Lutein suppresses ferroptosis of cardiac microvascular endothelial cells via positive regulation of IRF in cardiac hypertrophy.

Cardiac microvascular dysfunction contributes to cardiac hypertrophy (CH) and can progress to heart failure. Lutein is a carotenoid with various pharmacological properties, such as anti-apoptotic, anti-inflammatory, and antioxidant effects. Limited research has been conducted on the effects of lutein on pressure overload-induced CH. Studies have shown that CH is accompanied by ferroptosis in the cardiac microvascular endothelial cells (CMECs). This study aimed to investigate the effect of lutein on ferroptosis of CMECs in CH. The transcription factor interferon regulatory factor (IRF) is associated with immune system function, tumor suppression, and apoptosis. The results of this study suggested that pressure overload primarily inhibits IRF expression, resulting in endothelial ferroptosis. Administration of lutein increased the expression of IRF, providing protection to endothelial cells during pressure overload. IRF silencing downregulated solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, leading to the induction of ferroptosis in CMECs. Lutein supplementation suppressed endothelial ferroptosis by upregulating IRF. These data suggest that IRF may function as a transcription factor for SLC7A11 and that lutein represses ferroptosis in CMECs by upregulating IRF expression. Therefore, targeting IRF may be a promising therapeutic strategy for effective cardioprotection in patients with CH and heart failure.

Identification of non-coding RNA related prognosis biomarkers based on ceRNA network in thyroid cancer.

Introduction: Thyroid cancer (THCA) has become a serious malignant tumor worldwide. Identification of non-coding RNA related regulators is very necessary to improve the knowledge of THCA treatment. The aim of this study was to identify novel therapeutic targets and prognosis biomarkers for predicting pathological characteristics and subsequently treating THCA. Methods: We investigated the alterations of miRNAs, mRNAs and lncRNAs in THCA. Functional enrichment and clustering analysis were conducted for these aberrantly expressed RNAs. Multiple interaction networks among miRNAs, mRNAs and lncRNAs were constructed and the functional modules associated with THCA patients' prognosis were identified. Furthermore, we evaluated the prognostic roles of the important miRNAs, mRNAs and lncRNAs in THCA and investigated the regulatory potential of non-coding RNAs on immune cell infiltration. Results: We firstly identified that miR-4709-3p and miR-146b-3p could significantly classify patients into high/low risk groups, which may be potential prognosis biomarkers of THCA. Secondly, we constructed a THCA-related miRNA-mRNA network, which displayed small world network topological characters. Two THCA-related functional modules were identified from the miRNA-mRNA network by MCODE. Results showed that two modules could implicate in known cancer pathways, such as apoptosis and focal adhesion. Thirdly, a THCA-related miRNA-lncRNA network was constructed. A subnetwork of miRNA-lncRNA network showed strong prognosis effect in THCA. Fourthly, we constructed a THCA-related mRNA-lncRNA network and detected several typical lncRNA-miRNA-mRNA crosstalk, such as AC068138, BCL2, miR-21 and miR-146b, which had good prognosis effect in THCA. Immune infiltration results showed that lncRNAs LA16c-329F2, RP11-395N3, RP11-423H2, RP11-399B17 and RP11-1036E20 were high related to neutrophil and dendritic cell infiltration. Discussion: Non-coding RNA-mediated gene regulatory network has the strong regulatory potential in pathological processes of THCA. All these results could help us uncover the non-coding RNA-mediated regulatory mechanism in THCA.

Neutrophil membrane-coated taurine nanoparticles protect against hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion (I/R) injury is a multifactorial process caused by transient tissue hypoxia and the following reoxygenation, commonly occurring in liver transplantation and hepatectomy. Hepatic I/R can induce a systemic inflammatory response, liver dysfunction, or even multiple organ failure. Although we have previously reported that taurine could attenuate acute liver injury after hepatic I/R, only a tiny proportion of the systemically injected taurine could reach the targeted organ and tissues. In this present study, we prepared taurine nanoparticles (Nano-taurine) by coating taurine with neutrophil membranes and investigated the protective effects of Nano-taurine against I/R-induced injury and the underlying mechanisms. Our results showed that Nano-taurine restored liver function by declining AST and ALT levels and reducing histology damage. Nano-taurine decreased inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, NLR pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing CARD (ASC) and oxidants including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and reactive oxygen species (ROS), exhibiting anti-inflammatory and antioxidant properties. The expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was increased, while prostaglandin-endoperoxide synthase 2 (Ptgs2) was decreased upon administration of Nano-taurine, suggesting that inhibiting ferroptosis may be involved in the mechanism during hepatic I/R injury. These results suggest that Nano-taurine have a targeted therapeutic effect on hepatic I/R injury by inhibiting inflammation, oxidative stress, and ferroptosis.

MicroRNA-128-3p Mediates Lenvatinib Resistance of Hepatocellular Carcinoma Cells by Downregulating c-Met.

OBJECTIVE: Lenvatinib is a first-line multikinase inhibitor for advanced hepatocellular carcinoma (HCC), but resistance to the drug remains a major hurdle for its long-term anti-cancer activity. This resistance is thought to be due to overexpression of c-Met. This study aims to identify potential upstream microRNAs (miRNAs) that regulate c-Met, investigate the underlying mechanisms, and seek potential strategies that may reverse such resistance. METHODS: Lenvatinib-resistant HCC (LR-HCC) cells were established from human HCC Huh7 and SMMC-7721 cells. Assays of cell proliferation, cell cycle distribution, apoptosis, RT-qPCR, Western blot analysis and immunohistochemistry were employed. Potential miRNAs were screened by miRNA-target prediction tools and their regulatory effects were evaluated by luciferase reporter assays. Xenograft tumor models were used to evaluate the therapeutic effects. RESULTS: LR-HCC cells were refractory to lenvatinib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure of cells to lenvatinib resulted in increased expression and phosphorylation of c-Met, and c-Met inhibition enhanced the effects of lenvatinib in suppressing LR-HCC cells. Among eleven miRNA candidates, miR-128-3p displayed the most vigorous activity to negatively regulate c-Met and was downregulated in LR-HCC cells. MiR-128-3p mimics inhibited proliferation and induced apoptosis of LR-HCC cells, and enhanced the effects of lenvatinib in cell culture and animal models. MiR-128-3p and c-Met participate in the mechanisms underlying lenvatinib resistance through regulating Akt that mediates the apoptotic pathway and ERK (extracellular-signal-regulated kinase) modulating cell cycle progression. CONCLUSION: The present results indicate that the miR-128-3p/c-Met axis may be potential therapeutic targets for circumventing lenvatinib resistance in HCC and warrant further investigation.

Inorganic Nanozymes: Prospects for Disease Treatments and Detection Applications.

In recent years, with the development of nanomaterials, a slice of nanomaterials has been demonstrated to possess high catalytic activity similar to natural enzymes and counter the dilemmas including easy inactivation and low yield natural of enzymes, which are labeled as nanozymes. The catalytic activity of nanozymes could be easily regulated by size, structure, surface modification and other factors. In comparison with natural enzymes, nanozymes featured with a more stable structure, economical preparation and preservation, diversity of functions and adjustable catalytic activity, thus becoming the potentially ideal substitute for natural enzymes. Generally, the are mainly three types containing metal oxide nanozymes, noble metal nanozymes and carbon-based nanozymes, owing various applications in biomedical, energy and environmental fields. In this review, to summarize the recent representative applications of nanozymes, and potentially explore the scientific problems in this field at the same time, we are going to discuss the catalytic mechanisms of diverse nanozymes, with the emphasis on their applications in the fields of tumor therapy, anti-inflammatory and biosensing, hoping to help and guide the future development of nanozymes.

Galangin Alleviates Liver Ischemia-Reperfusion Injury in a Rat Model by Mediating the PI3K/AKT Pathway.

BACKGROUND/AIMS: Liver ischemia-reperfusion (I/R) injury is a pathological process that often occurs during liver and trauma surgery. There are numerous causes of liver I/R injury, but the mechanism is unknown. Galangin (GA) is a flavonoid, a polyphenolic compound widely distributed in medicinal herbs that has anti-inflammatory, antioxidant, and antitumor activity. This study evaluated the protective effect of GA on hepatic I/R injury. METHODS: An I/R model was created in male Wistar rats by clamping the hepatoportal vein, hepatic artery and hepatic duct for 30 min followed by reperfusion for 2 h. A hypoxia/restoration (H/R) model was established in buffalo rat liver (BRL) cells by hypoxia for 4 h followed by normoxic conditions for 10 h. The extent of liver injury was assayed by serum ALT/AST, hepatic histology, and MPO activity. Oxidative stress was assayed by serum superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA). Expression of apoptosis-related proteins in BRL cells was assayed in western blots. Expression of AKT and p-AKT proteins in vivo and vitro were assayed in western blots. RESULTS: GA significantly decreased ALT/AST expression, reversed changes in oxidative stress markers induced by I/R, and mediated caspase-3 activity expression of apoptosis-related proteins in vivo and in vitro. Methylthiazol tetrazolium (MTT) assay, flow cytometry, and Hoechst 33258 staining confirmed that GA inhibited apoptosis of BRL cells. GA also increased the expression of phosphorylated AKT after H/R. CONCLUSION: GA reduced liver I/R injury both in vivo and vitro and inhibited BRL cell apoptosis. PI3K/AKT signaling have been involved. GA may protect against liver I/R and be a potential therapeutic candidate.

DHA attenuates hepatic ischemia reperfusion injury by inhibiting pyroptosis and activating PI3K/Akt pathway.

Hepatic ischemia reperfusion (I/R) injury is very common in liver transplantation and major liver surgeries and may cause liver failure or even death. Docosahexaenoic acid (DHA) has displayed activities in reducing oxidative stress and inflammatory reaction in many disorders. In the present study, we investigated the protective effects of DHA against I/R-induced injury and the underlying mechanisms. Here, we show that DHA protected hepatic I/R injury by reducing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and decreasing the oxidative stress in liver tissues. The viability of Buffalo rat liver (BRL) cells was reduced by hypoxia/restoration (H/R) but restored by DHA. DHA significantly downregulated the expression of pyroptosis-related proteins including NLR pyrin domain containing 3 (NLRP3), apoptotic speck-like protein containing CARD (ASC) and cleaved caspase-1 and reduced the secretion of pro-inflammatory cytokines. The above results were supported by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. However, incubation with LY294002, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), abolished the effects of DHA, since it increased the expression of cleaved caspase-1 and the production of inflammatory cytokines. The present results have demonstrated that DHA ameliorated I/R-induced injury by inhibiting pyroptosis of hepatocytes induced in liver I/R injury in vivo and in vitro through the PI3K/Akt pathway, providing a potential therapeutic option to prevent liver injury by I/R.

MicroRNA-21-Regulated Activation of the Akt Pathway Participates in the Protective Effects of H2S against Liver Ischemia-Reperfusion Injury.

Maintaining a certain level of hydrogen sulfide (H2S) in ischemia-reperfusion (I/R) is essential for limiting injury to the liver. Exogenous H2S exerts protective effects against this injury, but the mechanisms remain unclear. Liver injury was induced in Wistar rats undergoing hepatic I/R for 30 min, followed by a 3-h reperfusion. Administration of GYY4137 (a slow-releasing H2S donor) significantly attenuated the severity of liver injury and was reflected by reduced inflammatory cytokine production and cell apoptosis, the levels of which were elevated by I/R, while DL-propargylglycine (PAG, an inhibitor of cystathionine γ-lyase [CSE]) aggravated liver injury. Delivery of GYY4137 significantly elevated the plasma levels of H2S and upregulated the expression of microRNA-21 (miR-21), leading to the activation of the Akt pathway, in rat livers subjected to I/R. To further investigate the protective mechanisms of H2S during liver I/R injury, we established a cell model of hypoxia/reoxygenation (H/R) by incubating Buffalo rat liver (BRL) cells under hypoxia for 4 h followed by normoxia for 10 h. The regulatory effect of miR-21 on the Akt pathway by downregulating phosphatase and tensin homolog (PTEN) was validated by luciferase assays. Incubation of sodium hydrosulfide (NaHS), an H2S donor, increased the expression of miR-21, attenuated the reduced cell viability and the increased apoptosis by H/R, in BRL cells. Anti-miR-21 abolished the protective effects of NaHS by inactivating the Akt pathway. In conclusion, the present results indicate the activation of the Akt pathway regulated by miR-21 participates in the protective effects of H2S against I/R-induced liver injury.

Partial splenic embolization has beneficial effects for the management of gastroesophageal variceal hemorrhage.

BACKGROUND/AIMS: Partial splenic embolization (PSE) is used in the management of gastroesophageal variceal hemorrhage (GEVH). However, it is uncertain whether it has beneficial effects for GEVH patients in preventing variceal recurrence and variceal hemorrhage, as well as promoting overall survival (OS), when it is combined with conventional therapies. MATERIALS AND METHODS: The databases including PubMed, EMBASE, Web of Science, Google scholar, and Cochrane Central Register of Controlled Trials were searched up to 11th of November, 2015. Meta-analyses were performed by using Review Manager 5.3 software for analyzing the risk of bias, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofiler software for assessing outcomes obtained from the meta-analyses. RESULTS: A total of 1505 articles were reviewed, and 1 randomized controlled trial and 5 cohort studies with 244 participants were eligible for inclusion. The pooled hazard ratio (HR) of variceal recurrence is 0.50 (95% confidence interval (CI) 0.37, 0.68; P< 0.00001; I2 = 0%). The pooled HR of variceal hemorrhage is 0.24 (95% CI 0.15, 0.39; P< 0.00001; I2 = 0%). The pooled HR of OS is 0.50 (95% CI 0.33, 0.67; P< 0.00001; I2 = 0%). Meta-analyses demonstrated statistically significant superiority of combinational therapies over conventional therapies in preventing variceal recurrence and variceal hemorrhage and prolonging OS. The complications related to PSE were mild or moderate and nonfatal. CONCLUSIONS: The results indicate that PSE has beneficial effects for GEVH patients, however, future investigation with a larger number of subjects in clinical trials is warranted.

Pentoxifylline inhibits pulmonary inflammation induced by infrarenal aorticcross-clamping dependent of adenosine receptor A2A.

Infrarenal aortic cross-clamping (IAC) is commonly used during infrarenal vascular operations. Prolonged IAC causes ischemia-reperfusion injury to local tissues, resulting in the release of inflammatory cytokines and acute lung injury (ALI). Pentoxifylline (PTX) is a clinically used drug for chronic occlusive arterial diseases and exerts protective effects against ALI induced by various factors in experimental models. In this study, we evaluated the protective effects of PTX in a rat model of IAC. Wistar rats underwent IAC for 2 h, followed by 4 h reperfusion. PTX alone, or in combination with ZM-241385 (an adenosine receptor A2A antagonist) or CGS-21680 (an A2A agonist), was pre-administered to rats 1 h prior to IAC, and the severity of lung injury and inflammation were examined. Administration of PTX significantly attenuated ALI induced by IAC, evidenced by reduced histological scores and wet lung contents, improved blood gas parameters, decreased cell counts and protein amounts in bronchoalveolar lavage fluids, and inhibition of MPO activity and ICAM-1 expression in lung tissues, and lower plasma levels of TNF-α, IL-6, IL-1ß and soluble ICAM-1. ZM-241385 significantly abrogated, while CGS-21680 slightly enhanced, the effects of PTX in ameliorating ALI and inhibiting pulmonary inflammation. In exploration of the mechanisms, we found that PTX stimulated IL-10 production through the phosphorylation of STAT3, and A2A receptor participated in this regulation. The study indicates PTX plays a protective role in IAC-induced ALI in rats by inhibiting pulmonary inflammation through A2A signaling pathways.

Changes in patients' symptoms and gastric emptying after Helicobacter pylori treatment.

AIM: To investigate the changes in clinical symptoms and gastric emptying and their association in functional dyspepsia (FD) patients. METHODS: Seventy FD patients were enrolled and divided into 2 groups Helicobacter pylori (H. pylori)-negative group (28 patients), and H. pylori-positive group (42 patients). Patients in the H. pylori-positive group were further randomly divided into groups: H. pylori-treatment group (21 patients) and conventional treatment group (21 patients). Seventy two healthy subjects were selected as the control group. The proximal and distal stomach area was measured by ultrasound immediately after patients took the test meal, and at 20, 40, 60 and 90 min; then, gastric half-emptying time was calculated. The incidence of symptoms and gastric half-emptying time between the FD and control groups were compared. The H. pylori-negative and conventional treatment groups were given conventional treatment: domperidone 0.6 mg/(kg/d) for 1 mo. The H. pylori-treatment group was given H. pylori eradication treatment + conventional treatment: lansoprazole 30 mg once daily, clarithromycin 0.5 g twice daily and amoxicillin 1.0 g twice daily for 1 wk, then domperidone 0.6 mg/(kg/d) for 1 mo. The incidence of symptoms and gastric emptying were compared between the FD and control groups. The relationship between dyspeptic symptoms and gastric half-emptying time in the FD and control groups were analyzed. Then total symptom scores before and after treatment and gastric half-emptying time were compared among the 3 groups. RESULTS: The incidence of abdominal pain, epigastric burning sensation, abdominal distension, nausea, belching, and early satiety symptoms in the FD group were significantly higher than in the control group (50.0% vs 20.8%; 37.1% vs 12.5%; 78.6% vs 44.4%; 45.7% vs 22.2%; 52.9% vs 15.3%; 57.1% vs 19.4%; all P < 0.05). The gastric half-emptying times of the proximal end, distal end, and the whole stomach in the FD group were slower than in the control group (93.7 ± 26.2 vs 72.0 ± 14.3; 102.2 ± 26.4 vs 87.5 ± 18.2; 102.1 ± 28.6 vs 78.3 ± 14.1; all P < 0.05). Abdominal distension, belching and early satiety had an effect on distal gastric half-emptying time (P < 0.05). Abdominal distension and abdominal pain had an effect on the gastric half-emptying time of the whole stomach (P < 0.05). All were risk factors (odds ratio > 1). The total symptom score of the 3 groups after treatment was lower than before treatment (P < 0.05). Total symptom scores after treatment in the H. pylori-treatment group and H. pylori-negative group were lower than in the conventional treatment group (5.15 ± 2.27 vs 7.02 ± 3.04, 4.93 ± 3.22 vs 7.02 ± 3.04, All P < 0.05). The gastric half-emptying times of the proximal end, distal end, and the whole stomach in the H. pylori-negative and H. pylori-treatment groups were shorter than in the conventional treatment group (P < 0.05). CONCLUSION: FD patients have delayed gastric emptying. H. pylori infection treatment helps to improve symptoms of dyspepsia and is a reasonable choice for treatment in clinical practice.

The calcium-sensing receptor participates in testicular damage in streptozotocin-induced diabetic rats.

Male infertility caused by testicular damage is one of the complications of diabetes mellitus. The calcium-sensing receptor (CaSR) is expressed in testicular tissues and plays a pivotal role in calcium homeostasis by activating cellular signaling pathways, but its role in testicular damage induced by diabetes remains unclear. A diabetic model was established by a single intraperitoneal injection of streptozotocin (STZ, 40 mg kg-1 ) in Wistar rats. Animals then received GdCl 3 (an agonist of CaSR, 8.67 mg kg-1 ), NPS-2390 (an antagonist of CaSR, 0.20 g kg-1 ), or a combination of both 2 months after STZ injection. Diabetic rats had significantly lower testes weights and serum levels of testosterone compared to healthy rats, indicating testicular damage and dysfunction in STZ-induced diabetic rats. Compared with healthy controls, the testicular tissues of diabetic rats overexpressed the CaSR protein and had higher levels of malondialdehyde (MDA), lower superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and higher numbers of apoptotic germ cells. The testicular tissues from diabetic rats also expressed lower levels of Bcl-2 and higher levels of Bax and cleaved caspase-3 in addition to higher phosphorylation rates of c-Jun NH 2 -terminal protein kinase (JNK), p38, and extracellular signaling-regulated kinase (ERK) 1/2. The above parameters could be further increased or aggravated by the administration of GdCl 3 , but could be attenuated by injection of NPS-2390. In conclusion, the present results indicate that CaSR activation participates in diabetes-induced testicular damage, implying CaSR may be a potential target for protective strategies against diabetes-induced testicular damage and could help to prevent infertility in diabetic men.

Carvacrol alleviates ischemia reperfusion injury by regulating the PI3K-Akt pathway in rats.

BACKGROUND: Liver ischemia reperfusion (I/R) injury is a common pathophysiological process in many clinical settings. Carvacrol, a food additive commonly used in essential oils, has displayed antimicrobials, antitumor and antidepressant-like activities. In the present study, we investigated the protective effects of carvacrol on I/R injury in the Wistar rat livers and an in vitro hypoxia/restoration (H/R) model. METHODS: The hepatoportal vein, hepatic arterial and hepatic duct of Wistar rats were isolated and clamped for 30 min, followed by a 2 h reperfusion. Buffalo rat liver (BRL) cells were incubated under hypoxia for 4 h, followed normoxic conditions for 10 h to establish the H/R model in vitro. Liver injury was evaluated by measuring serum levels of alanine aminotransferase (ALT) and aspatate aminotransferase (AST), and hepatic levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondiadehyde (MDA), and hepatic histology and TUNEL staining. MTT assay, flow cytometric analysis and Hoechst 33258 staining were used to evaluate the proliferation and apoptosis of BRL cells in vitro. Protein expression was examined by Western Blot analysis. RESULTS: Carvacrol protected against I/R-induced liver damage, evidenced by significantly reducing the serum levels of ALT and AST, histological alterations and apoptosis of liver cells in I/R rats. Carvacrol exhibited anti-oxidative activity in the I/R rats, reflected by significantly reducing the activity of SOD and the content of MDA, and restoring the activity of CAT and the content of GSH, in I/R rats. In the in vitro assays, carvacrol restored the viability and inhibited the apoptosis of BRL cells, which were subjected to a mimic I/R injury induced by hypoxia. In the investigation on molecular mechanisms, carvacrol downregulated the expression of Bax and upregulated the expression of Bcl-2, thus inhibited the activation of caspase-3. Carvacrol was also shown to enhance the phosphorylation of Akt. CONCLUSION: The results suggest that carvacrol could alleviate I/R-induced liver injury by its anti-oxidative and anti-apoptotic activities, and warrant a further investigation for using carvacrol to protect I/R injury in clinic.

Matrine attenuates endotoxin-induced acute liver injury after hepatic ischemia/reperfusion in rats.

PURPOSE: Hepatic ischemia/reperfusion (HIR) injury is an unavoidable consequence of major liver surgery, during which endotoxemia often takes place. This study aimed to investigate whether matrine has a protective effect against HIR-induced liver injury aggravated by endotoxin. METHODS: Wistar rats were subjected to 30 min of HIR followed by lipopolysaccharide (LPS) (0.5 mg/kg) administration. At the indicated time points, six rats from each group (24 rats) were randomly euthanized to collect blood samples and livers. RESULTS: Preadministration of matrine protected livers from injury induced by HIR+LPS as the histological score, myeloperoxidase activity and malondialdehyde contents, expression of macrophage-inflammatory protein-2, DNA-binding activity of nuclear factor κB, and serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, tumor necrosis factor-α, soluble intercellular adhesion molecule-1, and nitric oxide were significantly reduced, and serum levels of interleukin-6 were further increased. HIR+LPS markedly induced cell apoptosis and necrosis, and upregulated the expression of cleaved caspase-3, Fas, and FasL. Matrine significantly reduced cell necrosis, but had a nonsignificant inhibitory effect on cell apoptosis and expression of cleaved caspase-3 and FasL. CONCLUSIONS: Matrine attenuates endotoxin-induced acute liver injury after HIR mainly by its anti-inflammatory and antioxidative activities, and has little inhibitory effect on cell apoptosis.

Protective effects of taurine against endotoxin-induced acute liver injury after hepatic ischemia reperfusion.

Hepatic ischemia reperfusion (HIR) not only results in liver injury, but also leads to endotoxemia, which aggravates HIR-induced liver injury and dysfunction, or even causes liver failure. Taurine has been shown to protect organs from ischemia reperfusion or endotoxin by its anti-oxidant and anti-inflammatory activities. The aim of this study was to investigate whether taurine could attenuate endotoxin-induced acute liver injury after HIR. Wistar rats subjected to 30 min of hepatic ischemia followed by reperfusion and lipopolysaccharide (LPS) (0.5 mg/kg) administration, exhibited liver dysfunction (elevated serum levels of ALT, AST and LDH) and hepatic histopathological alteration. The serum levels of TNF-alpha and production of myeloperoxidase (MPO) and malondialdehyde (MDA) in liver tissues and apoptosis of hepatocytes were also increased after the combination of HIR and LPS. However, pre-administration of taurine protected livers from injury induced by the combination of HIR + LPS as the histological score, apoptotic index, MPO activity and production of MDA in liver tissues, and serum levels of AST, ALT, LDH and TNF-alpha, were significantly reduced. The expression of caspase-3, Fas and Fas ligand was upregulated in homogenates of livers from rats subjected to HIR and LPS, and this elevated expression could be inhibited by taurine. In summary, the results further emphasize the potential utilization of taurine in protecting livers against endotoxin-induced injury especially after HIR, by its anti-inflammatory, anti-oxidative and anti-apoptotic activities.

Oxymatrine attenuates intestinal ischemia/reperfusion injury in rats.

PURPOSE: Intestinal ischemia/reperfusion (I/R) is a common and serious clinical condition. The anti-inflammatory and anti-apoptotic properties of oxymatrine, the extract from a traditional Chinese herb, Sophora flavescens Ait, have been shown to protect the liver from I/R injury and attenuate colitis. The objective of this study was to investigate if oxymatrine could attenuate intestinal I/R injury induced in rats. METHODS: The experimental design consisted of three groups of 24 Wistar rats each: a sham-operation group (control group), a group subjected to intestinal I/R and then given saline (saline group), and a group subjected to intestinal I/R and then given oxymatrine (oxymatrine group). Intestinal I/R was induced by occluding the superior mesenteric artery for 45 min. Six rats from each group were killed at selected time points, and blood and intestinal samples were collected. RESULTS: Morphological alteration, reduction of gamma-glutamyl transpeptidase (gamma-GGT) activity, and increased cell apoptosis confirmed intestinal I/R injury. The oxymatrine group had a significantly lower histological score and apoptosis index than the saline group, demonstrating that the preadministration of oxymatrine attenuated gut damage. Moreover, oxymatrine inhibited the production of lipid peroxides (LPO), decreased the serum levels of tumor necrosis factor (TNF)-alpha, and downregulated expression of phosphorylated p38 mitogen-activated protein kinase, Fas, and FasL, which had been elevated by I/R. CONCLUSIONS: These results provide further evidence of the anti-inflammatory and anti-apoptotic activities of oxymatrine, which may become a potent drug for protecting the intestines against I/R injury.

Taurine attenuates multiple organ injury induced by intestinal ischemia reperfusion in rats.

BACKGROUND: Intestinal ischemia reperfusion (II/R) is a serious clinical condition associated with simultaneous multiple organ dysfunction. The purpose of this study was to investigate whether taurine, an anti-oxidative, anti-inflammatory, and anti-apoptotic agent, could attenuate multiple organ injury induced by II/R. MATERIALS AND METHODS: Taurine was intravenously injected to Wistar rats 30 min before II/R; physiological saline and sham operation served as controls. II/R was produced by occlusion of superior mesenteric artery for 60 min. Rats were randomly sacrificed 1.5, 3, 12, and 36 h after II/R; blood samples were collected for assessing alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), and tumor necrosis factor-alpha (TNF-alpha), and intestines, livers, kidneys, and lungs were removed for histological examination of scoring injury severity and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling analysis. The amount of lipid peroxides (LPO) was measured in intestinal tissues, and expression of caspase-3 was detected in all of the tissues with Western blot analysis. RESULTS: II/R resulted in injury to intestines as well as livers, kidneys, and lungs, evidenced by morphological alteration, increased cell apoptosis, and elevated serum levels of ALT, AST, BUN, and Cr. The damage reached peak 3 h after II/R. The intestinal LPO and serum levels of TNF-alpha were increased after II/R. Pre-administration of taurine significantly attenuated multiple organ injury as the histological score, apoptosis index, LPO, and levels of ALT, AST, BUN, Cr, and TNF-alpha were significantly lower compared with saline controls. CONCLUSIONS: Taurine attenuates multiple organ injury induced by II/R. Although the mechanism needs further investigation, taurine inhibits production of intestinal LPO, release of TNF-alpha, cell apoptosis, and expression of caspase-3.

Splenectomy ameliorates acute multiple organ damage induced by liver warm ischemia reperfusion in rats.

BACKGROUND: Liver ischemia/reperfusion (I/R) results in the release of destructive proinflammatory cytokines and oxygen-derived radicals, which in turn cause injury to liver and other organs such as kidney, lung, and intestine. Splenectomy protects organs from intestinal I/R injury. Therefore, the present study aims to investigate whether splenectomy could also ameliorate multiple organ damage caused by liver I/R. METHODS: Wistar rats randomly assigned into 4 groups underwent sham-operation, splenectomy, hepatic I/R induced by occlusion of hepatic artery and portal vein, and splenectomy plus hepatic I/R, respectively. Blood samples were collected for assessing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity, and tumor necrosis factor-alpha (TNF-alpha) levels. The activity of myeloperoxidase (MPO) in liver tissues was assessed. Livers, kidneys, lungs, and small intestines underwent histopathologic examination for scoring injury severity and TUNEL assay for cell apoptosis. The expression of caspase-3 was evaluated with Western blot analysis. RESULTS: Liver I/R resulted in liver injury as evidenced by morphologic abnormalities, increased serum activities of AST and ALT, and increased percentage of apoptotic cells. The activity of MPO in liver tissues and the serum levels of TNF-alpha were increased after I/R. Splenectomy significantly decreased the histologic severity score, apoptotic index, MPO activity, and serum levels of AST, ALT, and TNF-alpha. Hepatic I/R also caused damage to kidneys, lungs, and small intestines, as evaluated by histologic alterations and increased apoptotic cells; these changes were ameliorated by splenectomy. The expression of caspase-3 was upregulated in the 4 organs by hepatic I/R and inhibited by splenectomy. CONCLUSIONS: Splenectomy protects the liver as well as the kidney, lung, and intestine from injury by hepatic I/R. Although the mechanism needs further investigation, this study demonstrated that splenectomy inhibited leukocyte infiltration in livers, release of TNF-alpha, cell apoptosis, and expression of caspase-3.