Jingyao Zhang

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 livers 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.

Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice.

Background: Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic‐analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti‐tumor, anti‐diabetes, anti‐inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP‐induced liver failure. Methods: Male C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30 mg/kg or 60 mg/kg), APAP and APAP + ASX (30 mg/kg or 60 mg/kg) groups. Saline, olive oil and ASX were administered for 14 days. The APAP and APAP + ASX groups were given a peritoneal injection of 700 mg/kg or 300 mg/kg APAP to determine the 5‐day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen‐activated protein kinase (MAPK) family. Results: ASX pretreatment before APAP increased the 5‐day survival rate in a dose‐dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro‐inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c‐Jun N‐terminal kinase (JNK), extracellular signal‐regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF‐&agr;) and TNF receptor‐associated factor 2 (TRAF2). Conclusion: ASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS generation, inhibiting oxidative stress, and reducing apoptosis by inhibiting the TNF‐&agr;‐mediated JNK signal pathway and by phosphorylation of ERK and P38, which made sense in preventing and treating liver damage. HighlightsAstaxanthin is a fat‐soluble xanthophyll with powerful antioxidant capacity.Astaxanthin has anti‐inflammatory and immunomodulatory effects.Astaxanthin inhibits the inflammation in APAP induced liver injury.Astaxanthin inhibits the oxidative stress in APAP induced liver injury.Astaxanthin decreases the liver injury via TNF‐&agr;/TRAF2/JNK pathway.

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 24u2009hours 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.

Astaxanthin alleviated acute lung injury by inhibiting oxidative/nitrative stress and the inflammatory response in mice

The purpose of the present study was to assess the effect of astaxanthin (ASX) treatment on the acute lung injury (ALI) induced by cecal ligation and puncture (CLP) in mice. Mice were randomly allocated into the following groups: (1) the saline control group, in which mice were given saline before sham operation; (2) the ASX control group, in which mice received ASX before sham operation; (3) the ALI group, in which mice were given saline before CLP operation; and (4) the ALI+ASX group, in which mice received ASX before CLP operation. ASX was dissolved in olive oil and administrated by oral gavage for 14days consecutively before the CLP or sham operation. In experiment 1, Kaplan-Meier survival analysis was conducted for 72h after CLP. In experiment 2, blood, bronchoalveolar lavage fluid (BALF) and lung tissues were collected at 24h after the CLP or sham operation to determine the severity of lung injury. The results showed that ASX treatment could significantly decrease the CLP-induced mortality rate in mice. Meanwhile, ASX treatment significantly attenuated CLP-induced lung histopathological injury, inflammatory infiltration, total protein and albumin concentration, and total cell and neutrophil counts in the BALF. Furthermore, ASX treatment alleviated oxidative/nitrative stress, inflammation levels and pulmonary apoptosis in lung tissues. In addition, ASX treatment markedly down-regulated the expression of inducible nitric oxide synthase (i-NOS), nitrotyrosine (NT) and nuclear factor-kappa B (NF-Κb) P65 in the lung tissues compared with that in the ALI group. Astaxanthin treatment had markedly protective effect against ALI in mice, and the potential mechanism is associated with its ability to inhibit the inflammatory response, oxidative/nitrative stress, and pulmonary apoptosis, as well as down-regulate NF-κB P65 expression.

Peripheral serotonin regulates postoperative intra-abdominal adhesion formation in mice

The aim of the present study is to investigate the role and potential mechanisms of peripheral serotonin in postoperative intra-abdominal adhesion formation in mice. The caecum-rubbing operations were conducted for intra-abdominal adhesion formation modelling in wild-type and Tph1−/− mice. The deficiency of serotonin significantly decreased the adhesion scores, weight loss, and adhesion thickness as well as levels of collagen fibres and hydroxyproline in the adhesive tissues. The Tph1−/− mice exhibited a milder inflammatory response and oxidative stress in the adhesive tissues than did the wild-type mice. Moreover, the deficiency of serotonin reduced the levels of PAI-1 and fibrinogen, and raised the t-PA and t-PA/PAI levels in the peritoneal fluids. Moreover, the expressions of CD34, VEGF, TGF-β and 5-HT2B receptor in the adhesive tissues were significantly decreased in the Tph1−/− group mice. Furthermore, the Tph1−/−u2009+5-HTP group showed more severe adhesions than did the Tph1−/− group mice, and the p-chlorophenylalanine (PCPA) could markedly alleviated the adhesion formation in the WT mice. In conclusion, the present study showed that peripheral serotonin regulated postoperative intra-abdominal adhesion formation by facilitating inflammation, oxidative stress, disorder of the fibrinolytic system, angiopoiesis and TGF-β1 expression via the 5-HT2B receptor in the adhesive tissues.

Corrigendum: 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 livers 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.

Simvastatin protects against acetaminophen-induced liver injury in mice

The present study aimed to investigate the effect of simvastatin on acetaminophen (APAP) hepatotoxicity in a mouse model. Male C57BL/6 mice were allocated into the following groups: control, APAP, APAP+SIM10, APAP+SIM20, APAP+SIM100 and APAP+SIM200 groups. The mice in the APAP group were treated with saline intraperitoneally (i.p.) 72u202fh before and 24u202fh or 72u202fh after APAP challenge (i.p., 400u202fmg/kg of APAP). The simvastatin-treated groups were treated with different doses of simvastatin i.p. (10, 20, 100 and 200u202fmg/kg/day) as in the APAP group. After 24u202fh or 72u202fh of APAP challenge, blood and liver samples were collected to detect hepatic injury and liver regeneration. The results showed that low doses of simvastatin (10 and 20u202fmg/kg) could significantly reverse the histological change and decrease hepatic injury. Simvastatin also reduced the serum cytokine levels and transcriptional levels of tumor necrosis factor-α and interleukin-6 in the liver. The malonyldialdehyde and myeloperoxidase levels significantly decreased in the simvastatin treatment groups compared with the APAP group. Simvastatin restored the decrease in superoxide dismutase, catalase, glutathione and glutathione peroxidase activities induced by APAP hepatotoxicity. In addition, simvastatin inhibited hepatic C/EBP-homologous protein expression and hepatocyte apoptosis. However, simvastatin had no effect on liver regeneration after APAP hepatotoxicity. Moreover, high doses could aggravate APAP-induced liver injury. In conclusion, low doses of simvastatin had a significant therapeutic effect in APAP-induced liver injury by inhibiting oxidative stress, inflammation and apoptosis. However, high doses of simvastatin had adverse hepatotoxicity.

Remote ischemic conditioning protects against acetaminophen-induced acute liver injury in mice

Acetaminophen (APAP) overdose is a major cause of drug‐induced acute liver failure. Studies have shown that remote ischemic pre‐ and post‐conditioning (R‐IPC and R‐IPOST) can protect the liver against ischemia–reperfusion (I/R) and lipopolysaccharide‐induced injuries. The aim of this study was to investigate the effect of R‐IPC and R‐IPOST on APAP‐induced hepatotoxicity in mice.

Irisin alleviates liver ischemia-reperfusion injury by inhibiting excessive mitochondrial fission, promoting mitochondrial biogenesis and decreasing oxidative stress

Current management of liver ischemia-reperfusion (I/R) injury is mainly based on supportive care and no specific treatment is available. Irisin, a recently identified hormone, plays pivotal roles in energy expenditure and oxidative metabolism; however, it remains unknown whether irisin has any protective effects on hepatic I/R injury. In this study, we found that serum and liver irisin levels were markedly decreased at 24u202fh after hepatic I/R. Treatment with exogenous irisin improved liver function, reduced liver necrosis and cell apoptosis, and relieved inflammatory response after hepatic I/R. Meanwhile, exogenous irisin markedly inhibited mitochondrial fission related protein dynamin related protein 1 (drp-1) and fission 1 (Fis-1) expression in hepatic I/R. Additionally, treatment with exogenous irisin increased mitochondrial content and increased mitochondrial biogenesis related peroxisome proliferative activated receptor-γ (PPARγ) co-activator 1α (PGC-1α) and mitochondrial transcription factor (TFAM) expression. Furthermore, irisin decreased oxidative stress by upregulating uncoupling proteins (UCP) 2 expression in hepatic I/R. The results reveal that treatment with exogenous irisin alleviated hepatic I/R injury by restraining mitochondrial fission, promoting mitochondrial biogenesis and relieving oxidative stress. Irisin treatment appears to be a novel and promising therapeutic approach for hepatic I/R injury.

Methane Medicine: A Rising Star Gas with Powerful Anti-Inflammation, Antioxidant, and Antiapoptosis Properties

Methane, the simplest organic compound, was deemed to have little physiological action for decades. However, recently, many basic studies have discovered that methane has several important biological effects that can protect cells and organs from inflammation, oxidant, and apoptosis. Heretofore, there are two delivery methods that have been applied to researches and have been proved to be feasible, including the inhalation of methane gas and injection with the methane-rich saline. This review studies on the clinical development of methane and discusses about the mechanism behind these protective effects. As a new field in gas medicine, this study also comes up with some problems and prospects on methane and further studies.