scholarly journals Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

2020 ◽  
Vol 22 (1) ◽  
pp. 367
Author(s):  
Fumiko Sekiguchi ◽  
Atsufumi Kawabata
Keyword(s):  
Peripheral Neuropathy ◽  
Molecular Mechanisms ◽  
High Mobility ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
First Line ◽  
Soluble Thrombomodulin ◽  
Drug Candidates ◽  
Molecular Pattern

Chemotherapy-induced peripheral neuropathy (CIPN), one of major dose-limiting side effects of first-line chemotherapeutic agents such as paclitaxel, oxaliplatin, vincristine, and bortezomib is resistant to most of existing medicines. The molecular mechanisms of CIPN have not been fully understood. High mobility group box 1 (HMGB1), a nuclear protein, is a damage-associated molecular pattern protein now considered to function as a pro-nociceptive mediator once released to the extracellular space. Most interestingly, HMGB1 plays a key role in the development of CIPN. Soluble thrombomodulin (TMα), known to degrade HMGB1 in a thrombin-dependent manner, prevents CIPN in rodents treated with paclitaxel, oxaliplatin, or vincristine and in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy. In this review, we describe the role of HMGB1 and its upstream/downstream mechanisms in the development of CIPN and show drug candidates that inhibit the HMGB1 pathway, possibly useful for prevention of CIPN.

scholarly journals Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

2021 ◽  
Author(s):  
Young-Min Han ◽  
Min Sun Kim ◽  
Juyeong Jo ◽  
Daiha Shin ◽  
Seung-Hae Kwon ◽  
...  
Keyword(s):  
Inhibitory Action ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Middle Phase ◽  
Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review

2022 ◽  
Vol 20 ◽  
Author(s):  
Fathimath Zaha Ikram ◽  
Alina Arulsamy ◽  
Thaarvena Retinasamy ◽  
Mohd. Farooq Shaikh
Keyword(s):  
Systematic Review ◽  
Tissue Injury ◽  
High Mobility ◽  
High Mobility Group ◽  
Hmgb1 Protein ◽  
Toll Like Receptor 4 ◽  
Neuroinflammatory Response ◽  
Molecular Pattern ◽  
Glycation End Products

Background: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) molecule that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. Objective: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. Methods: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. Results: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington’s disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/diseases. Conclusion: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

scholarly journals Paradoxical role of high mobility group box 1 in glioma: a suppressor or a promoter?

2017 ◽  
Author(s):  
Richard A. Seidu ◽  
Min Wu ◽  
Zhaoliang Su ◽  
Huaxi Xu
Keyword(s):  
Molecular Mechanisms ◽  
High Mobility ◽  
Treatment Resistance ◽  
High Mobility Group ◽  
Tissue Invasion ◽  
Self Sufficiency ◽  
Glycation End Products ◽  
And Migration ◽  
Proliferation And Migration

Gliomas represent 60% of primary intracranial brain tumors and 80% of all malignant types, with highest morbidity and mortality worldwide. Although glioma has been extensively studied, the molecular mechanisms underlying its pathology remain poorly understood. Clarification of the molecular mechanisms involved in their development and/or treatment resistance is highly required. High mobility group box 1 protein (HMGB1) is a nuclear protein that can also act as an extracellular trigger of inflammation, proliferation and migration, through receptor for advanced glycation end products and toll like receptors in a number of cancers including gliomas. It is known that excessive release of HMGB1 in cancer leads to unlimited replicative potential, ability to develop blood vessels (angiogenesis), evasion of programmed cell death (apoptosis), self-sufficiency in growth signals, insensitivity to inhibitors of growth, inflammation, tissue invasion and metastasis. In this review we explore the mechanisms by which HMGB1 regulates apoptosis and autophagy in glioma. We also looked at how HMGB1 mediates glioma regression and promotes angiogenesis as well as possible signaling pathways with an attempt to provide potential therapeutic targets for the treatment of glioma.

scholarly journals Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus

2016 ◽  
Vol 90 (22) ◽  
pp. 10329-10338 ◽  
Author(s):  
Hadas Cohen-Dvashi ◽  
Hadar Israeli ◽  
Orly Shani ◽  
Aliza Katz ◽  
Ron Diskin
Keyword(s):  
Membrane Fusion ◽  
Molecular Mechanisms ◽  
Cell Entry ◽  
Lassa Virus ◽  
Dependent Manner ◽  
Acidic Ph ◽  
Ph Sensing ◽  
Positively Charged

ABSTRACTTo effectively infect cells, Lassa virus needs to switch in an endosomal compartment from its primary receptor, α-dystroglycan, to a protein termed LAMP1. A unique histidine triad on the surface of the receptor-binding domain from the glycoprotein spike complex of Lassa virus is important for LAMP1 binding. Here we investigate mutated spikes that have an impaired ability to interact with LAMP1 and show that although LAMP1 is important for efficient infectivity, it is not required for spike-mediated membrane fusionper se. Our studies reveal important regulatory roles for histidines from the triad in sensing acidic pH and preventing premature spike triggering. We further show that LAMP1 requires a positively charged His230 residue to engage with the spike complex and that LAMP1 binding promotes membrane fusion. These results elucidate the molecular role of LAMP1 binding during Lassa virus cell entry and provide new insights into how pH is sensed by the spike.IMPORTANCELassa virus is a devastating disease-causing agent in West Africa, with a significant yearly death toll and severe long-term complications associated with its infection in survivors. In recent years, we learned that Lassa virus needs to switch receptors in a pH-dependent manner to efficiently infect cells, but neither the molecular mechanisms that allow switching nor the actual effects of switching were known. Here we investigate the activity of the viral spike complex after abrogation of its ability to switch receptors. These studies inform us about the role of switching receptors and provide new insights into how the spike senses acidic pH.

scholarly journals The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xinyao Hu ◽  
Hua Zhu ◽  
Yang Shen ◽  
Xiaoyu Zhang ◽  
Xiaoqin He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Vital Role ◽  
Circular Rnas ◽  
First Line ◽  
Advanced Hcc ◽  
Chemotherapy Agent ◽  
Development Of Resistance ◽  
Non Coding Rnas

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Sorafenib is approved by the U.S. Food and Drug Administration to be a first-line chemotherapy agent for patients with advanced HCC. A portion of advanced HCC patients can benefit from the treatment with sorafenib, but many patients ultimately develop sorafenib resistance, leading to a poor prognosis. The molecular mechanisms of sorafenib resistance are sophisticated and indefinite. Notably, non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), are critically participated in the occurrence and progression of tumors. Moreover, growing evidence has suggested that ncRNAs are crucial regulators in the development of resistance to sorafenib. Herein, we integrally and systematically summarized the molecular mechanisms and vital role of ncRNAs impact sorafenib resistance of HCC, and ultimately explored the potential clinical administrations of ncRNAs as new prognostic biomarkers and therapeutic targets for HCC.

scholarly journals Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4402
Author(s):  
Antti Kukkula ◽  
Veera K. Ojala ◽  
Lourdes M. Mendez ◽  
Lea Sistonen ◽  
Klaus Elenius ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Recent Developments ◽  
Sumo Pathway ◽  
Multiple Levels

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

Hydroxytyrosol and Oleuropein Inhibit Migration and Invasion of MDA-MB-231 Triple-Negative Breast Cancer Cell via Induction of Autophagy

2020 ◽  
Vol 19 (16) ◽  
pp. 1983-1990 ◽  
Author(s):  
Hui-Yuan Lu ◽  
Jian-Sheng Zhu ◽  
Zhan Zhang ◽  
Wei-Jian Shen ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Viability ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Chemotherapeutic Agents ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Cell Migration And Invasion

Background: Breast Cancer (BC) is the leading cause of cancer-related deaths among women. As such, novel chemotherapeutic agents are urgently needed, especially for Triple-Negative Breast Cancer (TNBC). Hydroxytyrosol (HT) and Oleuropein (OL) are rich in olive oil, which is associated with a low occurrence of BC. However, the effects and mechanisms of action of HT and OL in BC cells are still unclear. This study aimed to explore the molecular mechanisms underlying the antitumor effect of HT and OL in TNBC. Methods: TNBC MDA-MB-231 cells were treated with HT and OL in combination with Hepatocyte Growth Factor (HGF), rapamycin (Rapa, an inducer of autophagy) or 3-methyladenine (3-MA, an inhibitor of autophagy). Cell viability, migration, invasion, and autophagy signaling were analyzed by scratch assays, transwell migration assays, and Western blot analysis. Results: Treatment with HT or OL reduced MDA-MB-231 cell viability in a dose-dependent manner. MDAMB- 231 cells were more sensitive to HT treatment than OL treatment. Rapa treatment could significantly block HGF-induced MDA-MB-231 cell migration and invasion, suggesting that inhibition of autophagy could promote migration and invasion. Moreover, HT or OL treatment significantly suppressed HGF or 3-MA induced cell migration and invasion by reversing LC3-II/LC3-I and Beclin-1 downregulation and reversing p62 upregulation. Conclusion: These data indicated that HT and OL may inhibit migration and invasion of TNBC cells by activating autophagy. These findings provide potential therapeutic strategies that target autophagy to limit the pathogenesis and progression of BC.

PRAMEF2-mediated dynamic regulation of YAP signaling promotes tumorigenesis

2021 ◽  
Vol 118 (40) ◽  
pp. e2105523118
Author(s):  
Madhurima Ghosh ◽  
Sanjeev Das
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Transcriptional Coactivator ◽  
Dynamic Regulation ◽  
Cancer Testis Antigens ◽  
Ubiquitin Ligase Complex ◽  
Insight Into ◽  
Cancer Testis

PRAMEF2 is a member of the PRAME multigene family of cancer testis antigens, which serve as prognostic markers for several cancers. However, molecular mechanisms underlying its role in tumorigenesis remain poorly understood. Here, we report that PRAMEF2 is repressed under conditions of altered metabolic homeostasis in a FOXP3-dependent manner. We further demonstrate that PRAMEF2 is a BC-box containing substrate recognition subunit of Cullin 2–based E3 ubiquitin ligase complex. PRAMEF2 mediates polyubiquitylation of LATS1 kinase of the Hippo/YAP pathway, leading to its proteasomal degradation. The site for ubiquitylation was mapped to the conserved Lys860 residue in LATS1. Furthermore, LATS1 degradation promotes enhanced nuclear accumulation of the transcriptional coactivator YAP, resulting in increased expression of proliferative and metastatic genes. Thus, PRAMEF2 promotes malignant phenotype in a YAP-dependent manner. Additionally, elevated PRAMEF2 levels correlate with increased nuclear accumulation of YAP in advanced grades of breast carcinoma. These findings highlight the pivotal role of PRAMEF2 in tumorigenesis and provide mechanistic insight into YAP regulation.

The Role of Protein Tyrosine Phosphatase, Shp2, in FLT3-ITD-Induced Leukemogenesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1804-1804
Author(s):  
Sarah C Nabinger ◽  
Seiji Fukuda ◽  
Reuben Kapur ◽  
Rebecca Chan
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Erk Activation ◽  
Protein Tyrosine ◽  
Knock Down ◽  
Mammalian Expression ◽  
Tandem Duplications

Abstract Internal tandem duplications of the FMS-like receptor tyrosine kinase (FLT3-ITDs), an in-fame insertion of several amino acids within the juxtamembrane domain, are present in 25% of acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3-ITDs induce FLT3 ligand (FL)-independent hyperactivation of Erk and promiscuous activation of STAT5; however, the molecular mechanisms underlying aberrant activation of these signaling molecules is largely unknown. Tyrosine 599 (Y599) of WT FLT3 recruits the protein tyrosine phosphatase, Shp2, upon stimulation with FL, resulting Erk activation. In several FLT3-ITDs, including N51-FLT3 and N73-FLT3, Y599 is duplicated. These findings led us to hypothesize that increased recruitment of Shp2 to N51-FLT3 or N73- FLT3, via Y599, results in enhanced Shp2 activation and contributes to N51-FLT3- and N73-FLT3-induced cellular hyperproliferation, Erk hyperactivation, and promiscuous STAT5 activation. Using Baf3 cells stably expressing WT FLT3, N51-FLT3, or N73- FLT3, co-immunoprecipitation assays demonstrated that Shp2 is phosphorylated and associates with WT FLT3 in a FL-dependent manner. However, in contrast, Shp2 is constitutively hyperphosphorylated and associated with FLT3-N51 and FLT3-N73 independent of FL stimulation. To investigate the functional role of Shp2 in Flt3-ITD-induced leukemogenesis, Baf3 cells expressing WT FLT3, N51-FLT3, or N73-FLT3 were transfected with a mammalian expression vector encoding a U6 polymerase III– directed Shp2-specific short-hairpin RNA (shRNA) or a scrambled shRNA and selected in puromycin. Western blot analysis revealed significant reduction of Shp2 expression by the Shp2-specific shRNA and no change in Shp2 expression by the scrambled shRNA in all cell lines. Upon knock-down of Shp2 in Baf3/WT-FLT3 cells, proliferation was minimally reduced based on thymidine incorporation assays; however, knock-down of Shp2 in Baf3/N51-FLT3 and Baf3/N73-FLT3 cells significantly reduced proliferation, both at baseline and in response to FL stimulation. Collectively, these data suggest that constitutive recruitment of Shp2 to N51-FLT3 and N73-FLT3 contributes to the FLT3- ITD-induced hyperproliferative phenotype and imply that inhibition of Shp2 function may provide a novel therapeutic approach to FLT3-ITD-bearing leukemias.

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.

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