Protective effects of morin on lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting TLR4/NF-κB and activating Nrf2/HO-1 signaling pathways

Morin, a bioactive flavonoid extracted from the bark of Moraceae plants and many medicinal herbs, has anti-inflammatory and antioxidative effects. In this research, we explored the protective effects of morin against lipopolysaccharide (LPS) and d-galactosamine (D-GalN) induced acute liver injury in mice. Mice were given an intraperitoneal injection of morin before LPS and D-GalN treatment and the HepG2 cells were only given morin to investigate its effects. The results showed that morin markedly inhibited the production of serum alanine transaminase (ALT), aspartate aminotransferase (AST), interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and hepatic TNF-α, IL-6, and myeloperoxidase (MPO) induced by LPS/D-GalN. In order to evaluate morin effect in the future, we investigated the expression of nuclear factor E2 related factor 2 (Nrf2), nuclear factor-kappaB (NF-κB), toll like receptor 4 (TLR4) on liver injury. Taken together, these results suggested that morin could exert the anti-inflammatory and anti-oxidative effects against LPS/D-GalN-induced acute liver injury by activating Nrf2 signal pathways and inhibiting NF-κB activation.     

Protective effect of baicalin against lipopolysaccharide/D-galactosamine-induced liver injury in mice by up-regulation of heme oxygenase-1

Baicalin, a traditional anti-inflammatory drug, has been found to protect against liver injury in several experimental animal hepatitis models; however, the mechanisms underlying the hepatoprotective properties of baicalin are poorly understood. In the present study,we investigated the effects of baicalin on the acute liver injury in mice induced by Lipopolysaccharide/D-galactosamine (LPS/D-GalN). Baicalin (50, 150, and 300 mg/kg) was pretreated intraperitoneally (i.p.) at 2, 24, and 48 h respectively before LPS/D-GalN injected in mice.The mortality, hepatic tissue histology, hepatic tissue Tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO), plasma levels of TNF-alpha and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed. Besides, western blotting analyses of nuclear factor kappa B (NF-kappaB) translocation and Heme oxygenase-1(HO-1) protein expression, as well as HO-1 activity were determined. The results showed that baicalin protected against LPS/D-GalN-induced liver injury, including dose-dependent alleviation of mortality and hepatic pathological damage, decrease of ALT/AST release and the rise of MPO. Baicalin reduced nuclear translocation of NF-kappa B, TNF-alpha mRNA and protein levels in hepatic tissues and plasma levels of TNF-alpha induced by LPS/D-GalN. Moreover, baicalin dose-dependently increased HO-1 protein expression and activity. Further, inhibition of HO-1 activity significantly reversed the protective effect of baicalin against LPS/D-GalN-induced liver injury. These results suggest that baicalin can effectively prevent LPS/D-GalN-induced liver injury by inhibition of NF-kappa B activity to reduce TNF-alpha production and the underlying mechanism may be related to up-regulation of HO-1 protein and activity.     

鹰嘴豆芽素A干预TXNIP-Wnt通路改善ox-LDL诱导脑血管内皮细胞凋亡的机制研究

目的：讨论鹰嘴豆芽素A改善ox-LDL诱导脑血管内皮细胞凋亡的作用机制。方法：将大鼠脑血管内皮细胞RBECs分为对照组、氧化型低密度脂蛋白ox-LDL诱导模型组及鹰嘴豆芽素A低、中、高剂量干预组。其中ox-LDL诱导是给予100 μg·mL^-1 ox-LDL诱导RBECs细胞凋亡,鹰嘴豆芽素A干预组是给予低、中、高剂量（25,50,100 μmol·L^-1）鹰嘴豆芽素A进行药物干预。免疫荧光法检测各组脑血管内皮细胞Dil细胞膜荧光标记的ox-LDL （Dil-ox-LDL）荧光强度的变化;Western blot法检测RBECs细胞中TXNIP、NLRP3、Wnt5a、β-catenin及bax、bcl-2、cleaved caspase-3的蛋白表达水平;免疫荧光法检测TXNIP、NLRP3蛋白在细胞中的定位表达。进一步转染siRNA-TXNIP沉默RBECs细胞中TXNIP,考察鹰嘴豆芽素A对于TXNIP介导的Wnt通路及凋亡相关蛋白表达的影响。结果：ox-LDL可诱导RBECs细胞凋亡,同时诱导NLRP3、Wnt5a、β-catenin及凋亡蛋白表达显著升高。不同剂量的鹰嘴豆芽素A干预后,均可降低RBECs细胞中Dil-ox-LDL的荧光强度,并且能够抑制TXNIP由细胞核向细胞质转移,同时显著降低凋亡蛋白bax和cleaved caspase-3的表达水平,并升高bcl-2表达。沉默TXNIP后能够明显减弱鹰嘴豆芽素A对NLRP3、Wnt5a、β-catenin蛋白的抑制作用,并减弱鹰嘴豆芽素A对ox-LDL诱导RBECs细胞凋亡的改善作用。结论：鹰嘴豆芽素A能够改善ox-LDL诱导的脑血管内皮细胞凋亡,其机制可能与TXNIP介导的Wnt信号通路的激活相关。     

Protective effects of probiotic Lactobacillus casei Zhang against endotoxin- and d-galactosamine-induced liver injury in rats via anti-oxidative and anti-inflammatory capacities

Lactobacillus casei Zhang (LcZ) has been recently isolated from the traditional Mongolian beverage koumiss and has a set of favorable probiotic properties, including aciduricity, bile resistance and ability to colonize the gastrointestinal tract. We have previously reported the anti-oxidative properties of LcZ in the hyperlipidemic rats. In this study, the hepatoprotective effects of LcZ against lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced liver injury were investigated. We found that pretreatment with LcZ significantly improved survival of rats challenged with LPS/D-GalN. In addition, pretreatment with LcZ significantly decreased alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in LPS/D-GalN-challenged rats, which were accompanied by diminished liver injuries, reduced malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity in liver homogenates. Pretreatment with LcZ also markedly reduced LPS/D-GalN-induced production of hepatic nitric oxide (NO), activation of inducible nitric oxide synthase (iNOS) and expression of tumor necrosis factor-α (TNF-α). Furthermore, hepatic toll-like receptor 4 (TLR4) mRNA and protein levels, the phosphorylation of I-κB and translocation of nuclear factor κB (NF-κB) were significantly down-regulated by pretreatment with LcZ. These results suggest that pretreatment with LcZ protects against LPS/D-GalN-induced liver injury in rats via its anti-oxidative and anti-inflammatory capacities. The hepatoprotective effects of LcZ are associated with an inhibition of TLR4 expression and TLR4 signaling.     

Protective effect of linalool against lipopolysaccharide/d-galactosamine-induced liver injury in mice

Linalool, a natural compound of the essential oils, has been shown to have antinociceptive, antimicrobial, and anti-inflammatory properties. The aim of this study was to investigate the effects of linalool against lipopolysaccharide (LPS)/d-galactosamine (GalN)-induced liver injury in mice. Mice were administered with linalool 1 h before receiving LPS (50 μg/kg) and GalN (800 mg/kg). The results demonstrated that linalool had a protective effect on LPS/GalN-induced acute liver injury, as evidenced by the attenuation of hepatic pathological damage, malondialdehyde (MDA) content, MPO activity and serum ALT and AST levels. Linalool alleviated serum and hepatic TNF-α and IL-6 production, as well as hepatic iNOS and COX-2 expression by inhibiting NF-κB activation. Treatment of linalool increased bcl-2 expression and inhibited caspase-3 and caspase-8 expression. In addition, linalool increased Nrf2 and heme oxygenase-1 expression up-regulation by LPS/GalN. In conclusion, our results suggested that linalool was protected against LPS/GalN-induced liver injury through induction of antioxidant defense via Nrf2 activating and reduction inflammatory response via NF-κB inhibition.     

Ellagic acid protects Lipopolysaccharide/d-galactosamine-induced acute hepatic injury in mice

Ellagic acid, a natural polyphenol found in certain fruits, nuts and vegetables, has been reported to have anti-inflammatory, anti-tumor, and antioxidant activities. However, the effects of ellagic acid on acute hepatic injury have not been reported. In the present study, we investigated the effects of ellagic acid on Lipopolysaccharide/d-galactosamine-induced acute hepatic injury in mice. The results showed that LPS/GalN increased hepatic malondialdehyde (MDA) content, TNF-α level, serum ALT and AST levels and TNF-α level. However, these changes were attenuated by ellagic acid. Western blot analysis showed that ellagic acid inhibited LPS/GalN-induced NF-κB activation. Furthermore, ellagic acid induced the expression of Nrf2 and heme oxygenase-1. In conclusion, our results showed that ellagic acid protected against LPS/GalN-induced liver injury by enhancing the antioxidative defense system and reducing inflammatory response.     

Activation of Nrf2 pathway and inhibition of NLRP3 inflammasome activation contribute to the protective effect of chlorogenic acid on acute liver injury

Chlorogenic acid (CGA), a kind of polyphenol found in coffee, fruits and vegetables, has potent anti-oxidant and anti-inflammatory properties. Our previous studies showed CGA could efficiently alleviate liver fibrosis in rats. However, whether CGA regulates nuclear factor erythroid-2-related factor 2 (Nrf2) anti-oxidant pathway and NLRP3 inflammasome activation and protects against carbon tetrachloride (CCl₄)-induced acute liver injury are unknown. We found that CGA could increase Nrf2 activation and expression of Nrf2-related anti-oxidant genes, including HO-1, NQO1 and GCLC. Pretreatment with CGA could reduce CCl₄-induced elevation of serum transaminases and alleviate liver pathological abnormalities. CGA also reversed CCl₄-induced increase in MDA level and decrease in the levels of GSH, SOD and CAT in liver tissues. Meanwhile, CGA inhibited NLRP3 inflammasome activation, as indicated by the reduced protein expression of NLRP3, Pro-Caspase-1, Caspase-1, Pro-IL-1β and IL-1β. Moreover, CGA reduced serum levels and liver mRNA expression of TNF-α, IL-6 and IL-1β. These results demonstrate that CGA protects against CCl₄-induced acute liver injury probably through enhancing Nrf2-mediated anti-oxidant pathway and inhibiting NLRP3 inflammasome activation.     

益母草碱抑制NLRP3炎症小体过度激活调控巨噬细胞M1/M2表型分化

目的 研究益母草碱对脂多糖(LPS)诱导小鼠腹腔巨噬细胞免疫应答影响及相关机制.方法 分离小鼠腹腔巨噬细胞,用脂多糖和益母草碱预处理24 h,MMT法检测巨噬细胞活性;Griess法检测NO释放量;ELISA法检测IL-1β、IL-18、IL-6、TNF-α的释放量;RT-PCR法检测NLRP3、ASC、caspase...     

Protective effect of SKLB010 against d-galactosamine/lipopolysaccharide-induced acute liver failure via nuclear factor-κB signaling pathway in macrophages

Acute liver failure is characterized by the sudden loss of hepatic function and a high mortality. SKLB010, a derivative of thiazolidinediones, has been proved to be effective in protecting mice from acute liver failure caused by concanavalin A and carbon tetrachloride in our previous work. The purpose of the current study was to evaluate whether SKLB010 could prevent acute liver injury caused by d-galactosamine/lipopolysaccharide (LPS) in mice, and to investigate the underlying mechanisms. In the macrophage-mediated D-GalN/LPS model of acute liver injury, serum enzyme activity was suppressed and liver injury was attenuated by SKLB010. The serum levels of TNF-α and hepatic TNF-α mRNA expression were also markedly decreased after the treatment of SKLB010. In the liver of mice receiving injections of D-GalN/LPS, hepatocytes apoptosis and the infiltration of monocytes/macrophages were blocked by SKLB010. Furthermore, the survival rate of mice following D-GalN/LPS treatment was significantly improved by a single injection with SKLB010. In vivo, the luminescence intensity was suppressed by SKLB010 in NF-κB-luc mice after D-GalN/LPS treatment. In vitro, the production of tumor necrosis factor (TNF)-α and nitrite/nitrate in LPS-stimulated RAW264.7 macrophages was decreased by SKLB010 in a dose-dependent manner. Our further studies demonstrated that SKLB010 inhibited the phosphorylation of IκBα and p38MAPK, and the DNA binding activity of NF-κB in RAW264.7 cells. In conclusion, treatment with only a single injection of SKLB010 could significantly attenuate acute inflammation in mice induced by D-GalN/LPS, and these effects are likely associated with the inhibition of NF-κB activity.     

CQMUH-011, a novel adamantane sulfonamide compound,inhibits lipopolysaccharide- and D-galactosamine-induced fulminant hepatic failure in mice

CQMUH-011, a novel adamantane sulfonamide compound, was shown to suppress macrophage activation and proliferation in our previous study. However, it is unknown whether CQMUH-011 has anti-inflammatory and hepatoprotective properties. In this study, we investigated the potential effects and mechanisms of CQMUH-011 on lipopolysaccharide (LPS)-induced RAW264.7 cell activation in vitro and LPS- and D-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF) in vivo. The results showed that in RAW264.7 cells challenged by LPS, CQMUH-011 inhibited cell proliferation and induced cell cycle arrest and apoptosis. Furthermore, CQMUH-011 reduced tumor necrosis factor (TNF)-α and interleukin (IL)-1β production and down-regulated the overexpression of toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB induced by LPS in RAW264.7 cells. In vivo, CQMUH-011 reduced serum levels of aspartic aminotransferase and alanine transaminase and improved the mortality and hepatic pathological damage induced by LPS/D-GalN in mice. Moreover, CQMUH-011 significantly inhibited the serum levels of proinflammatory mediators, including TNF-α, IL-6, IL-1β, nitric oxide (NO), and prostaglandin E2 (PGE₂), and down-regulated the protein expression of TLR4, p38 mitogen-activated protein kinases, NF-κB, NF-κB inhibitor α (IκBα), IκB kinase β (IKKβ), cyclooxygenase-2 (COX-2) and inducible NO synthases (iNOS) induced by LPS/D-GalN in mice. In conclusion, these results demonstrated that CQMUH-011 has a notable anti-inflammatory effect and protects mice from LPS/D-GalN-induced FHF and that the molecular mechanisms might be related to the inhibition of the TLR4/NF-κB signaling pathway activation, the subsequent decrease in proinflammatory mediator production, and the inhibition of macrophage activation.     

丹参多糖对小鼠免疫性肝损伤的保护作用

目的探讨丹参多糖对卡介苗（BCG）和脂多糖（LPS）诱导的小鼠免疫性肝损伤的保护作用。方法尾静脉注射BCG和LPS诱导小鼠免疫性肝损伤,对比小鼠脏器系数,检测血清谷草转氨酶（AST）、谷丙转氨酶（ALT）、一氧化氮（NO）的水平以及比较肝组织匀浆中肿瘤坏死因子α（TNF-α）、白介素1β（IL-1β）的含量。结果丹参多糖可显著改善免疫性肝损伤小鼠的胸腺、肝脏、脾脏系数,降低血清中ALT、AST、NO的活性以及肝组织匀浆中TNF-α、IL-1β的含量。结论丹参多糖对免疫性肝损伤具有显著的保护作用。     

4-hydroxybenzo[d]oxazol-2(3H)-one ameliorates LPS/D-GalN-induced acute liver injury by inhibiting TLR4/NF-κB and MAPK signaling pathways in mice

The purpose of this study was to synthesize 4-hydroxybenzo[d]oxazol-2(3H)-one (HBO) and to investigate its protective effects on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury. HBO (C₇H₅O₃N) was synthesized based on 2-nitro-resorcinol and identified by physicochemical analysis. In the animal experiment, mice were pretreated with HBO (50, 100, 200 mg/kg) for 10 days. At the end of pretreatment, the animals were injected with LPS (10 µg/kg)/D-GalN (700 mg/kg). The results showed that HBO significantly alleviated liver injury induced by LPS/D-GalN in mice. It remarkably decreased inflammatory response by reducing the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, HBO notably attenuated hepatocyte apoptosis by inhibiting the release of Cytochrome C (Cyt C) from mitochondria into the cytoplasm and regulating the expression of B-cell lymphoma-2 (Bcl-2) family. Furthermore, the result showed that HBO inhibited the expressions of nuclear factor kappa-B p50 (NF-κBp50), toll-like receptor 4 (TLR4), and myeloid differentiation factor 88 (MyD88), as well as the phosphorylation of inhibitor of nuclear factor kappa-B (IκB), inhibitor of nuclear factor kappa-B kinase-α/β (IKK-α/β), nuclear factor kappa-B p65 (NF-κBp65), suggesting that HBO had a certain influence on the TLR4/NF-κB pathway. In addition, the mitogen-activated protein kinase (MAPK) signaling pathway was also affected by HBO, as evidenced by the decrease in the phosphorylation levels of extracellular regulated protein kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38). In conclusion, our study suggested that HBO could protect against LPS/D-GalN-induced liver injury, moreover, treatment with HBO appeared to be capable of further regulating the TLR4/NF-κB and MAPK signaling pathways.     

Anti-inflammatory effect of Yam Glycoprotein on lipopolysaccharide-induced acute lung injury via the NLRP3 and NF-κB/TLR4 signaling pathway

Acute lung injury (ALI) is a common lung disease accompanied by acute and persistent pulmonary inflammatory response syndrome, which leads to alveolar epithelial cells and capillary endothelial cell damage. Yam glycoprotein, separated from traditional Chinese yam, has been shown to have anti-inflammatory and immunomodulatory effects. In this experiment, we mainly studied the therapeutic effect and mechanism of a glycoprotein on the lipopolysaccharide (LPS)-induced ALI mice. An oral glycoprotein method was used to treat the mouse ALI model induced by LPS injection in the peritoneal cavity. Afterward, we measured the wet/dry (W/D) ratio, the activity of myeloperoxidase (MPO), the oxidative index superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-PX) and the production of inflammatory cytokines interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), and interleukin-6 (IL-6) to evaluate the effect of yam glycoprotein on lung tissue changes. We examined the protein expression of TLR4, ASC, NF-κBp65, p-NF-κBp65, Caspase-1, IκB, NLRP3, p-IκB, and β-actin by western blot analysis. Immunohistochemical analyses of NLRP3 and p-p65 in lung tissue were carried out to assess the mechanism of glycoprotein action. This result suggests that glycoprotein markedly depressed LPS-induced lung W/D ratio, MPO activity, MDA content SOD and GSH-Px depletion, and the contents of inflammatory cytokines IL-1β, IL-6, and TNF-α. Moreover, glycoprotein blocked TLR4/NF-κBp65 signaling activation and NLRP3inflammasome expression in LPS-induced ALI mice. As this particular study shows, glycoprotein has a safeguarding effects on LPS-induced ALI mice, possibly via activating NLRP3inflammasome and TLR4/NF-κB signaling pathways.     

Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats

Pyroptosis pathway is closely related to inflammation. However, Celastrol effect on pyroptosis pathway after spinal cord injury (SCI) are poorly understood. We studied the anti-inflammatory and neuroprotective effects of Celastrol on acute spinal cord injury in rats, and its anti-inflammatory effects on lipopolysaccharide (LPS)/ATP-induced microgliosis. Our results show that Celastrol can improve the recovery of hindlimb motor function after SCI in Sprague-Dawley (SD) rats, and reduce the cavity area of spinal cord injury along with the neuronal loss. Celastrol simultaneously reduced the activation of microglia (especially M1 microglia) in the spinal cord, inhibited the pyroptosis-related proteins (NLRP3 ASC Caspase-1 GSDMD), reduced the release of TNF-α IL-1β and IL-18 inflammatory factors, and increased the release of IL10 cytokines. In vitro studies showed that Celastrol reduced the toxicity resulting from the administration of LPS with ATP to BV-2 cells, inhibited the pyroptosis-related proteins (NLRP3 Caspase-1 GSDMD), and inhibited the release of corresponding inflammatory factors. Finally, Celastrol can inhibit the expression of NFκB/p-p65 in vitro and in vivo. Our results show that Celastrol can attenuate the inflammatory response of the spinal cord after SCI, which is associated with inhibition of microglial activation and pyroptosis pathway. Further study to explore the use of Celastrol to treat SCI is warranted.     

6-Gingerol ameliorates sepsis-induced liver injury through the Nrf2 pathway

Sepsis-induced liver injury is very common in intensive care units. Here, we investigated the effects of 6-gingerol on sepsis-induced liver injury and the role of the Nrf2 pathway in this process. 6-Gingerol is the principal ingredient of ginger that exerts anti-inflammatory and antioxidant effects. Using cecal ligation and puncture (CLP) to induce polymicrobial sepsis and related liver injury, we found that mice pre-treated with 6-Gingerol showed less incidences of severe liver inflammation and death than untreated CLP groups. 6-Gingerol administration also inhibited the expression of pyroptosis-related proteins, including NOD-like receptor protein 3 (NLRP3), IL-1β, and caspase-1. Consistent with these findings, 6-gingerol reduced the effects of pyroptosis induced by lipopolysaccharide (LPS) and adenosine 5′-triphosphate (ATP) in RAW 264.7 cells, as evidenced by IL-1β and caspase-1 protein levels in the supernatant and propidium iodide (PI) staining. 6-Gingerol was shown to activate the Nrf2 pathway in vivo and in vitro. Notably, Nrf2 siRNA transfection nullified the inhibitory effects of 6-gingerol on pyroptosis in vitro. In summary, these findings suggested that 6-gingerol alleviated sepsis-induced liver injury by inhibiting pyroptosis through the Nrf2 pathway.     

Genipin alleviates LPS-induced acute lung injury by inhibiting NF-κB and NLRP3 signaling pathways

Genipin has been reported to have anti-inflammatory effect. However, its role on lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored. This study aimed to evaluate the effect of genipin on murine model of acute lung injury induced by LPS. The mice were treated with genipin 1 h before LPS administration. 12 h later, the myeloperoxidase (MPO) in lung tissues and lung wet/dry ratio were detected. The levels of TNF-α, IL-1β and IL-6 in bronchoalveolar lavage fluid (BALF) were measured by ELISA. Apart from this, we use western blot to detect the protein expression in the NF-κB and NLRP3 signaling pathways. The results showed that the treatment of genipin markedly attenuated the lung wet/dry ratio and the MPO activity. Moreover, it also inhibited the levels of TNF-α, IL-1β, IL-6 in the BALF. In addition, genipin significantly inhibited LPS-induced NF-κB and NLRP3 activation. In conclusion, these results demonstrate that genipin protected against LPS-induced ALI through inhibiting NF-κB and NLRP3 signaling pathways.     

Schisandrin B inhibits LPS-induced inflammatory response in human umbilical vein endothelial cells by activating Nrf2

Schisandrin B (SchB), an active ingredient extracted from Schisandra chinensis (Turcz.) Baill, has been known to have anti-oxidant and anti-inflammatory activities. In this study, we investigated the anti-inflammatory effects and mechanism of SchB in LPS-stimulated human umbilical vein endothelial cells (HUVECs). The effects of SchB on VCAM-1, ICAM-1, NF-κB and Nrf2 expression were detected by western blot analysis. The effects of SchB on TNF-α and IL-8 production were detected by ELISA. The results showed that SchB strongly suppressed the production of TNF-α and IL-8 in HUVECs stimulated with LPS. SchB also inhibited LPS-induced VCAM-1 and ICAM-1 expression. Furthermore, SchB blocked the activation of NF-κB induced by LPS. In addition, SchB increased the expression of Nrf2 and HO-1 in a concentration-dependent manner. And the inhibition of TNF-α and IL-8 production by SchB was blocked by transfection with Nrf2 siRNA. Our findings showed that SchB inhibited LPS-induced inflammation in HUVECs by activating Nrf2 signaling pathway.     

Hepatoprotective effect of taxiresinol and (7'R)-7'-hydroxylariciresinol on D-galactosamine and lipopolysaccharide-induced liver injury in mice

The hepatoprotective effect of taxiresinol ( 1) and (7' R)-7'-hydroxylariciresinol ( 2), two tetrahydrofuran-type lignans isolated from the wood of Taxus yunnanensis, were investigated on D-galactosamine ( D-GalN)/lipopolysaccharide (LPS)-induced hepatic liver injury in mice. Pre-administration of 1 or 2 at doses of 50 and 10 mg/kg ( i. p.) at 12 and 1 h before D-GalN/LPS injection significantly inhibited hepatocyte DNA fragmentation and apoptotic body formation. Pre-treatment of these two lignans further suppressed hepatic necrosis which occur at later stage of D-GalN/LPS intoxication as demonstrated by the significant and dose-dependent reduction in serum glutamic pyruvic transaminase (sGPT) and serum glutamic oxaloacetic transaminase (sGOT) at 8 h after intoxication. The elevation of serum tumor necrosis factor-alpha (TNF- alpha) level by D-GalN/LPS toxication was significantly inhibited by 1 or 2 at doses of 50 and 10 mg/kg. Moreover, both of these lignans significantly protected hepatocytes from D-GalN/TNF- alpha-induced cell death in primary cultured mouse hepatocytes. These results suggested that 1 and 2 had protected the hepatocytes from apoptosis via an inhibition of TNF- alpha production by activated macrophages and a direct inhibition of apoptosis induced by TNF- alpha in D-GalN/LPS-treated mice.     

Glaucocalyxin A alleviates LPS-mediated septic shock and inflammation via inhibiting NLRP3 inflammasome activation

Glaucocalyxin A (GLA) is a bioactive ent-kauranoid diterpenoid derived from the herbal medicine, Rabdosia japonica var. glaucocalyx, and it has been reported to possess marked anti-inflammatory properties. However, the underlying mechanisms are not fully understood. Here, we reported that GLA dramatically inhibited canonical and non-canonical NLRP3 inflammasome activation induced by multiple agonists. In addition, GLA also blocked NLRC4 inflammasome activation but had no effect on AIM2 inflammasome. Furthermore, we found that GLA inhibited NLRP3 or NLRC4 agonists-induced ASC oligomerization, which is an upstream event of the inflammasomes assembly. Most importantly, administration of GLA significantly reduced lipopolysaccharide (LPS)-induced mortality in septic-shock mouse model. Additionally, GLA dose-dependently inhibited the production of interleukin (IL)-1β, but had no effect on NLRP3-independent TNF-α production induced by LPS in vivo. In conclusion, our study suggests that GLA alleviates LPS-induced septic shock and inflammation via inhibiting NLRP3 inflammasome activation and provides a promising candidate drug for the treatment of NLRP3-driven diseases.     

Protective effects of Mg-CUD against D-galactosamine-induced hepatotoxicity in rats

This study examined the protective effects of magnesium chenoursodeoxycholic acid (Mg-CUD), a magnesium trihydrate salt of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), against D-galactosamine (D-GalN)-induced liver injury. Hepatotoxicity was induced by intraperitoneal injection of D-GalN (700mg/kg) and Mg-CUD (15.625, 31.25 and 62.5mg/kg) was administered orally once a day for 2weeks and 6h after D-GalN injection. Significant increases in the level of serum alanine aminotransferase activity and lipid peroxidation were attenuated by Mg-CUD 24h after D-GalN treatment. Hepatic glutathione/oxidized glutathione ratio was decreased, and this decrease was attenuated by Mg-CUD. Mg-CUD attenuated the increase in the levels of serum tumor necrosis factor (TNF)-α and interleukin (IL)-6, while it augmented the increase in serum IL-10 level and heme oxygenase (HO)-1 protein expression. Mg-CUD attenuated increased levels of TNF-α, IL-6, and IL-1β mRNA expression. Increased levels of IL-10 and HO-1 mRNA expression were augmented by Mg-CUD. The increased nuclear level of nuclear factor-κB (NF-κB) and decreased cytosolic level of Inhibitory κB-α protein were attenuated by Mg-CUD. Nuclear phosphorylated c-Jun (p-c-Jun) level showed a significant increase and this increase was attenuated by Mg-CUD. Our results suggest that Mg-CUD ameliorates D-GalN-induced acute hepatitis and that this protection is likely due to its anti-oxidative and anti-inflammatory activities, and inhibition of NF-κB nuclear translocation and nuclear p-c-Jun expression.