC risk factors. A receiver operating characteristic (ROC) curve was used to assess the diagnosis value of the risk factors. By comparing the characteristic of GBC and cholelithiasis patients, the following factors exhibited statistical difference: age, gender, gallstones, total bilirubin (TB), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count (PLT), CA125 (carcinoembryonic antigen 125), and CA199 (carbohydrate antigen 199). Logistic regression analysis indicated that age [odds ratio (OR), 1.032; 95%confidence interval (95% CI), 1.004 to 1.061; P = 0.024], gender (OR, 0.346; 95% CI, 0.167 to 0.716; P = 0.004), gallstones (OR, 0.027; 95% CI, 0.007 to 0.095; P < 0.001), ALP (OR, 1.003; 95% CI, 1.000 to 1.006; P = 0.032), TB (OR, 1.004; 95% CI, 1.000 to 1.009; P = 0.042), and CA125 (OR, 1.007; 95% CI, 1.002 to 1.013; P = 0.011) were independent risk factors for GBC. According to the ROC curve, CA125 [area under curve (AUC), 0.720], ALP (AUC, 0.713), TB (AUC, 0.636), and age (AUC, 0.573) were valuable diagnosis markers. Additionally, based on the independent risk factors, the GBC diagnosis model was established. Age, TB, ALP, and CA125 can be used as auxiliary diagnosis factors of GBC. The diagnosis model provides a quantitative tool for GBC diagnosis when comprehensively considering various risk factors.

Hydrogen-rich water protects against acetaminophen-induced hepatotoxicity in mice.

AIM: To investigate the hepatoprotective effects and mechanisms of hydrogen-rich water (HRW) in acetaminophen (APAP)-induced liver injury in mice. METHODS: Male mice were randomly divided into the following four groups: normal saline (NS) control group, mice received equivalent volumes of NS intraperitoneally (ip); HRW control group, mice were given HRW (same volume as the NS group); APAP + NS group, mice received NS ip for 3 d (5 mL/kg body weight, twice a day at 8 am and 5 pm) after APAP injection; APAP + HRW group, mice received HRW for 3 d (same as NS treatment) after APAP challenge. In the first experiment, mice were injected ip with a lethal dose of 750 mg/kg APAP to determine the 5-d survival rates. In the second experiment, mice were injected ip with a sub-lethal dose of 500 mg/kg. Blood and liver samples were collected at 24, 48, and 72 h after APAP injection to determine the degree of liver injury. RESULTS: Treatment with HRW resulted in a significant increase in the 5-d survival rate compared with the APAP + NS treatment group (60% vs 26.67%, P < 0.05). HRW could significantly decrease the serum alanine aminotransferase level (24 h: 4442 ± 714.3 U/L vs 6909 ± 304.8 U/L, P < 0.01; 48 h: 3782 ± 557.5 U/L vs 5111 ± 404 U/L, P < 0.01; and 3255 ± 337.4 U/L vs 3814 ± 250.2 U/L, P < 0.05, respectively) and aspartate aminotransferase level (24 h: 4683 ± 443.4 U/L vs 5307 ± 408.4 U/L, P < 0.05; 48 h: 3392 ± 377.6 U/L vs 4458 ± 423.6 U/L, P < 0.01; and 3354 ± 399.4 U/L vs 3778 ± 358 U/L, respectively) compared with the APAP treatment group. The alkaline phosphatase, total bilirubin and lactate dehydrogenase levels had the same result. Seventy-two hours after APAP administration, liver samples were collected for pathological examination and serum was collected to detect the cytokine levels. The liver index (5.16% ± 0.26% vs 5.88% ± 0.073%, P < 0.05) and percentage of liver necrosis area (27.73% ± 0.58% vs 36.87% ± 0.49%, P < 0.01) were significantly lower in the HRW-treated animals. The malonyldialdehyde (MDA) contents were significantly reduced in the HRW pretreatment group, but they were increased in the APAP-treated group (10.44 ± 1.339 nmol/mg protein vs 16.70 ± 1.646 nmol/mg protein, P < 0.05). A decrease in superoxide dismutase (SOD) activity in the APAP treatment group and an increase of SOD in the HRW treatment group were also detected (9.74 ± 0.46 U/mg protein vs 12.1 ± 0.67 U/mg protein, P < 0.05). Furthermore, HRW could significantly increase the glutathione (GSH) contents (878.7 ± 76.73 mg/g protein vs 499.2 ± 48.87 mg/g protein) compared with the APAP treatment group. Meanwhile, HRW could reduce the inflammation level (serum TNF-α: 399.3 ± 45.50 pg/L vs 542.8 ± 22.38 pg/L, P < 0.05; and serum IL-6: 1056 ± 77.01 pg/L vs 1565 ± 42.11 pg/L, P < 0.01, respectively). In addition, HRW could inhibit 4-HNE, nitrotyrosine formation, JNK phosphorylation, connexin 32 and cytochrome P4502E expression. Simultaneously, HRW could facilitate hepatocyte mitosis to promote liver regeneration. CONCLUSION: HRW has significant therapeutic potential in APAP-induced hepatotoxicity by inhibiting oxidative stress and inflammation and promoting liver regeneration.

FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma.

AIM: To investigate the expression of forkhead box protein M1 (FoxM1) in the process of epithelial mesenchymal transition in hepatocellular carcinoma (HCC) and its role in metastasis. METHODS: FoxM1 and E-cadherin expression in HCC tissue microarray specimens was evaluated by immunohistochemical staining, and statistical methods were applied to analyze the correlation between FoxM1 and epithelial-mesenchymal transition (EMT). Kaplan-Meier analysis of the correlation between the FoxM1 expression level and recurrence or overall survival of HCC patients was performed. The expression of FoxM1, E-cadherin and snail homologue 1 (SNAI1) in HCC cell lines was evaluated by real-time reverse transcription-polymerase chain reaction and Western blot. Hepatocyte growth factor (HGF) was used to induce EMT and stimulate cell migration in HCC cells. The expression of FoxM1 and SNAI1 was regulated by transfection with plasmids pcDNA3.1 and siRNAs in vitro. The occurrence of EMT was evaluated by Transwell assay, morphologic analysis and detection of the expression of EMT markers (E-cadherin and vimentin). Luciferase and chromatin immunoprecipitation assays were used to evaluate whether SNAI1 is a direct transcriptional target of FoxM1. RESULTS: FoxM1 expression was increased significantly in HCC compared with para-carcinoma (10.7 ± 0.9 vs 8.2 ± 0.7, P < 0.05) and normal hepatic (10.7 ± 0.9 vs 2.7 ± 0.4, P < 0.05) tissues. Overexpression of FoxM1 was correlated with HCC tumor size, tumor number, macrovascular invasion and higher TNM stage, but was negatively correlated with E-cadherin expression in microarray specimens and in cell lines. FoxM1 overexpression was correlated significantly with HCC metastasis and EMT. In vitro, we found that FoxM1 plays a key role in HGF-induced EMT, and overexpression of FoxM1 could suppress E-cadherin expression and induce EMT changes, which were associated with increased HCC cell invasiveness. Next, we confirmed that FOXM1 directly binds to and activates the SNAI1 promoter, and we identified SNAI1 as a direct transcriptional target of FOXM1. Moreover, inhibiting the expression of SNAI1 significantly inhibited FoxM1-mediated EMT. CONCLUSION: FoxM1 overexpression promotes EMT and metastasis of HCC, and SNAI1 plays a critical role in FoxM1-mediated EMT.

Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH2-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

Role of Serotonin in MODS: Deficiency of Serotonin Protects Against Zymosan-Induced Multiple Organ Failure in Mice.

Zymosan-induced multiple organ dysfunction syndrome (MODS) is a multifactorial pathology that involves the deterioration of function of several organs. 5-Hydroxytryptamine (5-HT) is a small monoamine molecule that is primarily known for its role as a neurotransmitter. Previous studies have shown that 5-HT could serve as an important inflammatory mediator in the peripheral immune system. In the present study, we investigated the effect of 5-HT on the development of non-septic shock caused by zymosan in mice. Tryptophan hydroxylase 1-knockout mice (TPH1, leading to the absence of 5-HT), TPH1 + 5-hydroxytryptophan (precursor of 5-HT) treatment mice, wild-type (TPH1) mice, and wild-type plus p-chlorophenylalanine (PCPA, TPH1 inhibitor) treatment mice received zymosan intraperitoneally at a dose of 500 mg/kg. Organ failure and systemic inflammation in the mice were assessed 18 h after the administration of zymosan. Deficiency of 5-HT caused a significant reduction of the 1) peritoneal exudate formation, 2) neutrophil infiltration, 3) MODS, 4) nitrosative stress, and 5) cytokine formation. In addition, at the end of the observation period (7 days), deficiency of 5-HT in the mice was shown to be able to alleviate the severe illness characterized as systemic toxicity, significant loss of body weight, and high mortality caused by zymosan. In conclusion, the lack of 5-HT by genetic knockout or by pharmacologic inhibition of the TPH1 enzyme significantly attenuated zymosan-induced MODS.

Effect of hydrogen-rich water on acute peritonitis of rat models.

OBJECTIVE: To study the effect of hydrogen-rich water (HRW) on acute peritonitis with three different rat models. METHODS: Acute peritonitis was induced by three methods including intraperitoneal injection of lipopolysaccharide (LPS), rats' feces or cecal ligation and puncture (CLP) operation. For each model, male Sprague Dawley rats were used and distributed into saline control group, HRW control group, saline plus model group, and HRW plus model group. Saline or HRW (3 ml per rat) was orally administered by gavage for 7 days beforehand and 3 days after modeling. The efficacy was tested by detecting concentrations of white blood cells (WBCs), plasma endotoxin, interleukin (IL)-6 and tumor necrosis factor (TNF)-α. The activities of malondialdehyde (MDA), myeloperoxidase (MPO) and glutathione (GSH) in visceral peritoneum tissues were also evaluated. Meanwhile, histopathology examination of visceral peritoneum was performed using hematoxylin and eosin staining. The expression and location of nuclear factor kappaB (NF-κB) in the visceral peritoneum were detected by immunohistochemistry. RESULTS: Three models showed the same result that hydrogen-rich water had an efficient protective effect on acute peritonitis. HRW could significantly lower the levels of WBCs, plasma endotoxin and cytokines, enhance GSH activity and reduce MPO and MDA activities in the peritoneum tissue when compared with that of groups with only saline treated. Simultaneously, we found that HRW could also decrease the NF-κB expression in the peritoneum tissues. CONCLUSION: Hydrogen-rich water could alleviate the severity of acute peritonitis, and it might perform this function by its anti-inflammation, anti-oxidation and anti-bacterial effects and reducing NF-κB expression in the peritoneum tissues.