Insulin-induced gene 2 protects against hepatic ischemia-reperfusion injury via metabolic remodeling.

BACKGROUND: Hepatic ischemia-reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. METHODS: Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. RESULTS: Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). CONCLUSIONS: Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

Hemostatic effects of traditional Inula viscosa and Capsella bursa-pastoris plant mixture extract on rat liver parenchymal bleeding model.

BACKGROUND: Failure to achieve effective bleeding control and problems related to transfusion in liver surgery are the most common causes of post-operative mortality and morbidity. Various methods/drugs including topical hemostatic agents have been em-ployed for bleeding control in liver surgery. This study was aimed to investigate the hemostatic properties of the herb mixture extract of Inula viscosa and Capsella bursa-pastoris (IvCbp) in rat liver laceration model, which have been traditionally used as antiseptic and hemostatic agents public in Hatay/Tukey. METHODS: Thirty rats were divided into three groups equally and blood samples were taken from all rats for preoperative hemoglobin (Hb) measurements. Then, the standard liver resection model was applied to all rats. Sponge for the first rat group, Ankaferd Blood Stopper® Trend-Tech for the second rat group and IvCbp plant extract mixture for the third group were applied to resection areas for 3 minutes. Liver samples of all rats were evaluated in terms of inflammation and necrosis intensity on the 5th post-operative day. RESULTS: Post-operative Hb values were found as 11.0±1.1 g/dL in the sponge group, 11.9±2.0 g/dL in the Ankaferd group, and 14.1±1.2 g/dL in the IvCbp herb mixture group (p<0.001). In the histopathological examination, less necrosis was observed in the herb mixture group compared to the sponge and Ankaferd groups (p=0.001). In addition, no statistically significant necrosis difference was observed between sponge and Ankaferd groups. While less inflammation was observed in the herb mixture group compared to the other groups, Ankaferd group had the highest inflammation score (p<0.001). CONCLUSION: IvCbp herb mixture extract group provide effective hemostatic control, caused less Hb decrease and resulted in less inflammation and necrosis compared to Ankaferd and sponge groups in a rat liver resection model.

Melatonin and zinc supplements with physical and mental activities subside neurodegeneration and hepatorenal injury induced by aluminum chloride in rats: Inclusion of GSK-3ß-Wnt/ß-catenin signaling pathway.

Alzheimer's disease (AD) is an irreversible, progressive cognitive dysfunction. Inflammaging is the greatest common factor between AD and hepatorenal malfunction. This study aimed to use melatonin (MEL) and zinc sulfate (Zn) in addition to physical and mental activities (PMA) to ameliorate AlCl3-induced AD as well as investigate their impact on the associated hepatorenal impairment. METHODS: Seven groups of rats each received: saline (control group), AlCl3 (70 mg/kg, i.p.), PMA, either alone or with a combination of Mel (10 mg/kg, p.o) and/or Zn (16 mg/kg, p.o). Neurological deterioration was assessed after 5 weeks using behavioral tests, histopathological examination, and measurements of acetylcholinesterase (ACHE), brain monoamines, oxidative stress, and inflammatory markers, Amyloid precursor protein (APP), amyloid-ß (Aß), tau levels, and brain derived neurotrophic factor (BDNF). Moreover, the GSK-3ß-Wnt/ß-catenin signaling pathway was assessed. Additionally, oxidative stress and inflammatory markers were determined in liver and kidney tissues with concurrent evaluation of hepatic and renal functions. RESULTS: The histopathological examination revealed a cerebral cortex and hippocampus deterioration in the AD group with a decline in spatial learning and memory, besides a significant increase in AD markers in the brain and disturbance in GSK-3ß-Wnt/ß-catenin signaling. The AD group showed hepatorenal injuries supported by elevated oxidative stress and inflammatory markers. However, adding Mel and Zn to PMA significantly attenuated the neurodegeneration and enhanced hepatic and renal functions by ameliorating oxidant and inflammatory markers. CONCLUSIONS: Combining Mel and Zn supplements with PMA defends against AlCl3-induced AD by modulating GSK-3ß-Wnt/ß-catenin signaling and palliates the associated hepatorenal dysfunction.

Ginger and 6-gingerol prevent lipopolysaccharide-induced intestinal barrier damage and liver injury in mice.

BACKGROUND: Inflammation-related diseases present a significant public health problem. Ginger is a flavoring spice and medicinal herb with anti-inflammatory activity. This study investigated the preventive effects of ginger extract (GE) and its main bioactive component, 6-gingerol (6G), on lipopolysaccharide (LPS)-induced intestinal barrier dysfunction and liver injury in mice. RESULTS: GE and 6G were orally administered to mice for seven consecutive days before LPS administration. After 24 h, the mice were sacrificed. GE and 6G were found to significantly reverse LPS-induced inflammation in the mouse ileum by modifying the NF-κB pathway. They also alleviated apoptosis in the ileum by downregulating Bax and cytochrome c gene expression and by inhibiting the caspase-3 pathway. Through the aforementioned mechanisms, GE and 6G restored the intestinal barrier by increasing ZO-1 and claudin-1 protein expressions. Gut-derived LPS induced inflammation and apoptosis in the liver; these effects were markedly reversed through GE and 6G treatment. 6G was the most abundant component in GE, as evidenced through liquid chromatography-mass spectrometry, and accounted for >50% of total gingerols and shogaols in GE. CONCLUSION: The current results support the use of GE and 6G as dietary supplements to protect against gut-derived endotoxemia-associated inflammatory response and disorders. © 2021 Society of Chemical Industry.

Inflammatory Response and Oxidative Stress as Mechanism of Reducing Hyperuricemia of Gardenia jasminoides-Poria cocos with Network Pharmacology.

Hyperuricemia (HUA) is a metabolic disease, closely related to oxidative stress and inflammatory responses, caused by reduced excretion or increased production of uric acid. However, the existing therapeutic drugs have many side effects. It is imperative to find a drug or an alternative medicine to effectively control HUA. It was reported that Gardenia jasminoides and Poria cocos could reduce the level of uric acid in hyperuricemic rats through the inhibition of xanthine oxidase (XOD) activity. But there were few studies on its mechanism. Therefore, the effective ingredients in G. jasminoides and P. cocoa extracts (GPE), the active target sites, and the further potential mechanisms were studied by LC-/MS/MS, molecular docking, and network pharmacology, combined with the validation of animal experiments. These results proved that GPE could significantly improve HUA induced by potassium oxazine with the characteristics of multicomponent, multitarget, and multichannel overall regulation. In general, GPE could reduce the level of uric acid and alleviate liver and kidney injury caused by inflammatory response and oxidative stress. The mechanism might be related to the TNF-α and IL-7 signaling pathway.

Zinc as a Drug for Wilson's Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury.

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.

Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease, Hepatic Fibrosis, and Insulin Resistance in Mice.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.

Study on the effect of active components of Schisandra chinensis on liver injury and its mechanisms in mice based on network pharmacology.

The aim of this study was to analyze the active components of Schisandra chinensis on liver injury and its mechanism in mice by network pharmacology. The active components of S. chinensis were found through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and their corresponding targets were predicted. The targets of liver injury were searched through Therapeutic Targets Database (TTD), DisGeNET and drugbank databases, and the Venn diagram was constructed to obtain the action targets. The "drug-active component-target" network and protein-protein interaction network (PPI) were constructed by using STRING database and Cytoscape software, and the key targets were further screened by the enrichment analysis of relevant KEGG pathways. Finally, a CCl4-induced mouse liver injury model was established to verify the efficacy and related targets of S. chinensis and clarify its mechanism. Eight active components and 56 related targets of S. chinensis were screened out based on their oral bioavailability (OB) and drug likeness (DL). Five targets of S. chinensis related to liver injury were found by using the Venn diagram. The key targets, namely Ptgs2 and Nos2 genes, were further screened out by constructing a PPI network, and Schisandrol B (SCB) was considered the key component most closely related to the liver injury in S. chinensis. The results indicate that SCB may play a role in the treatment of the CCl4-induced liver injury by down-regulating the expression of iNOS and COX-2, and regulating the expression of NF-κB and IL-17 signaling pathway to inhibit the expression of proinflammatory factors.

Tandem mass tag-based quantitative proteomic analysis of the liver reveals potential protein targets of Xiaochaihutang in CUMS model of depression.

Depression is a global mental disorder disease and greatly threatened human health. Xiaochaihutang (XCHT) has been used successfully in treatment of depression for many years in China, but the mechanism is unclear. Using the chronic unpredictable mild stress (CUMS) mice model of depression, the present study aimed to reveal possible antidepressant mechanisms of XCHT from the perspective of liver by analyzing hepatic proteomics in mice. Bioinformatics analysis identified 31 differentially expressed proteins (DEPs), including 5 upregulated and 26 downregulated proteins, between the CUMS model and XCHT groups. The bile secretion pathway was found by KEGG pathway analysis of these DEPs. Four of the 31 differentially expressed proteins, including 2 active proteins involved in bile secretion, carbonic anhydrase 2 (CA2) and cystic fibrosis transmembrane conductance regulator (CFTR), were selected to verify their genes. Four genes (Cyp7a1, Fxr, Shp and Ntcp) related to bile acid synthesis and transport were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Both biochemical tests and gene studies demonstrated that CUMS affected bile acid synthesis and transport, while XCHT regulated this pathway. The results indicated that there may be a potential relationship between CUMS induced depression and hepatic injury caused by increased bile acid, and also provide a novel insight to understand the underlying anti-depression mechanisms of XCHT.

Glabridin ameliorates methotrexate-induced liver injury via attenuation of oxidative stress, inflammation, and apoptosis.

Despite unprecedented advances in modern medicine, no safe and effective drug is available to date for oral administration to combat drug-induced liver injury, which is a vital concern nowadays. The present study deals with the hepatoprotective effect of pure glabridin, a key phytoconstituent from Glycyrrhiza glabra with mechanistic investigations using an in-vivo methotrexate-induced liver injury model as there is no such precedent. The study was performed in the Swiss mice model where a single dose of methotrexate (40 mg/kg) was given on the 7th day through an intraperitoneal route to induce hepatotoxicity, and glabridin as a test compound was administered orally for eleven consecutive days at 10 to 40 mg/kg. Glabridin markedly improved serum biochemical parameters (SGPT, SGOT), proinflammatory cytokine (TNF-α) level, oxidative stress markers (MDA, GSH, SOD, CAT) as compared to methotrexate alone. Alterations in methotrexate-induced liver architecture were considerably prevented by glabridin treatment as suggested by liver histopathological examination and SEM investigation. Glabridin substantially prevented methotrexate-induced down-regulation of Nrf2, & activation of NF-κB, and caused up-regulation of BAX at different dose levels. Overall, glabridin is found to protect methotrexate-induced hepatotoxicity by improving important factors for oxidative stress, inflammation, and apoptosis.

Study on Hepatotoxicity of Rhubarb Based on Metabolomics and Network Pharmacology.

BACKGROUND: Rhubarb, as a traditional Chinese medicine, is the preferred drug for the treatment of stagnation and constipation in clinical practice. It has been reported that rhubarb possesses hepatotoxicity, but its mechanism in vivo is still unclear. METHODS: In this study, the chemical components in rhubarb were identified based on UPLC-Q-TOF/MS combined with data postprocessing technology. The metabolic biomarkers obtained through metabolomics technology were related to rhubarb-induced hepatotoxicity. Furthermore, the potential targets of rhubarb-induced hepatotoxicity were obtained by network pharmacology involving the above components and metabolites. Meanwhile, GO gene enrichment analysis and KEGG pathway analysis were performed on the common targets. RESULTS: Twenty-eight components in rhubarb were identified based on UPLC-Q-TOF/MS, and 242 targets related to rhubarb ingredients were predicted. Nine metabolic biomarkers obtained through metabolomics technology were closely related to rhubarb-induced hepatotoxicity, and 282 targets of metabolites were predicted. Among them, the levels of 4 metabolites, namely dynorphin B (10-13), cervonoyl ethanolamide, lysoPE (18:2), and 3-hydroxyphenyl 2-hydroxybenzoate, significantly increased, while the levels of 5 metabolites, namely dopamine, biopterin, choline, coenzyme Q9 and P1, P4-bis (5'-uridyl) tetraphosphate significantly decreased. In addition, 166 potential targets of rhubarb-induced hepatotoxicity were obtained by network pharmacology. The KEGG pathway analysis was performed on the common targets to obtain 46 associated signaling pathways. CONCLUSION: These data suggested that rhubarb may cause liver toxicity due to its action on dopamine D1 receptor (DRD1), dopamine D2 receptor (DRD2), phosphodiesterase 4B (PDE4B), vanilloid receptor (TRPV1); transient receptor potential cation channel subfamily M member 8 (TRPM8), prostanoid EP2 receptor (PTGER2), acetylcholinesterase (ACHE), muscarinic acetylcholine receptor M3 (CHRM3) through the cAMP signaling pathway, cholinergic synapses, and inflammatory mediators to regulate TRP channels. Metabolomics technology and network pharmacology were integrated to explore rhubarb hepatotoxicity to promote the reasonable clinical application of rhubarb.

Severe Liver Injury Associated With High-Dose Atorvastatin Therapy.

Statins are recommended for first-line management of elevated cholesterol in the primary and secondary prevention of atherosclerotic cardiovascular disease. Statins may occasionally be associated with mild transaminase elevations but can also result in life-threatening liver injury. Atorvastatin is the most common cause of clinically significant liver injury in this drug class. We report a case of severe, asymptomatic liver injury in a hepatocellular pattern in a 71-year-old man occurring within 3 months of switching from simvastatin to high-intensity atorvastatin therapy. Hepatitis improved rapidly with cessation of atorvastatin and did not recur after resuming simvastatin.

Cynaroside prevents macrophage polarization into pro-inflammatory phenotype and alleviates cecal ligation and puncture-induced liver injury by targeting PKM2/HIF-1α axis.

The treatment of sepsis is still challenging and the liver is an important target of sepsis-related injury. Macrophages are important innate immune cells in liver, and modulation of macrophages M1/M2 polarization may be a promising strategy for septic liver injury treatment. Macrophage polarization and inflammation of liver tissue has been shown regulated by pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis and immune inflammatory pathways. Therefore, modulating PKM2-mediated immunometabolic reprogramming presents a novel strategy for inflammation-associated diseases. In this study, cynaroside, a flavonoid compound, promoted macrophage phenotypic transition from pro-inflammatory M1 to anti-inflammatory M2, and mitigated sepsis-associated liver inflammatory damage. We established that cynaroside reduced binding of PKM2 to hypoxia-inducible factor-1α (HIF-1α) by abolishing translocation of PKM2 to the nucleus and promoting PKM2 tetramer formation, as well as suppressing phosphorylation of PKM2 at Y105 in vivo and in vitro. Moreover, cynaroside restored pyruvate kinase activity, inhibited glycolysis-related proteins including PFKFB3, HK2 and HIF-1α, and inhibited glycolysis-related hyperacetylation of HMGB1 in septic liver. Therefore, this study reports a novel function of cynaroside in hepatic macrophage polarization, and cecum ligation and puncture-induced liver injury in septic mice. The findings provide crucial information with regard to therapeutic efficacy of cynaroside in the treatment of sepsis.

Protective Effect of n-Butanol Extract from Viola yedoensis on Immunological Liver Injury.

Viola yedoensis Makino was used to treat inflammation, viral hepatitis, acute pyogenic infection, and ulcerative carbuncles. However, the protective effect on immunological liver injury (ILI) of V. yedoensis had been rarely reported. This study aimed to explore the protective effect of n-butanol extract (BE) from V. yedoensis on ILI in vitro and in vivo. In vitro, the BE significantly inhibited the secretions of Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) in the HepG2.2.15 cells and the replication of HBV DNA. The research data in vivo revealed that the BE reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), and methane dicarboxylic aldehyde (MDA) in liver tissues of the ConA-induced mice, while increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and the effective contents of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and the BE could ameliorate liver histological lesions. These results motivated a further investigation into the chemical constituents of BE. Four coumarins (esculetin, prionanthoside, cichoriin, and esculin) and one flavonoid (quercetin-3-O-galactoside) were isolated from the BE by silica gel column chromatography and recrystallization, of which structures were eventually confirmed by 1 H-NMR, 13 C-NMR, and MS.

Liver Damage Produced by Malnutrition is Improved by Dietary Supplementation in Mice: Assessment of a Supplement Based on Buriti (A Cerrado Fruit) and Dairy By-products.

BACKGROUND: Malnutrition induced by dietary restriction produces several metabolic changes that affect body weight, the digestive system, and annex organs, including the liver. Malnutrition generates an inflammatory state and increases oxidative stress. The liver is one of the body vital organs, becoming necessary to analyze the impact of food supplementation on the repair of possible changes that may occur in this organ due to malnutrition. AIMS: To evaluate the effects of a low-cost supplementation derived from Buriti and dairy byproducts on liver recovery in malnourished mice, focusing on the expression of oxidative stressrelated genes, as well as biochemical and histological parameters. METHODS: Swiss mice were divided into six groups and submitted to two treatment phases: food restriction, for malnutrition onset; and renutrition, with mice being fed with different diets. RESULTS: Our results indicate that dietary supplementation was successful in recovering liver damage caused by malnutrition in animal models. The new supplement has been shown to recover liver damage with similar or superior results compared to the commercial reference supplement on the market. CONCLUSION: Our work presents a new composition of low cost food supplement based on buriti and dairy by-products, proven to be effective in the malnutrition treatment of malnutrition. The improvements were proven through the recovery of body weight, reduction of inflammation and oxidative stress.

Purified anthocyanins from Zea mays L. cob ameliorates chronic liver injury in mice via modulating of oxidative stress and apoptosis.

BACKGROUND: Purple corn (Zea mays L.) is one of the main economic crops in China and has been used in the treatment of cystitis, urinary infections and obesity. However, purple corncobs, the by-product remaining after processing and having an intense purple-black color, are normally disposed of as waste or used as animal feed. Therefore, to further expand the medicinal value of purple corncob, its content was analyzed and, after purification, the effect and mechanism of purified purple corncob anthocyanins (PPCCA) on CCl4 -induced chronic liver injury in mice were investigated. RESULTS: It was observed that the total anthocyanin content (TAC) from PPCCA (317.51 ± 9.30 mg cyanidin 3-O-glucoside (C-3-G) g-1 dry weight) was significantly higher than that from the purified purple corn seed anthocyanin (266.73 ± 3.67 mg C-3-G g-1 dry weight), of which C-3-G accounted for 90.6% and 90.4% of the TAC, respectively. Furthermore, compared with the CCl4 group, PPCCA treatment significantly reduced liver index, serum total bilirubin, alanine transaminase, aspartate transaminase and liver malondialdehyde levels, but increased liver superoxide dismutase activity. The pathological changes were also improved, such as more regular arrangement of hepatocytes, less swelling, and fewer vacuoles and apoptotic cells. Additionally, mechanistic studies showed that PPCCA downregulated the expression of Caspase-3, Bax and cytochrome P450 2E1 proteins in the liver and upregulated the expression of Bcl-2. CONCLUSION: These results demonstrated that PPCCA could ameliorate CCl4 -induced chronic liver injury by regulating oxidative stress and hepatocyte apoptosis pathways. © 2021 Society of Chemical Industry.

Protective effect of Coriandrum sativum extract against inflammation and apoptosis in liver ischaemia/reperfusion injury.

BACKGROUND: The aim of this study was to investigate the anti-inflammatory and antioxidant effects of Coriandrum sativum extract on liver ischaemia reperfusion injury at light microscopic and biochemical levels. MATERIALS AND METHODS: Sham, ischaemia/reperfusion injury (IRI), IRI + Coriandrum sativum extract and only Coriandrum sativum extract groups were formed. Sixty minutes of ischaemia and 60 minutes of reperfusion were performed. In the treatment group, 300 mg/kg/day Coriandrum sativum was given by gavage. Hepatic tissues were fixed in 4% paraformaldehyde. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) enzymes were measured. Nuclear factor-kappa beta (NF-κB), tumour necrosis factor-alpha (TNF-α) and caspase-3 immunohistochemistry staining was performed. Microscopic scoring was performed in terms of sinusoidal congestion, vacuolisation, and necrosis. RESULTS: Sinusoidal enlargement and diffuse congestion, Kupffer cell increase, neutrophil increase in necrotic areas, vacuolisation in hepatocytes, and bile duct proliferation in the portal triad were observed in ischaemia/reperfusion hepatic tissue. Very rare, necrotic areas were observed in the Coriandrum sativum treatment group, while congestion and vacuolisation and bile duct proliferation were decreased compared to the ischaemic group. The AST and ALT levels were increased in the IRI and IRI + Coriandrum sativum groups. When compared to the IRI group, the AST and ALT levels of the Coriandrum sativum were considerably decreased. The IRI and IRI + Coriandrum sativum groups had statistically significant differences in ALP compared to that of the Coriandrum sativum and Sham groups. There was no significant difference between the ALP levels of the IRI and IRI + Coriandrum sativum groups TNF-α, NF-κB and caspase-3 immune positive stained hepatocytes were numerous and widely observed in the injury group. There were positive TNF-α immunohistochemical staining Kupffer cells in the IRI group. In the group treated with Coriandrum sativum, Kupffer cells were not stained, while TNF-α, NF κB and caspase-3 expressing hepatocytes were found to be decreased compared to the IRI group. When the expression values of the TNF-α, NF-κB and caspase-3 groups were evaluated statistically, it was seen that there was a significant decrease in the group treated with Coriandrum sativum. CONCLUSIONS: It was found that Coriandrum sativum extract decreased proinflammatory cytokine TNF-α and apoptotic cell death and liver enzymes in liver ischaemia/reperfusion injury.

Amelioration of non-alcoholic fatty liver disease by sodium butyrate is linked to the modulation of intestinal tight junctions in db/db mice.

The intestinal microenvironment, a potential factor that contributes to the development of non-alcoholic fatty liver disease (NALFD) and type 2 diabetes (T2DM), has a close relationship with intestinal tight junctions (TJs). Here, we show that the disruption of intestinal TJs in the intestines of 16-week-old db/db mice and in high glucose (HG)-cultured Caco-2 cells can both be improved by sodium butyrate (NaB) in a dose-dependent manner in vitro and in vivo. Accompanying the improved intestinal TJs, NaB not only relieved intestine inflammation of db/db mice and HG and LPS co-cultured Caco-2 cells but also restored intestinal Takeda G-protein-coupled (TGR5) expression, resulting in up-regulated serum GLP-1 levels. Subsequently, the GLP-1 analogue Exendin-4 was used to examine the improvement of lipid accumulation in HG and free fatty acid (FFA) co-cultured HepG2 cells. Finally, we used 16-week-old db/db mice to examine the hepatoprotective effects of NaB and its producing strain Clostridium butyricum. Our data showed that NaB and Clostridium butyricum treatment significantly reduced the levels of blood glucose and serum transaminase and markedly reduced T2DM-induced histological alterations of the liver, together with improved liver inflammation and lipid accumulation. These findings suggest that NaB and Clostridium butyricum are a potential adjuvant treatment strategy for T2DM-induced NAFLD; their hepatoprotective effect was linked to the modulation of intestinal TJs, causing the restoration of glucose and lipid metabolism and the improvement of inflammation in hepatocytes.

Selenium or ozone: Effects on liver injury caused by experimental iron overload.

AIMS: Iron is an important metal ion as a biocatalyst on the other hand iron overload causes various diseases. Iron overload can result in fibrosis and hepatocellular carcinoma with various pathophysiological mechanisms, including oxidative damage in the liver. Therefore; in this study the effects of ozone and selenium -whose antioxidant properties are known- were evaluated in liver injury induced by iron overload. MATERIALS AND METHODS: Iron overload model was provided by intraperitoneal administration of 88 mg/kg iron dextrate for 4 weeks. After iron dextran administration, ozone and selenium administrations were made for 3 weeks. From the obtained blood and tissue samples total oxidant status (TOS) and total antioxidant status (TAS) were determined and histopathological examination was performed in liver tissue samples. KEY FINDINGS: In rats with iron overload, the lowest mean serum TOS was observed in the selenium administration group. The highest tissue TOS means and the lowest tissue TAS means were determined in the group in which ozone and selenium were administrated together. When histopathological data were evaluated, the presence of increased apoptosis in the ozone group compared to the iron group (p = 0.019) and selenium group (p = 0.019) was noted. Similarly, increased periportal inflammation (p = 0.001) and fibrosis (p = 0.005) were observed in the ozone group compared to the selenium group. SIGNIFICANCE: In iron-induced liver damage, ozone was thought to be effective by decreasing ROS, but contrary to expectations, it was observed that it may negatively affect the picture by showing synergistic effect. However, the effects of selenium on both serum and tissue levels are promising.

PL-S2, a homogeneous polysaccharide from Radix Puerariae lobatae, attenuates hyperlipidemia via farnesoid X receptor (FXR) pathway-modulated bile acid metabolism.

Polysaccharides are important active constituents of Radix Puerariae lobatae (RPL). In this study, a novel homogeneous polysaccharide from RPL was successfully obtained by HP-20 macroporous resin and purified by Sepharose G-100 column chromatography. Nuclear magnetic resonance (NMR) analysis showed that the main glycosidic bonds were composed of α-1,3-linked and α-1,4-linked glucose. The molecular weight of PL-S2 was 18.73 kDa. The hypolipidemic effect of PL-S2 on hyperlipidemic rats was evaluated in histopathology and metabolomics analyses. PL-S2 significantly reduced plasma lipid levels and inhibited bile acid metabolism. We also demonstrated that treatment with PL-S2 activated FXR, CYP7A1, BESP, and MRP2 in rat liver. Our findings first indicate that PL-S2 decreases plasma lipid levels in hyperlipidemic rats by activating the FXR signaling pathway and promoting bile acid excretion. Therefore, PL-S2 derived from RPL is implicated as a functional food factor with lipid-regulating activity, and highlighted as a potential food supplement for the treatment of hyperlipidemia.