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Testicular immunoregulation
Published in C. Yan Cheng, Spermatogenesis, 2018
Fei Wang, Qian Jiang, Daishu Han
From an immunological perspective, phagocytic removal of apoptotic cells by phagocytes is a critical mechanism in the elimination of endogenous autoantigens for the prevention of an autoimmune response.20 Impairment of apoptotic cell clearance is associated with autoimmune diseases.21 Late-stage male germ cells are formed after the establishment of immune self-tolerance and synthesize a large number of autoantigens that are immunogenetic. Phagocytic removal of apoptotic germ cells and residual bodies by Sertoli cells can prevent immunogenetic autoantigens from inducing immune responses. Therefore, TAM receptors may contribute to testicular immune homeostasis by promoting the removal of germ cell autoantigens. Moreover, damaged germ cells also induce the production of inflammatory cytokines in Sertoli cells through the activation of TLR2 and TLR4.22 Therefore, apoptotic germ cells and residual bodies, if not removed in time, may release endogenous TLR ligands and trigger an inflammatory response through TLR activation (Figure 3.2). The most well-characterized endogenous TLR ligands include high-mobility group box 1 (HMGB1) and several heat shock proteins (HSPs), which induce endogenous inflammation through the activation of TLR2 and TLR4.23,24 Notably, HMGB1 and HSPs are abundantly expressed in male germ cells25,26 and HMGB1 is involved in testicular inflammation.27 The role of endogenous TLR ligands in testicular endogenous inflammation remains largely unknown.
Testis Cancer
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Danish Mazhar, Michael Williams
The basis for cisplatin sensitivity observed in germ cell cancers has been the subject of investigation. Exposure of cells to cisplatin causes crucial intrastrand cross-links, and this is followed by nuclear excision repair (NER). Testis cancer cells have been shown to be deficient in this process. NER is complex and includes the recognition of DNA damage by high mobility group (HMG) proteins. There is a testis-specific HMG protein. When this has been transfected into HeLa cells, the amount of apoptosis following cisplatin exposure was increased in some cases (152). Of the other proteins involved in the NER, the xeroderma pigmentosum group A (XPA) protein and the ERCC1-XPF endonuclease complex are present in low levels in testis cancer cells. When these proteins were added to testis tumor cell extracts, full NER capacity was restored (153), suggesting a pivotal role for these proteins.
Polynuclear Platinum Drugs
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
As the understanding of the cellular mechanism of anticancer activity by drugs has progressed, it is clear that it is not Pt-DNA adducts per se which are responsible for the cytotoxicity but rather the effect these cellular signals have on downstream effects such as protein recognition, cell cycle arrest and especially DNA repair which dictates cellular response to any (drug) insult. In principle, if genuinely different biological activity is due to a different pattern of cellular responses then these should be observable as differential protein recognition. It is therefore of interest to examine the recognition by high mobility group proteins because of the structural information available on the cisplatin case and the comparisons that can be made. The survey has shown that these proteins do not recognize to any great extent the polynuclear platinum adducts. Logically, whatever role these proteins may play in mediating cisplatin toxicity is irrelevant in the case of I and II. HMG-domain proteins are only one of a host of proteins which recognize the bending motif of cisplatin - as a corrolary the polynuclear platinum adduct structures may not serve as substrate for other proteins with affinity for the DNA bending motif.
Role of RAGE and its ligand HMGB1 in the development of COPD
Published in Postgraduate Medicine, 2022
Lin Chen, Xuejiao Sun, Xiaoning Zhong
RAGE can bind to several endogenous DAMPs and activate immune and pro-inflammatory cascades by activating multiple signaling pathways, which are critical to the development of COPD [7]. RAGE is characterized by sustained activation of the pro-inflammatory transcription factor NF-κB induced by endogenous positive feedback loops, thus transforming a transient pro-inflammatory response into a long-term cellular dysfunction [7]. HMGB1 belongs to the high mobility group box protein family which is a protein motifs involved in DNA-binding [12]. HMGB1 is also the most widely studied DAMP and the ligand with the strongest affinity to RAGE [22]. The function of HMGB1 is related to its subcellular location and redox state. In the nucleus, HMGB1 is involved in many physiological processes such as DNA transcription, replication, and repair; in the cytoplasm, it activates inflammasome and autophagy; while on the extracellular space it binds and activates RAGE and Toll-like receptors 2/4 (TLR) receptors, which are critical to innate and acquired immunity [12,53]. The function of extracellular HMGB1 is related to its redox state. The reduced form of HMGB1 has chemotaxis properties, the disulfide form has pro-inflammatory activity, and the oxidized form is inactive [54]. The following sections will focus on the pathogenic role of extracellular HMGB1 in COPD.
Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets
Published in Expert Opinion on Therapeutic Targets, 2022
Alberto Zambelli, Riccardo Sgarra, Rita De Sanctis, Elisa Agostinetto, Armando Santoro, Guidalberto Manfioletti
DNA methyltrasferase 1 (DNMT1) is the most crucial enzyme in the DNMTs family in humans and it is highly expressed in TNBC compared to other subtypes [128]. Notably, a preclinical study suggests that DNMT inhibitors such as 5-azacytidine can increase the efficacy of PARP inhibitors in BC cells with wild-type BRCA1 [129]. Moreover, hypomethylating agents might play a role in selected cases of breast cancer with sporadic abnormally BRCA1 gene promoter methylation [130]. The HDACs are a class of enzymes that deacetylate histones leading to chromatin condensation, repressing transcription. Therefore, HDAC inhibitors could induce tumor cell apoptosis, inhibit cell migration and invasion and sensitize cancer cells to chemotherapy [131]. Preclinical and clinical studies with HDAC inhibitors in combination with other drugs showed promising results in TNBC [125]. Another relevant candidate target, which is involved in chromatin regulation, is the architectural chromatin family of high mobility group A proteins (HMGA). Indeed, HMGA are overexpressed in cancers, regulate chromatin plasticity and, in TNBC, can act as master regulators of genes involved in epithelial-to-mesenchymal transition, migration, invasion, and angiogenesis [132,133].
Mitochondria autophagy: a potential target for cancer therapy
Published in Journal of Drug Targeting, 2021
Yu-Han Qiu, Tian-Shu Zhang, Xiao-Wei Wang, Meng-yan Wang, Wen-Xia Zhao, Hui-Min Zhou, Cong-Hui Zhang, Mei-Lian Cai, Xiao-Fang Chen, Wu-Li Zhao, Rong-Guang Shao
High mobility group box1 protein (HMGB1) is a chromatin-related nuclear protein that participates in DNA replication, transcription, repair and cell movement. Recent evidence suggests that HMGB1 may also be involved in both autophagy induction and mitochondrial initiation. On the one hand, cytoplasmic HMGB1 directly interacts with autophagy protein Beclin-1 to increase the production of ROS that was a promoter of mitophagy [134,135]. On the other hand, nuclear HMGB1 regulates the expression of heat shock protein β-1 (HSPB1/HSP27). HSPB1 is a kind of cytoskeleton regulatory factor, which is very important for intracellular dynamic transport in the process of autophagy [136]. The phenotype produced by the deletion of HMGB1 or HSPB1 is similar to that of mitochondrial fragmentation, resulting in a decrease in the level of ATP to trigger mitophagy. However, unlike Nix and Parkin, HMGB1 or HSPB1 can regulate actin cytoskeleton and affect the transport of damaged mitochondria to autophagosomes, thus indirectly affecting mitophagy.