Lactobacillus reuteri ZJ617 Culture Supernatant Attenuates Acute Liver Injury Induced in Mice by Lipopolysaccharide

ABSTRACT Background Lactobacillus rhamnosus GG culture supernatant (LGGs) promotes intestinal integrity and ameliorates acute liver injury induced by alcohol in mice. Objectives The aim of this study was to investigate the protective effects and molecular mechanisms of Lactobacillus reuteri ZJ617 culture supernatant (ZJ617s) on acute liver injury induced by lipopolysaccharide (LPS) in mice. Methods Male C57BL/6 mice (20 ± 2 g, 8 wk old) were randomly divided into 4 groups (6 mice/group): oral inoculation with phosphate-buffered saline (control), intraperitoneal injection of LPS (10 mg/kg body weight) (LPS), oral inoculation with ZJ617s 2 wk before intraperitoneal injection of LPS (ZJ617s + LPS), or oral inoculation with LGGs 2 wk before intraperitoneal injection of LPS (LGGs + LPS). Systemic inflammation, intestinal integrity, biomarkers of hepatic function, autophagy, and apoptosis signals in the liver were determined. Results Twenty-four hours after LPS injection, the activities of serum alanine transaminase and aspartate transaminase were 32.2% and 30.3% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). The ZJ617s + LPS group exhibited higher intestinal expression of claudin 3 (62.5%), occludin (60.1%), and zonula occludens 1 (60.5%) compared with the LPS group (P < 0.05). The concentrations of hepatic interleukin-6 and tumor necrosis factor-α were 21.4% and 27.3% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). However, the concentration of interleukin-10 was 22.2% higher in the ZJ617s + LPS group. LPS increased the expression of Toll-like receptor 4 (TLR4; by 50.5%), phosphorylation p38 mitogen-activated protein kinase (p38MAPK; by 57.1%), extracellular signal-regulated kinase (by 77.8%), c-Jun N-terminal kinase (by 42.9%), and nuclear factor-κB (NF-κB; by 36.0%) compared with the control group. Supplementation with ZJ617s or LGGs ameliorated these effects (P < 0.05). Moreover, the hepatic expression of active caspase-3 and microtubule-associated protein 1 light chain 3 II was 23.8% and 28.6% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). Conclusions ZJ617s exerts beneficial effects on the mouse liver through suppression of hepatic TLR4/MAPK/NF-κB activation, apoptosis, and autophagy. This trial was registered at Zhejiang University (http://www.lac.zju.edu.cn) as NO.ZJU20170529.

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Fucosterol Protects against Concanavalin A-Induced Acute Liver Injury: Focus on P38 MAPK/NF-κB Pathway Activity

Gastroenterology Research and Practice ◽

10.1155/2018/2824139 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Wenhui Mo ◽

Chengfen Wang ◽

Jingjing Li ◽

Kan Chen ◽

Yujing Xia ◽

...

Keyword(s):

Liver Injury ◽

P38 Mapk ◽

Concanavalin A ◽

Molecular Mechanisms ◽

Therapeutic Agent ◽

Acute Liver Injury ◽

Biological Activities ◽

Hepatic Necrosis ◽

Protective Effects ◽

Eisenia Bicyclis

Objective. Fucosterol is derived from the brown alga Eisenia bicyclis and has various biological activities, including antioxidant, anticancer, and antidiabetic properties. The aim of this study was to investigate the protective effects of fucosterol pretreatment on Concanavalin A- (ConA-) induced acute liver injury in mice, and to understand its molecular mechanisms. Materials and Methods. Acute liver injury was induced in BALB/c mice by ConA (25 mg/kg), and fucosterol (dissolved in 2% DMSO) was orally administered daily at doses of 25, 50, and 100 mg/kg. The levels of hepatic necrosis, apoptosis, and autophagy associated with inflammatory cytokines were measured at 2, 8, and 24 h. Results. Fucosterol attenuated serum liver enzyme levels and hepatic necrosis and apoptosis induced by TNF-α, IL-6, and IL-1β. Fucosterol also inhibited apoptosis and autophagy by upregulating Bcl-2, which decreased levels of functional Bax and Beclin-1. Furthermore, reduced P38 MAPK and NF-κB signaling were accompanied by PPARγ activation. Conclusion. This study showed that fucosterol could alleviate acute liver injury induced by ConA by inhibiting P38 MAPK/PPARγ/NF-κB signaling. These findings highlight that fucosterol is a promising potential therapeutic agent for acute liver injury.

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Beneficial Impact and Molecular Mechanism of Bacillus Coagulans on Piglets Intestine

10.20944/preprints201805.0084.v1 ◽

2018 ◽

Author(s):

Tao Wu ◽

Yang Lv ◽

Xueni Li ◽

Lin Zhang ◽

Yutao Shi ◽

...

Keyword(s):

Molecular Mechanism ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Bacillus Coagulans ◽

Basal Diet ◽

Control Group ◽

Villus Height ◽

Intestinal Integrity ◽

Beneficial Impact ◽

Related Proteins

This research was to investigate beneficial impact and molecular mechanism of B. coagulans on piglets intestine. Twenty-four 21 days old weaned piglets were allotted to three treatments: control group (basal diet), B6 group (basal diet + 2×106 CFU/g B. coagulans), B7 group (basal diet + 2×107 CFU/g B. coagulans). The results showed that compared with control group, B6 and B7 group significantly decreased diarrhea rate and the concent of CHOL, GGT and DAO in plasma; decreased villus height and increase crypt depth in jejunum and ileum; increased the activities of SOD and CAT and decreased the concent of MDA and H2O2 in intestine. These data suggested that supplementing B. coagulans had beneficial impacts on promoting nutrients metabolism, maintaining intestinal integrity and alleviating oxidative stress and diarrhea. Futher research of molecular mechanisms showed that, these beneficial impacts were regulated by changing expression levels of related proteins (including HSP70, Caspase-3, Bax, Villin and Occludin), and genes (including RPL4, IFN-α, IFN-β, IFN-γ, MX1, MX2, OAS1, IL-1β, IL-4, CXCL-9, CCL-2, AQP3, SGLT-1, LPL, INSR and b0,+AT), and altering community composition of gut microbiota (particularly family Clostridiaceae, Enterobacteriaceae, and Veillonellaceae and genus Prevotella, Turicibacter, and Lactobacillus).

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Mechanism of KLF4 Protection against Acute Liver Injury via Inhibition of Apelin Signaling

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6140360 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Weitao Ji ◽

Hongyun Shi ◽

Hailin Shen ◽

Jing Kong ◽

Jiayi Song ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Acute Liver Injury ◽

Control Group ◽

Necrosis Factor Alpha ◽

Protein Levels ◽

Klf4 Expression ◽

Mrna And Protein Expression

Krüppel-like factor 4 (KLF4) is a key transcription factor that regulates genes involved in the proliferation or differentiation in different tissues. Apelin plays roles in cardiovascular functions, metabolic disease, and homeostatic disorder. However, the biological function of apelin in liver disease is still ongoing. In this study, we investigated the mechanism of KLF4-mediated protection against acute liver injury via the inhibition of the apelin signaling pathway. Mice were intraperitoneally injected with carbon tetrachloride (CCl4; 0.2 mL dissolved in 100 mL olive oil, 10 mL/kg) to establish an acute liver injury model. A KLF4 expression plasmid was injected through the tail vein 48 h before CCl4 treatment. In cultured LX-2 cells, pAd-KLF4 or siRNA KLF4 was overexpressed or knockdown, and the mRNA and protein levels of apelin were determined. The results showed that the apelin serum level in the CCl4-injected group was higher than that of control group, and the expression of apelin in the liver tissues was elevated while KLF4 expression was decreased in the CCl4-injected group compared to the KLF4-plasmid-injected group. HE staining revealed serious hepatocellular steatosis in the CCl4-injected mice, and KLF4 alleviated this steatosis in the mice injected with KLF4 plasmid. In vitro experiments showed that tumor necrosis factor-alpha (TNF-α) could downregulate the transcription and translation levels of apelin in LX-2 cells and also upregulate KLF4 mRNA and protein expression. RT-PCR and Western blotting showed that the overexpression of KLF4 markedly decreased basal apelin expression, but knockdown of KLF4 restored apelin expression in TNF-α-treated LX-2 cells. These in vivo and in vitro experiments suggest that KLF4 plays a key role in inhibiting hepatocellular steatosis in acute liver injury, and that its mechanism might be the inhibition of the apelin signaling pathway.

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Polydeoxyribonucleotide Exerts Protective Effect Against CCl4-Induced Acute Liver Injury Through Inactivation of NF-κB/MAPK Signaling Pathway in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21217894 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7894 ◽

Cited By ~ 2

Author(s):

Il-Gyu Ko ◽

Jun-Jang Jin ◽

Lakkyong Hwang ◽

Sang-Hoon Kim ◽

Chang-Ju Kim ◽

...

Keyword(s):

Liver Injury ◽

Protective Effect ◽

Inflammatory Cytokines ◽

Intraperitoneal Injection ◽

Acute Liver Injury ◽

Adenosine A2a Receptor ◽

Liver Index ◽

A2a Receptor ◽

Adenosine A2a ◽

Pro Inflammatory Cytokines

Acute liver injury (ALI) causes life-threatening clinical problem, and its underlying etiology includes inflammation and apoptosis. An adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), exhibits anti-inflammatory and anti-apoptotic effects by inhibiting the secretion of pro-inflammatory cytokines. In the current study, the protective effect of PDRN against carbon tetrachloride (CCl4)-induced ALI was investigated using mice. For the induction of ALI, mice received intraperitoneal injection of CCl4 twice over seven days. Mice from the PDRN-treated groups received an intraperitoneal injection of 200 μL saline containing PDRN (8 mg/kg), once a day for seven days, starting on day 1 after the first CCl4 injection. In order to confirm that the action of PDRN occurs through the adenosine A2A receptor, 8 mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX), an adenosine A2A receptor antagonist, was treated with PDRN. Administration of CCl4 impaired liver tissue and increased the liver index and histopathologic score. The expression of pro-inflammatory cytokines was increased, and apoptosis was induced by the administration of CCl4. Administration of CCl4 activated nuclear factor-kappa B (NF-κB) and facilitated phosphorylation of signaling factors in mitogen-activated protein kinase (MAPK). In contrast, PDRN treatment suppressed the secretion of pro-inflammatory cytokines and inhibited apoptosis. PDRN treatment inactivated NF-κB and suppressed phosphorylation of signaling factors in MAPK. As a result, liver index and histopathologic score were reduced by PDRN treatment. When PDRN was treated with DMPX, the anti-inflammatory and anti-apoptotic effect of PDRN disappeared. Therefore, PDRN can be used as an effective therapeutic agent for acute liver damage.

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Hepatoprotective Effect of Melatonin in Toxic Liver Injury in Rats

Medicina ◽

10.3390/medicina55060304 ◽

2019 ◽

Vol 55 (6) ◽

pp. 304 ◽

Cited By ~ 3

Author(s):

Oleshchuk ◽

Ivankiv ◽

Falfushynska ◽

Mudra ◽

Lisnychuk

Keyword(s):

Liver Injury ◽

Hepatoprotective Effect ◽

Male Rats ◽

Saline Control ◽

Control Group ◽

Radical Scavenger ◽

Thiobarbituric Acid Reactive Substance ◽

Lipid Hydroperoxides ◽

Significant Difference ◽

Toxic Liver Injury

Background and objectives: toxic liver injury results in nitrooxidative stress. Melatonin is a potent free radical scavenger, an inducible nitric oxide synthase (iNOS) inhibitor and an activator of antioxidant enzymes. The aim of this study was to investigate the hepatoprotective effect of exogenous melatonin on animals with acute toxic hepatitis. Material and methods: 36 healthy Sprague-Dawley male rats were split into three equal groups and given carbon tetrachloride (CCl4), 2 g/kg (CCl4 group) or the same dose of CCl4 and melatonin, 10 mg/kg (CCl4/melatonin group) or saline (control group). The effect of melatonin on prooxidant and antioxidant system indexes, NO and NOS levels in serum and liver, data of mitochondrial chain functions and cytolysis in liver were evaluated in all three groups. Results: melatonin significantly decreased activities of AST, ALT, ceruloplasmine and thiobarbituric acid reactive substance (TBARS) in serum. Catalase activity was lowered in serum but not in the liver. Hepatic TBARS, lipid hydroperoxides and glutathione concentrations were decreased, while superoxide dismutase, mitochondrial cytochrome oxidase and succinate dehydrogenase activities increased. Melatonin inhibited synthesis of stable NO metabolites in serum: NO2-by 37.9%; NO3-by 29.2%. There was no significant difference in content NO2-in the liver, but concentration of NO3-increased by 32.6%. Melatonin significantly reduced iNOS concentrations both in serum (59.7%) and liver (57.8%) but did not affect endothelial isoform enzyme activities neither in serum, nor in liver. The histopathological liver lesions observed in the CCl4/melatonin group were less severe than those seen in the CCl4 group. Conclusions: we demonstrated an ameliorating effect of melatonin on prooxidants and antioxidants, NO-NOS systems balance, mitochondrial function and histopathological lesions in the liver in rats with CCl4-induced hepatitis.

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Protective Effect of Polydeoxyribonucleotide Against CCl4-Induced Acute Liver Injury in Mice

International Neurourology Journal ◽

10.5213/inj.2040430.215 ◽

2020 ◽

Vol 24 (Suppl 2) ◽

pp. 88-95

Author(s):

Seunghwan Lee ◽

Kyu Yeoun Won ◽

Sunhyung Joo

Keyword(s):

Liver Injury ◽

Intraperitoneal Injection ◽

Acute Liver Injury ◽

B Cell Lymphoma ◽

Terminal Deoxynucleotidyl Transferase ◽

Treatment Groups ◽

Accelerate Wound Healing ◽

Tnf Α ◽

Hematoxylin And Eosin ◽

Urogenital Injury

Purpose: Polydeoxyribonucleotide (PDRN) is a substance known to suppress inflammation and accelerate wound healing. In this experiment, the effect of PDRN treatment on carbon tetrachloride (CCl4)-evoked acute liver injury (ALI) was investigated using mice.Methods: We analyzed the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and conducted hematoxylin and eosin staining in accompany with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Western blot analysis was also conducted to assess the expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, adenosine A2A receptor, Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2). The mice were received intraperitoneal injection of 10-mL/kg CCl4, 4 times, once every 2 days. The mice in the PDRN treatment groups received intraperitoneal injection of 200-μL distilled water comprising each concentration of PDRN for 7 days starting 1 day after first CCl4 injection.Results: ALT and AST concentrations in the serum were reduced and TNF-α, IL-1β, and IL-6 expressions were decreased by PDRN injection in CCl4-evoked ALI mice. PDRN injection suppressed Bax versus Bcl-2 ratio and reduced the percentage of TUNE-positive cells in CCl4-evoked ALI mice. PDRN injection overexpressed adenosine A2A receptor in CCl4-evoked ALI mice.Conclusions: The therapeutic efficacy of PDRN also can be expected for CCl4-evoked acute urogenital injury in addition to ALI. The current research suggests that PDRN may be used for the therapeutic agent of CCl4-evoked ALI.

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Puerarin mitigates acute liver injury in septic rats by regulating proinflammatory factors and oxidative stress levels

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v20i11.11 ◽

2021 ◽

Vol 20 (11) ◽

pp. 2305-2310

Author(s):

Jinan Zheng ◽

Qing Huang ◽

Jingjing Fang

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Acute Liver Injury ◽

Serum Levels ◽

Expression Level ◽

Sepsis Group ◽

Control Group ◽

Sprague Dawley ◽

Tnf Α ◽

Proinflammatory Factors

Purpose: To determine the protective effect of puerarin against acute liver injury in septic rats, and the mechanism involved.Methods: Eighty-seven Sprague-Dawley (SD) rats were assigned to control, sepsis and puerarin groups (each having 29 rats). Serum levels of NF-kB, TNF-α, IL-1 β, IL-6, ALT and AST were assayed. Liver lesions and levels of NO, SOD, iNOS and malondialdehyde (MDA) were measured using standard procedures.Results: Compared with the control group, the levels of NF-kB, TNF-α, IL-1β, IL-6, AST, ALT, NO, MDA and iNOS significantly increased in the sepsis group, while SOD level decreased significantly. In contrast, there were marked decreases in NF-kB, TNF-α, IL-1β, AST, ALT, NO, MDA and iNOS in puerarin group, relative to the sepsis group, while SOD expression level was significantly increased (p <0.05). The level of p-p38 in liver of septic rats was up-regulated, relative to control rats, while Nrf2 significantly decreased (p < 0.05). The expression level of p-p38 in the puerarin group was significantly decreased, relative to the sepsis group, while the expression level of Nrf2 significantly increased (p < 0.05).Conclusion: Puerarin mitigates acute liver injury in septic rats by inhibiting NF-kB and p38 signaling pathway, down-regulating proinflammatory factors, and suppressing oxidative stress. Thus, puerarin may be developed for use in the treatment liver injury.

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Lactobacillus rhamnosus GG Attenuates Lipopolysaccharide-Induced Inflammation and Barrier Dysfunction by Regulating MAPK/NF-κB Signaling and Modulating Metabolome in the Piglet Intestine

Journal of Nutrition ◽

10.1093/jn/nxaa009 ◽

2020 ◽

Vol 150 (5) ◽

pp. 1313-1323 ◽

Cited By ~ 4

Author(s):

Jiangdi Mao ◽

Siri Qi ◽

Yanjun Cui ◽

Xiaoxiao Dou ◽

Xin M Luo ◽

...

Keyword(s):

P38 Mapk ◽

Intraperitoneal Injection ◽

Intestinal Barrier ◽

Mitogen Activated Protein Kinase ◽

Intestinal Barrier Function ◽

Saline Control ◽

Barrier Dysfunction ◽

Large White ◽

Oral Inoculation ◽

Tnf Α

ABSTRACT Background Probiotic Lactobacillius rhamnosus GG (LGG) shows beneficial immunomodulation on cultured cell lines in vitro and in mouse models. Objective The aim was to investigate the effects of LGG on intestinal injury and the underlying mechanisms by elucidating inflammatory signaling pathways and metabolomic response to LPS stimulation in the piglet intestine. Methods Piglets (Duroc × Landrace × Large White, including males and female; 8.6 ± 1.1 kg) aged 28 d were assigned to 3 groups (n = 6/group): oral inoculation with PBS for 2 wk before intraperitoneal injection of physiological saline [control (CON)] or LPS (25 μg/kg body weight; LPS) or oral inoculation with LGG for 2 wk before intraperitoneal injection of LPS (LGG+LPS). Piglets were killed 4 h after LPS injection. Systemic inflammation, intestinal integrity, inflammation signals, and metabolomic characteristics in the intestine were determined. Results Compared with CON, LPS stimulation significantly decreased ileal zonula occludens 1 (ZO-1; 44%), claudin-3 (44%), and occludin (41%) expression; increased serum diamineoxidase (73%), D-xylose (19%), TNF-α (43%), and IL-6 (55%) concentrations; induced p38 mitogen-activated protein kinase (p38 MAPK; 85%), extracellular signal-regulated kinase (ERK; 96%), and NF-κB p65 phosphorylation (37%) (P < 0.05). Compared with LPS stimulation alone, LGG pretreatment significantly enhanced the intestinal barrier by upregulating expressions of tight junction proteins (ZO-1, 73%; claudin-3, 55%; occludin, 67%), thereby decreasing serum diamineoxidase (26%) and D-xylose (28%) concentrations, and also reduced serum TNF-α expression (16%) and ileal p38 MAPK (79%), ERK (43%) and NF-κB p65 (37%) phosphorylation levels (P < 0.05). Metabolomic analysis showed clear separation between each group. The concentrations of caprylic acid [fold-change (FC) = 2.39], 1-mono-olein (FC = 2.68), erythritol (FC = 4.62), and ethanolamine (FC = 4.47) significantly increased in the intestine of LGG + LPS piglets compared with the LPS group (P < 0.05). Conclusions These data suggest that LGG alleviates gut inflammation, improves intestinal barrier function, and modulates the metabolite profile of piglets challenged with LPS. This trial was registered at the Zhejiang University (http://www.lac.zju.edu.cn) as ZJU20170529.

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The Hepatoprotection by Oleanolic Acid Preconditioning: Focusing on PPARαActivation

PPAR Research ◽

10.1155/2018/3180396 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 8

Author(s):

Wenwen Wang ◽

Kan Chen ◽

Yujing Xia ◽

Wenhui Mo ◽

Fan Wang ◽

...

Keyword(s):

Liver Injury ◽

Oleanolic Acid ◽

Molecular Mechanisms ◽

Liver Enzymes ◽

Acute Liver Injury ◽

Inflammatory Factors ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Anti Inflammatory ◽

Major Factors

Objective. Previous studies have characterized the hepatoprotective and anti-inflammatory properties of oleanolic acid (OA). This study aimed to investigate the molecular mechanisms of OA hepatoprotection in concanavalin A- (ConA-) induced acute liver injury.Materials and Methods. ConA (20 mg/kg) was intravenously injected to induce acute liver injury in Balb/C mice. OA pretreatment (20, 40, and 80 mg/kg) was administered subcutaneously once daily for 3 consecutive days prior to treatment with ConA; 2, 8, and 24 h after ConA injection, the levels of serum liver enzymes and the histopathology of major factors and inflammatory cytokines were determined.Results. OA reduced the release of serum liver enzymes and inflammatory factors and prevented ConA mediated damage to the liver. OA elevated the expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and decreased the phosphorylation of c-Jun NH2-terminal kinase (JNK).Conclusion. OA exhibits anti-inflammatory properties during ConA-induced acute liver injury by attenuating apoptosis and autophagy through activation of PPARαand downregulation of JNK signaling.

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