scholarly journals Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

2019 ◽  
Vol 39 (01) ◽  
pp. 026-042 ◽  
Author(s):  
Yoon Yang ◽  
So Kim ◽  
Ekihiro Seki
Keyword(s):  
Adaptive Immunity ◽  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Therapeutic Targets ◽  
Nonalcoholic Fatty Liver ◽  
Adaptive Immune Cells ◽  
Early Hcc ◽  
Nonalcoholic Fatty Liver Diseases ◽  
Factor Α

AbstractHepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th17 cells, and B cells, can also stimulate HCC development. Thus, the role of the hepatic immune system in HCC development is a highly complex topic. This review highlights the role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC and discusses whether these pathways could be therapeutic targets. The authors will also discuss cholangiocarcinoma and liver metastasis because biliary inflammation and tumor-associated stroma are essential for cholangiocarcinoma development and because primary tumor-derived inflammatory mediators promote the formation of a “premetastasis niche” in the liver.

scholarly journals Deficiency of the Purinergic Receptor 2X7 Attenuates Nonalcoholic Steatohepatitis Induced by High-Fat Diet: Possible Role of the NLRP3 Inflammasome

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Claudia Blasetti Fantauzzi ◽  
Stefano Menini ◽  
Carla Iacobini ◽  
Chiara Rossi ◽  
Eleonora Santini ◽  
...  
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Purinergic Receptor ◽  
High Fat ◽  
Liver Sinusoidal Endothelial Cells ◽  
Nonalcoholic Fatty Liver ◽  
Markers Of Inflammation

Molecular mechanisms driving transition from simple steatosis to nonalcoholic steatohepatitis (NASH), a critical step in the progression of nonalcoholic fatty liver disease (NAFLD) to cirrhosis, are poorly defined. This study aimed at investigating the role of the purinergic receptor 2X7 (PR2X7), through the NLRP3 inflammasome, in the development of NASH. To this end, mice knockout for the Pr2x7 gene (Pr2x7−/−) and coeval wild-type (WT) mice were fed a high-fat diet (HFD) or normal-fat diet for 16 weeks. NAFLD grade and stage were lower in Pr2x7−/− than WT mice, and only 1/7 Pr2x7−/− animals showed evidence of NASH, as compared with 4/7 WT mice. Molecular markers of inflammation, oxidative stress, and fibrosis were markedly increased in WT-HFD mice, whereas no or significantly reduced increments were detected in Pr2x7−/− animals, which showed also decreased modulation of genes of lipid metabolism. Deletion of Pr2x7 gene was associated with blunted or abolished activation of NLRP3 inflammasome and expression of its components, which were induced in liver sinusoidal endothelial cells challenged with appropriate stimuli. These data show that Pr2x7 gene deletion protects mice from HFD-induced NASH, possibly through blunted activation of NLRP3 inflammasome, suggesting that PR2X7 and NLRP3 may represent novel therapeutic targets.

scholarly journals Translational Research Studies Unraveling the Origins of Psoriatic Arthritis: Moving Beyond Skin and Joints

2021 ◽  
Vol 8 ◽  
Author(s):  
Janne W. Bolt ◽  
Chaja M. J. van Ansenwoude ◽  
Ihsan Hammoura ◽  
Marleen G. van de Sande ◽  
Lisa G. M. van Baarsen
Keyword(s):  
Psoriatic Arthritis ◽  
Translational Research ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Treatment Strategies ◽  
Continuous Treatment ◽  
Adaptive Immune Cells ◽  
Novel Treatment Strategies

Patients with psoriatic arthritis (PsA) are suffering from a decreased quality of life despite currently available treatments. In the latest years, novel therapies targeting the IL-17/IL-23 and TNF pathways improved clinical outcome. Despite this, remission of disease is not achieved in a considerable group of patients, continuous treatment is very often required to reach clinical remission, and prevention of PsA in patients with psoriasis (PsO) is currently impossible. A better understanding of PsA pathogenesis is required to develop novel treatment strategies that target inflammation and destruction more effectively and at an early stage of the disease, or even before clinically manifest disease. The skin is considered as one of the sites of onset of immune activation, triggering the inflammatory cascade in PsA. PsO develops into PsA in 30% of the PsO patients. Influenced by environmental and genetic factors, the inflammatory process in the skin, entheses, and/or gut may evolve into synovial tissue inflammation, characterized by influx of immune cells. The exact role of the innate and adaptive immune cells in disease pathogenesis is not completely known. The involvement of activated IL-17A+ T cells could implicate early immunomodulatory events generated in lymphoid organs thereby shaping the pathogenic inflammatory response leading to disease. In this perspective article, we provide the reader with an overview of the current literature regarding the immunological changes observed during the earliest stages of PsA. Moreover, we will postulate future areas of translational research aimed at increasing our knowledge on the molecular mechanisms driving disease development, which will aid the identification of novel potential therapeutic targets to limit the progression of PsA.

scholarly journals Role of the Ubiquitin System in Chronic Pain

2021 ◽  
Vol 14 ◽  
Author(s):  
Jiurong Cheng ◽  
Yingdong Deng ◽  
Jun Zhou
Keyword(s):  
Chronic Pain ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Public Health Issue ◽  
Deubiquitinating Enzyme ◽  
Ubiquitin System ◽  
Significant Public Health ◽  
Underlying Mechanisms ◽  
Insight Into

As a significant public health issue, chronic pain, mainly neuropathic pain (NP) and inflammatory pain, has a severe impact. The underlying mechanisms of chronic pain are enigmatic at present. The roles of ubiquitin have been demonstrated in various physiological and pathological conditions and underscore its potential as therapeutic targets. The dysfunction of the component of the ubiquitin system that occurs during chronic pain is rapidly being discovered. These results provide insight into potential molecular mechanisms of chronic pain. Chronic pain is regulated by ubiquitination, SUMOylation, ubiquitin ligase, and deubiquitinating enzyme (DUB), etc. Insight into the mechanism of the ubiquitin system regulating chronic pain might contribute to relevant therapeutic targets and the development of novel analgesics.

scholarly journals The Emerging Role of PIWI-Interacting RNAs (piRNAs) in Gastrointestinal Cancers: An Updated Perspective

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 202
Author(s):  
Ismael Riquelme ◽  
Pablo Pérez-Moreno ◽  
Pablo Letelier ◽  
Priscilla Brebi ◽  
Juan Carlos Roa
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Molecular Characteristics ◽  
Clinical Markers ◽  
Rna Transcripts ◽  
Gi Cancers ◽  
Tumor Types ◽  
Cumulative Evidence

Gastrointestinal (GI) cancers produce ~3.4 million related deaths worldwide, comprising 35% of all cancer-related deaths. The high mortality among GI cancers is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do not adequately guide patient management, thereby new and more reliable biomarkers and therapeutic targets are still needed for these diseases. RNA-seq technology has allowed the discovery of new types of RNA transcripts including PIWI-interacting RNAs (piRNAs), which have particular characteristics that enable these molecules to act via diverse molecular mechanisms for regulating gene expression. Cumulative evidence has described the potential role of piRNAs in the development of several tumor types as a likely explanation for certain genomic abnormalities and signaling pathways’ deregulations observed in cancer. In addition, these piRNAs might be also proposed as promising diagnostic or prognostic biomarkers or as potential therapeutic targets in malignancies. This review describes important topics about piRNAs including their molecular characteristics, biosynthesis processes, gene expression silencing mechanisms, and the manner in which these transcripts have been studied in samples and cell lines of GI cancers to elucidate their implications in these diseases. Moreover, this article discusses the potential clinical usefulness of piRNAs as biomarkers and therapeutic targets in GI cancers.

Essential role of ROS-mediated NFAT activation in TNF-α induction by crystalline silica exposure

2006 ◽  
Vol 291 (2) ◽  
pp. L257-L264 ◽  
Author(s):  
Qingdong Ke ◽  
Jingxia Li ◽  
Jin Ding ◽  
Min Ding ◽  
Liying Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Crystalline Silica ◽  
Dependent Manner ◽  
Activated T Cells ◽  
Silica Exposure ◽  
Tnf Α ◽  
Nfat Activation ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α

Occupational exposure to crystalline silica has been associated with progressive pulmonary silicosis and lung cancer, but the underlying molecular mechanisms are not well understood. Previous studies have shown that crystalline silica exposure can generate reactive oxygen species (ROS) and induce the expression of the inflammatory cytokine tumor necrosis factor-α (TNF-α) in cells. TNF-α is believed to be critical in the development of silica-related diseases. Thus it will be of significance to understand the mechanisms of TNF-α induction by silica exposure. Given the fact that the transcription factor nuclear factor of activated T cells (NFAT) plays an important role in the regulation of TNF-α and can also be activated by ROS, in this study we investigated the potential role of ROS in silica-induced NFAT activity as well as TNF-α expression in Cl41 cells. The results showed that exposure of cells to silica led to NFAT transactivation and TNF-α induction, where superoxide anion radical (O2−·), but not H2O2, was involved. The knockdown of NFAT3 by its specific small interfering RNA significantly attenuated the silica-induced TNF-α transcription. This study demonstrated that silica was able to activate NFAT in an O2−·-dependent manner, which was required for TNF-α induction.

scholarly journals Autophagy in Alcohol-Induced Multiorgan Injury: Mechanisms and Potential Therapeutic Targets

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Yuan Li ◽  
Shaogui Wang ◽  
Hong-Min Ni ◽  
Heqing Huang ◽  
Wen-Xing Ding
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Degradation Pathway ◽  
Protective Mechanism ◽  
Intracellular Degradation ◽  
Injury Mechanisms ◽  
Evolutionarily Conserved

Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.

scholarly journals Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

2020 ◽  
Vol 21 (11) ◽  
pp. 4113
Author(s):  
Julio M. Martinez-Moreno ◽  
Miguel Fontecha-Barriuso ◽  
Diego Martin-Sanchez ◽  
Juan Guerrero-Mauvecin ◽  
Elena Goma-Garces ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epigenetic Regulation ◽  
Diabetic Kidney Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Sglt2 Inhibitors ◽  
Post Translational Modifications ◽  
Diabetic Kidney ◽  
Bet Inhibitor

Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.

scholarly journals Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Zhanpeng Wang ◽  
Zhuonan Li ◽  
Yanshuo Ye ◽  
Lijuan Xie ◽  
Wei Li
Keyword(s):  
Oxidative Stress ◽  
Liver Cancer ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
The Body ◽  
Liver Carcinogenesis ◽  
Cancer Etiology ◽  
Nonalcoholic Fatty Liver ◽  
The Impact ◽  
The Relationship

Accumulating evidence has indicated that oxidative stress (OS) is associated with the development of hepatocellular carcinoma (HCC). However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal—from either an internal or external source—and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD). The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC.

scholarly journals The Role of theγδT Cell in Allergic Diseases

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Rui Zheng ◽  
Qintai Yang
Keyword(s):  
T Cells ◽  
Adaptive Immunity ◽  
Immune Surveillance ◽  
External Environment ◽  
Allergic Diseases ◽  
Mucosal Inflammation ◽  
Innate And Adaptive Immunity ◽  
Epithelial Tissues

The predominant distribution ofγδT cells in the mucosal and epithelial tissues makes these unconventional lymphocytes the “guards” to contact external environment (like allergens) and to contribute to immune surveillance, as well as “vanguards” to participate in initiating mucosal inflammation. Therefore,γδT cells have been considered to bridge the innate and adaptive immunity. The role these cells play in allergy seems to be complicated and meaningful, so it makes sense to review the characteristics and role ofγδT cells in allergic diseases.

scholarly journals ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

2021 ◽  
Vol 10 (15) ◽  
pp. 3373
Author(s):  
Margherita Sisto ◽  
Domenico Ribatti ◽  
Sabrina Lisi
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
Smooth Muscle Actin ◽  
Mesenchymal Transition ◽  
Inflammatory Conditions ◽  
Fibrotic Process ◽  
Factor Α ◽  
Necrosis Factor

For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.

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