Hepatoprotective Potential of Partially Hydrolyzed Guar Gum against Acute Alcohol-Induced Liver Injury in Vitro and Vivo

Natural polysaccharides, particularly galactomannans, are potential candidates for treatment of alcoholic liver diseases (ALD). However, applications are restricted due to the physicochemical properties associated with the high molecular weight. In this work, guar gum galactomannans were partially hydrolyzed by β-mannanase, and the molecular mechanisms of hepatoprotective effects were elucidated both in vitro and in vivo. Release of lactate dehydrogenase and cytochrome C were attenuated by partially hydrolyzed guar gum (PHGG) in HepG2 cells, due to protected cell and mitochondrial membrane integrity. PHGG co-administration decreased serum amino transaminases and cholinesterase levels of acute alcohol intoxicated mice, while hepatic pathologic morphology was depleted. Activity of superoxide dismutase, catalase, and glutathione peroxidase was recovered to 198.2, 34.5, 236.0 U/mg protein, respectively, while malondialdehyde level was decreased by 76.3% (PHGG, 1000 mg/kg∙day). Co-administration of PHGG induced a 4.4-fold increment of p-AMPK expression, and lipid metabolism was mediated. PHGG alleviated toll-like-receptor-4-mediated inflammation via the signaling cascade of MyD88 and IκBα, decreasing cytokine production. Moreover, mediated expression of Bcl-2 and Bax was responsible for inhibited acute alcohol-induced apoptosis with suppressed cleavage of caspase 3 and PARP. Findings gained suggest that PHGG can be used as functional food supplement for the treatment of acute alcohol-induced liver injury.

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Integrating Network Pharmacology and Experimental Models to Investigate the Efficacy of Coptidis and Scutellaria Containing Huanglian Jiedu Decoction on Hepatocellular Carcinoma

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500093 ◽

2020 ◽

Vol 48 (01) ◽

pp. 161-182 ◽

Cited By ~ 4

Author(s):

Jihan Huang ◽

Wei Guo ◽

Fan Cheung ◽

Hor-Yue Tan ◽

Ning Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Experimental Models ◽

Network Pharmacology ◽

Disease Networks ◽

Cycle Arrest ◽

Single Target ◽

Induced Apoptosis

Unlike Western medicines with single-target, the traditional Chinese medicines (TCM) always exhibit diverse curative effects against multiple diseases through its “multi-components” and “multi-targets” manifestations. However, discovery and identification of the major therapeutic diseases and the underlying molecular mechanisms of TCM remain to be challenged. In the current study, we, for the first time, applied an integrated strategy by combining network pharmacology with experimental evaluation, for exploration and demonstration of the therapeutic potentials and the underlying possible mechanisms of a classic TCM formula, Huanglian Jiedu decoction (HLJDD). First, the herb–compound, compound–protein, protein–pathway, and gene–disease networks were constructed to predict the major therapeutic diseases of HLJDD and explore the underlying molecular mechanisms. Network pharmacology analysis showed the top one predicted disease of HLJDD treatment was cancer, especially hepatocellular carcinoma (HCC) and inflammation-related genes played an important role in the treatment of HLJDD on cancer. Next, based on the prediction by network pharmacology analysis, both in vitro HCC cell and in vivo orthotopic HCC implantation mouse models were established to validate the curative role of HLJDD. HLJDD exerted its antitumor activity on HCC in vitro, as demonstrated by impaired cell proliferation and colony formation abilities, induced apoptosis and cell cycle arrest, as well as inhibited migratory and invasive properties of HCC cells. The orthotopic HCC implantation mouse model further demonstrated the remarkable antitumour effects of HLJDD on HCC in vivo. In conclusion, our study demonstrated the effectiveness of integrating network pharmacology with experimental study for discovery and identification of the major therapeutic diseases and the underlying molecular mechanisms of TCM.

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Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression

Scientific Reports ◽

10.1038/s41598-020-75288-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Minyoung Lee ◽

Eugene Shin ◽

Jaehyun Bae ◽

Yongin Cho ◽

Ji-Yeon Lee ◽

...

Keyword(s):

Molecular Mechanisms ◽

Dipeptidyl Peptidase ◽

Trail Receptor ◽

Dipeptidyl Peptidase 4 ◽

Alcoholic Steatohepatitis ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Group 2 ◽

Induced Apoptosis

Abstract Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.

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Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins

Blood ◽

10.1182/blood-2008-12-197236 ◽

2009 ◽

Vol 114 (9) ◽

pp. 1987-1998 ◽

Cited By ~ 27

Author(s):

Tong-Young Lee ◽

Stefan Muschal ◽

Elke A. Pravda ◽

Judah Folkman ◽

Amir Abdollahi ◽

...

Keyword(s):

Molecular Mechanisms ◽

Antiangiogenic Therapy ◽

Krebs Cycle ◽

In Vivo Studies ◽

Antitumor Effects ◽

Down Regulation ◽

Proteolytic Fragment ◽

Induced Apoptosis

Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow–derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.

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LINC00152 Acts as a Potential Marker in Gliomas and Promotes Tumor Proliferation and Invasion Through The LINC00152/miR-107/RAB10 Axis

10.21203/rs.3.rs-615132/v1 ◽

2021 ◽

Author(s):

qing liu ◽

gang peng ◽

Jun Su ◽

zeyou wang ◽

songhua xiao

Keyword(s):

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Experimental Studies ◽

Pivotal Role ◽

Aberrant Expression ◽

Potential Marker ◽

Induced Apoptosis ◽

Proliferation And Invasion

Abstract Aberrant expression of long noncoding RNAs plays a pivotal role in tumorigenesis. Recently, several studies have showed that the LINC00152 gene is upregulated in a variety of tumors and plays an oncogene role; however, its underlying molecular mechanisms in glioblastoma remain unclear. In this study, we found that LINC00152 was upregulated in gliomas and its expression was significantly associated with high tumor aggressiveness and poor outcomes for glioma patients through bioinformatics analysis. Functionally, the knockdown of LINC00152 not only inhibited malignant behaviors of glioma, such as proliferation and invasion of glioma cells and induced apoptosis in vitro but also suppressed tumorigenesis in vivo. Mechanistically, results of the bioinformatics analysis and experimental studies confirmed that LINC00152 and RAB10 as the targets of miR-107, and LINC00152 might act as a sponge for miR-107 to regulate the expression of RAB10 in glioblastoma. Additionally, silencing miR-107 reversed the effects induced by LINC00152 knockdown on glioblastoma cells both in vitro and in vivo. Taken together, our data suggested that LINC00152 is a candidate prognostic marker of glioma, and that the LINC00152/MIR-107/RAB10 axis plays a pivotal role in regulation of the glioma malignancy, and therefore, targeting the axis might be an effective therapeutic strategy to treat glioma.

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Lycorine Modulates the Expression of p21 Via a p53-Independent Pathway in HL-60 Cells

Blood ◽

10.1182/blood.v118.21.4297.4297 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4297-4297

Author(s):

Jing Liu ◽

Shu-Ling Wang ◽

Lin Fang ◽

Mao Ye ◽

Zhi-Wei Sun ◽

...

Keyword(s):

Molecular Mechanisms ◽

Kinase Inhibitor ◽

Conflicts Of Interest ◽

Fold Increase ◽

Alternative Pathways ◽

Cyclin Dependent Kinase Inhibitor ◽

M Phase ◽

Induced Apoptosis

Abstract Abstract 4297 Leukemia is one of the most life-threatening cancers today, and acute promyelogenous leukemia is a common type of leukemia. We have previously shown that lycorine, a natural alkaloid extract from Amaryllidaceae, exhibited anti-leukemia effects in vitro and in vivo. Lycorine treatment of HL-60 cell arrested cell cycle at G2/M phase and induced apoptosis. In the present study, we sought to explore the molecular mechanisms for the anti-leukemia action of lycorine. Gene chip analysis revealed that lycorine treatment of HL-60 cells induced more than 9 fold increase of p21, a cyclin-dependent kinase inhibitor, whose expression is mainly regulated by p53. Since HL-60 cells are p53 null, the above findings suggest that lycorine activates p21 expression through p53-independent pathway. To further explore the alternative pathways for the activation of p21 induced by lycorine, we examined the effect of lycorine on the expression of Rb, pRb, E2F, c-Myc and HDACs which have shown to regulate p21 expression. We show that expression of pRb (ser780) and c-Myc was down-regulated, Rb and E2F were up-regulated, while the expression of HDAC1 and HDAC3 was not changed. Together these findings suggest that lycorine exerts its anti-leukemia effect by activating p21 expression via pRb/E2F and c-Myc pathways. Disclosures: No relevant conflicts of interest to declare.

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Yi-Qi-Jian-Pi Formula Suppresses RIPK1/RIPK3-Complex-Dependent Necroptosis of Hepatocytes Through ROS Signaling and Attenuates Liver Injury in Vivo and in Vitro

Frontiers in Pharmacology ◽

10.3389/fphar.2021.658811 ◽

2021 ◽

Vol 12 ◽

Author(s):

Feixia Wang ◽

Li Tang ◽

Baoyu Liang ◽

Chun Jin ◽

Liyuan Gao ◽

...

Keyword(s):

Protein Kinase ◽

Liver Injury ◽

Protective Effect ◽

Molecular Mechanisms ◽

Positive Role ◽

Interacting Protein ◽

Ros Signaling ◽

Tnf Α

Acute-on-chronic liver failure (ACLF) is described as a characteristic of acute jaundice and coagulation dysfunction. Effective treatments for ACLF are unavailable and hence are urgently required. We aimed to define the effect of Yi-Qi-Jian-Pi Formula (YQJPF) on liver injury and further examine the molecular mechanisms. In this study, we established CCl4-, LPS-, and d-galactosamine (D-Gal)-induced ACLF rat models in vivo and LPS- and D-Gal-induced hepatocyte injury models in vitro. We found that YQJPF significantly ameliorates liver injury in vivo and in vitro that is associated with the regulation of hepatocyte necroptosis. Specifically, YQJPF decreased expression of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and pseudokinase mixed lineage kinase domain-like (MLKL) to inhibit the migration of RIPK1 and RIPK3 into necrosome. YQJPF also reduces the expression of inflammatory cytokines IL-6, IL-8, IL-1β, and TNF-α, which were regulated by RIPK3 mediates cell death. RIPK1 depletion was found to enhance the protective effect of YQJPF. Furthermore, we showed that YQJPF significantly downregulates the mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization, with ROS scavenger, 4-hydroxy-TEMPO treatment recovering impaired RIPK1-mediated necroptosis and reducing the expression of IL-6, IL-8, IL-1β, and TNF-α. In summary, our study revealed the molecular mechanism of protective effect of YQJPF on hepatocyte necroptosis, targeting RIPK1/RIPK3-complex-dependent necroptosis via ROS signaling. Overall, our results provided a novel perspective to indicate the positive role of YQJPF in ACLF.

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Ishige okamurae Suppresses Trimethyltin-Induced Neurodegeneration and Glutamate-Mediated Excitotoxicity by Regulating MAPKs/Nrf2/HO-1 Antioxidant Pathways

Antioxidants ◽

10.3390/antiox10030440 ◽

2021 ◽

Vol 10 (3) ◽

pp. 440

Author(s):

Oh Yun Kwon ◽

Seung Ho Lee

Keyword(s):

Molecular Mechanisms ◽

Long Term Memory ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Ht22 Cells ◽

Ishige Okamurae ◽

Mapk Inhibitors ◽

Induced Apoptosis

Many neurodegenerative diseases have several similar cellular dysregulations. We investigated the inhibitory role of Ishige okamurae, an edible brown alga, on neurodegenerative processes by estimating the effects of Ishige okamurae on excitotoxicity induced by glutamate in vitro and neurodegeneration induced by trimethyltin (TMT) in vivo. This study aimed to describe the molecular mechanisms responsible for the mediating anti-neurodegenerative effects of Ishige okamurae extract (IOE). The oral administration of IOE to TMT-injected mice impeded the TMT-mediated short- and long-term memory impairments investigated by the Morris water maze and Y-maze test. IOE attenuated TMT-mediated cellular apoptosis and the expression of brain-derived neurotrophic factor, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in mice brains. Glutamate-induced apoptosis and the expression of reactive oxygen species, Nrf2, and HO-1 in HT22 cells were also attenuated by IOE. In addition, TMT- and glutamate-induced phosphorylation of mitogen-activated protein kinases (MAPKs) in mouse brain tissues and HT22 cells were attenuated by the treatment of IOE. In HT22 cells, administration of MAPK inhibitors recovered the glutamate induced by the expression of Nrf2, HO-1, and cellular dysregulation to the equal extent to IOE administration. Taken together, these results suggest that IOE could attenuate neurodegenerative processes, such as TMT- and glutamate-mediated neuronal dysregulation, by regulating MAPKs/Nrf-2/HO-1 antioxidant pathways.

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A20 protects cells from TNF-induced apoptosis through linear ubiquitin-dependent and -independent mechanisms

Cell Death and Disease ◽

10.1038/s41419-019-1937-y ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 17

Author(s):

Dario Priem ◽

Michael Devos ◽

Sarah Druwé ◽

Arne Martens ◽

Karolina Slowicka ◽

...

Keyword(s):

Cell Death ◽

Complex I ◽

Molecular Mechanisms ◽

Feedback Mechanism ◽

Dependent Manner ◽

Negative Feedback Mechanism ◽

Signaling Complex ◽

Induced Apoptosis

Abstract The cytokine TNF promotes inflammation either directly by activating the MAPK and NF-κB signaling pathways, or indirectly by triggering cell death. A20 is a potent anti-inflammatory molecule, and mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in human and in the mouse. Binding of TNF to TNFR1 triggers the NF-κB-dependent expression of A20 as part of a negative feedback mechanism preventing sustained NF-κB activation. Apart from acting as an NF-κB inhibitor, A20 is also well-known for its ability to counteract the cytotoxic potential of TNF. However, the mechanism by which A20 mediates this function and the exact cell death modality that it represses have remained incompletely understood. In the present study, we provide in vitro and in vivo evidences that deletion of A20 induces RIPK1 kinase-dependent and -independent apoptosis upon single TNF stimulation. We show that constitutively expressed A20 is recruited to TNFR1 signaling complex (Complex I) via its seventh zinc finger (ZF7) domain, in a cIAP1/2-dependent manner, within minutes after TNF sensing. We demonstrate that Complex I-recruited A20 protects cells from apoptosis by stabilizing the linear (M1) ubiquitin network associated to Complex I, a process independent of its E3 ubiquitin ligase and deubiquitylase (DUB) activities and which is counteracted by the DUB CYLD, both in vitro and in vivo. In absence of linear ubiquitylation, A20 is still recruited to Complex I via its ZF4 and ZF7 domains, but this time protects the cells from death by deploying its DUB activity. Together, our results therefore demonstrate two distinct molecular mechanisms by which constitutively expressed A20 protect cells from TNF-induced apoptosis.

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Phospholipase D1 Ameliorates Apoptosis in Chronic Renal Toxicity Caused by Low-Dose Cadmium Exposure

BioMed Research International ◽

10.1155/2020/7091053 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Ke Huang ◽

Yaotang Deng ◽

Wenya Yuan ◽

Jian Geng ◽

Guanghai Wang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Kidney Tissue ◽

Kidney Injury ◽

Sprague Dawley ◽

Protein Levels ◽

Phospholipase D1 ◽

Induced Apoptosis ◽

Kidney Impairment

Exposure to cadmium (Cd), a common heavy metal used in industry, can result in long-term chronic toxicity. It has been well characterized that kidneys are the main organs that are targeted by toxicity, which can cause apoptosis, necrosis, and atrophy of renal tubular epithelial cells. However, the molecular mechanisms associated with Cd toxicity remain unclear. In this study, the expression of renal proteins in Sprague-Dawley rats exposed to chronic Cd was analyzed with iTRAQ proteomics. Bioinformatics analysis indicated that phospholipase D1 (PLD1) was significantly underexpressed and may correlate strongly with Cd-induced chronic kidney impairment. Previous studies have shown that PLD1 promotes cell proliferation and inhibits apoptosis, indicating that PLD1 may be implicated in the pathogenesis of kidney injury induced by Cd. Studies in vivo and in vitro all demonstrate that the mRNA and protein levels of PLD1 decrease significantly both in kidney tissue and in proximal tubular cell lines exposed to Cd. Overexpression of PLD1 and its downstream product PA could ameliorate Cd-induced apoptosis. Moreover, we identified that miR-122-5p was a regulatory miRNA of PLD1. miR-122-5p was overexpressed after Cd exposure and promoted cell apoptosis by downregulating PLD1 through binding the 3′UTR of the locus at 1761–1784 nt. In conclusion, our results indicated that PLD1 and its downstream PA were strongly implicated in Cd-induced chronic kidney impairment and could be a novel player in the defense against Cd-induced nephrotoxicity.

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NT157 Inhibits Hepatocellular Carcinoma Growth and Sensitizes Cells to Sorafenib

10.21203/rs.3.rs-216140/v1 ◽

2021 ◽

Author(s):

Yu Wang ◽

Si-Zhe Yu ◽

Shi-Rong Zhang ◽

Jia Hou ◽

Min Jiao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Mapk Signaling ◽

Advanced Hepatocellular Carcinoma ◽

Downstream Signaling ◽

Potential Strategy ◽

Induced Apoptosis ◽

Hcc Cells

Abstract Background: Sorafenib has been recognized as the standard therapy for advanced hepatocellular carcinoma (HCC). Besides, efficacy of sorafenib was unsatisfactory and vast patients are resistant to sorafenib. Thus, molecular mechanisms underlying regulation of sorafenib resistance and seeking potential strategy to improve its efficacy have attracted much attention. As a small-molecule inhibitor of IGF-1R, NT157 has potent antitumor activity against some human cancers. However, whether NT157 has potential anti-tumor effects and its molecular mechanisms in HCC remain poorly understood. Methods: We assessed the effects and explored the mechanism of NT157 and sorafenib as single agents or in combination with sorafenib in HCC cells and mouse model. Further, we further demonstrated that NT157 reversed resistance to sorafenib in HCC.Results: Here, we found NT157 inhibited HCC growth and induced apoptosis in vitro and in vivo. In terms of mechanism, NT157 phosphorylated IRS-1 through ERK-MAPK signaling to be degraded by the ubiquitin-proteasome pathway, lowered p-AKT to deactivate IGF-1R signaling to inhibit proliferation and induce apoptosis. Surprisingly, we further demonstrated that NT157 acted synergistically with sorafenib to inhibit proliferation and contributed to sensitize HCC cells to sorafenib by down-regulation of p-AKT. Conclusions: Overall, our findings provide a translational rationale for inhibition of IGF-1R and downstream signaling pathways by NT157 as a novel targeted therapy alone or combined with sorafenib in HCC.

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