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Primary Biliary Cirrhosis Bench to Bedside
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Shinji Shimoda, Akiyoshi Nishio, Hiromi Ishibashi, M. Eric Gershwin
Approximately 30% to 50% patients with PBC have antinuclear antibodies. Interestingly some ANA subtypes are nearly 100% specific for PBC including peripheral labeling of the nuclear envelope and multiple nuclear dots when examined by immunofluorescence microscopy.51 However the predominant ANA recognizes a nuclear envelope antigen coined gp210.52 Gp210 is a 210 KD integral membrane glycoprotein of the nuclear pore membrane with the majority of its molecular mass in the perinuclear space, a single transmembrane segment and a carboxyl-terminal tail of 58 amino acids that faces the nuclear pore complex.53,54 The results of several studies show that from about 10% to 40% of patients with PBC have gp210 autoantibodies.55–58 Less frequendy, patients with PBC have autoantibodies against other nuclear envelope antigens, including (Lamin Β receptor) LBR,57–59 a polytopic integral protein of the inner nuclear membrane,60 and possibly nucleoporin p62,61,62 a nonmembrane protein of the nuclear pore complex.63 The predominant antigen recognized by autoantibodies that produce the multiple nuclear dot pattern is Sp100, a protein of nuclear bodies.64 Various studies have reported that anti-Spl00 autoantibodies are present in approximately 20% to 40% of patients with PBC.65–67 The promyelocytic leukemia protein of nuclear bodies (PML) is also recognized by autoantibodies in some patients with PBC.67,68
Mitochondrial Stress and Cellular Senescence
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Irene L. Tan, Michael C. Velarde
Low ATP production may be associated with low intracellular concentration of the reduced form of nicotinamide adenine dinucleotide (NADH), NAD+, a cofactor required for glycolysis and mitochondrial electron transport chain. Decreased levels of intracellular NAD+ can activate AMPK and promote senescence in a p53-dependent manner (Wiley et al. 2016). In addition, NAD+ is also important for many enzymatic reactions such as DNA repair and protein acetylation (Genova and Lenaz 2014; Ziegler, Wiley, and Velarde 2015). NAD+ associates with poly-ADP ribose polymerase (PARP), which senses DNA damage and facilitates DNA repair (Choi and Mostoslavsky 2014; Fang and Bohr 2017). PARP requires NAD+ to produce poly-ADP ribose needed to recruit DNA repair proteins at the site of genetic lesion (Fang and Bohr 2017). NAD+ is also needed by sirtuin 1 (SIRT1), a deacetylase that regulates genetic stability, cellular metabolism, and longevity (Imai and Guarente 2016; Longo and Kennedy 2006). SIRT1 delays cellular senescence through activation of ERK and S6K1 (Huang et al. 2008) or by silencing p53 through deacetylation (Langley et al. 2002). However, SIRT1-overexpression in primary mouse embryo fibroblasts (MEFs) antagonizes promyelocytic leukemia protein (PML)-induced acetylation of p53 and rescues the cells from premature cellular senescence (Langley et al. 2002). Consequently, perturbations in the PARPs and sirtuins contributes to the onset of cellular senescence (Efimova et al. 2010).
Oncolytic Viruses and Histone Deacetylase Inhibitors
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Vaishali M. Patil, Satya P. Gupta
Various studies have found pretreatment of oncolytic HSV therapy with HDIs as a beneficial option. One of the examples includes pretreatment with VPA showing enhanced viral replication and spread only in tumor cells where the innate antiviral response was found to be correlated with several IFN-responsive genes. Pretreatment with VPA decreased expression levels of STAT1, PKR, and promyelocytic leukemia protein (PML). Thus, STAT1-deficient cells resulted in significant enhancement in HSV replication, and treatment with VPA does not further increase HSV replication. Therefore, decreased STAT1 activity is partially responsible for VPA-treated HSV replication. Also, VPA counteracts inhibition of OV replication by IFN-β treatment and thus highlights the inhibitory mechanism of the IFN antiviral response. The timing of HDI treatment is also an important factor in HDI/OV combination therapy. Concurrent treatment with VPA in HSV infection failed to show enhancing effect compared to pretreatment. Further, HSV/TSA combination resulted in synergistic enhancement of anti-angiogenesis and inhibition of the angiogenic factor, vascular endothelial growth factor (VEGF), to a better extent (Cinatl et al. 2004). In the case of HSV or TSA-treated cells, decreased VGEF was observed.
pH-Responsive and liver-targeting drug delivery system for combination delivery of artesunate with arsenic trioxide prodrug against hepatocellular carcinoma
Published in Drug Development and Industrial Pharmacy, 2023
Xuwang Pan, Jinsong Huang, Shourong Liu, Yidan Shao, Jianjun Xi, Ruoyu He, Tingting Shi, Rangxiao Zhuang, Wenying Yu
Arsenic trioxide (ATO) is effective against acute promyelocytic leukemia (APL) [2]. ATO exerts therapeutic effects on leukemia and solid tumors, including breast cancer, lung cancer, and HCC [3,4]. However, ATO is effective only in HCC patients with negative expression of the promyelocytic leukemia protein, and phase-II clinical trials have revealed limited efficacy of ATO alone in treating HCC [5,6]. The dose of ATO required for solid tumors is much higher than that for hematological malignancy and can cause liver, heart, kidney toxicity and even sudden death [7]. Intrinsic resistance caused by dose-dependent toxicity is the main cause of treatment failure of ATO in HCC and the main reason for ATO’s genetic toxicity [8]. The lack of specificity in its in vivo distribution induces gastrointestinal reactions and an unclear metabolic process, which limits the clinical application of ATO [9,10].
The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study
Published in Pediatric Hematology and Oncology, 2019
Rebecca Ronsley, Amina Kariminia, Bernard Ng, Sara Mostafavi, Gregor Reid, Peter Subrt, Nobuko Hijiya, Kirk R. Schultz
In our study subjects, only promyelocytic leukemia protein (PML) and HRAS mRNA increased significantly following GNKG168 treatment. Promyelocytic leukemia protein (PML) is a member of the tripartite motif family protein and functions as a tumor suppressor gene with diverse activities in cell growth and death. Previous work has demonstrated that PML is involved in regulating p53 response to oncogenic signals.16 Furthermore, Lai et al showed that in mouse models, PML may contribute to activation of B and T lymphocytes.17PML also plays a role in immune responses for viral responses and appears to play a role in innate responses through the TLR and NFκB pro-survival pathways.18PML may also play a prominent role of autophagy in RA-mediated IgG-production in normal human B cells.19
Mutant ATRX: uncovering a new therapeutic target for glioma
Published in Expert Opinion on Therapeutic Targets, 2018
Santiago Haase, María Belén Garcia-Fabiani, Stephen Carney, David Altshuler, Felipe J. Núñez, Flor M. Méndez, Fernando Núñez, Pedro R. Lowenstein, Maria G. Castro
Promyelocytic leukemia nuclear bodies (PML-NBs) are ubiquitous nuclear structures mainly composed of PML (promyelocytic leukemia protein) [49], a tumor suppressor protein. PML-NBs are found in most mammalian cell nuclei [50] and have a dynamic composition and functionality. These characteristics depend on the cell type as well as the metabolic and developmental states. PML-NBs have been implicated in diverse cellular functions, such as regulation of gene expression, tumor suppression, apoptosis, cellular senescence, genomic stability, differentiation, and immune responses. PML-NBs functions are commonly disrupted in leukemia and solid tumors. PML expression is induced in response to stress and senescence. Additionally, it is transcriptionally regulated by P53 [51]. PML is also regulated at the posttranslational level, being phosphorylated in response to DNA damage to trigger translocation of PML-NBs to the nucleus or inducing apoptosis. Sumoylation of PML is also essential for the function of PML-NBs [49].