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Miscellaneous Myths and Misinformation
Published in David Lightsey, The Myths about Nutrition Science, 2019
In 2017, the journal Clinical Gastroenterology and Hepatology published “Suspected Nonceliac Gluten Sensitivity Confirmed in Few Patients After Gluten Challenge in Double-Blind, Placebo-Controlled Trials.”5 The authors reviewed ten previous studies in which individuals ate either a gluten-containing capsule or a placebo for a specified period and then switched, and neither the physician or the individual new the order. After each trail, gastrointestinal symptoms were evaluated. There were 231 NCGS individuals involved. The authors stated in the discussion section of the paper, “more than 80% of nonceliac patients, labeled as suffering from NCGS after a favorable response to a gluten-free diet, cannot reach a formal diagnosis of NCGS after a double-blind, placebo-controlled gluten challenge.”6 In the conclusion section of the report, the authors stated “the nocebo effect was detected in up to 40% of patients.”7
Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Lixin Zheng, Richard M. Siegel, Jagan R. Muppidi, Felicita Hornung, Michael J. Lenardo
The discovery of TCR-induced apoptosis has led our group and others to determine whether harnessing this powerful immunoregulatory mechanism can achieve the therapeutic goal of ameliorating T cell mediated autoimmune diseases. Indeed, it was found that repeated doses of self-antigen could reduce autoimmunity in the mouse model of experimental autoimmune encephalomyelitis.130 In rheumatoid arthritis, as well as inflammatory bowel disease, blocking the effects of TNF with soluble receptor compounds or anti-cytokine antibodies has significant clinical benefit.131,132 These agents may affect both the inflammatory as well as apoptotic signals delivered through TNFR. Since TRAIL was found to be more active at inducing apoptosis in a panel of tumor lines than in normal cells, some have used exogenous TRAIL to successfully treat experimental malignancies in mice.133 Our recent identification of pre-ligand association by members of the TNF receptor family also opens up new possibilities for therapeutic intervention by blocking receptor pre-association.100,101 These therapeutic opportunities show how far this fast moving field has come in only the first ten years after the identification of the basic molecular events underlying immune cell homeostasis.
Antileukemic Treatment Targeted at Apoptosis Regulators
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Simone Fulda, Klaus-Michael Debatin
Several strategies have been developed to target TRAIL receptors therapeutically. One approach is the use of trimeric TRAIL itself as a recombinant natural ligand. Recombinant soluble TRAIL triggered apoptosis in a wide range of cancer cell lines including hematologic malignancies and also in vivo in several xenograft models of human cancers (107,116–123). An alternative therapeutic strategy is based on agonistic monoclonal antibodies (mAb) that specifically target one of the agonistic TRAIL receptors TRAJL-R1 and TRAIL-R2, which demonstrated antitumor activity in cancer cell lines and xenograft-bearing mice (124–126). The existence of decoy receptors that can bind TRAIL, yet not deliver a death signal, suggests a potential advantage to the use of antibodies that specifically target one of the two agonistic TRAIL receptor. Another potential advantage of these antibodies is their longer half-life compared with that of recombinant TRAIL. However, it remains to be determined in future studies which of these agents triggering the TRAIL pathway will turn out to be superior for clinical application.
Elevated soluble death receptor 5 can predict poor prognosis in patients with acute respiratory distress syndrome
Published in Expert Review of Respiratory Medicine, 2022
Jiangyue Qin, Hao Wang, Zhuoyao Lyu, Yue Liao, Ni Zeng, Ke Wang, Yongfang Zhou, Zijian Zeng, Zenglin Liao, Yufang Cao, Junyun He, Tao Wang, Fuqiang Wen
On the other hand, TRAIL (a ligand of DR5) was found to be increased in the BALF of patients with ARDS. This was consistent with previous studies, which showed that TRAIL was elevated in the BALF of patients with ARDS or respiratory viral infection [12,29,30]. Interestingly, this study found that TRAIL was decreased in the serum of patients with ARDS. Previous studies showed that the changes in the serum TRAIL levels differed in various disorders. TRAIL levels were increased in the serum of patients with COPD [10], asthma [31], and pulmonary hypertension [32], but were decreased in the serum of patients with IPF [33]. Interestingly, animal studies showed that although chronic cigarette smoke-induced airway inflammation and remodeling were reduced in mice with TRAIL deletion [22], bleomycin-induced lung fibrosis was enhanced, as the apoptotic cells were decreased in the lungs of these TRAIL-deleted mice [33]. These findings imply that TRAIL might act as a ‘double-edge sword’ in the pathogenesis of pulmonary disorders. The source of serum TRAIL might vary: it might be released in the circulation or by the lungs. There aspects are worth investigating in future clinical and basic science studies.
TRAIL-conjugated silver nanoparticles sensitize glioblastoma cells to TRAIL by regulating CHK1 in the DNA repair pathway
Published in Neurological Research, 2020
Ilknur Sur-Erdem, Kerem Muslu, Nareg Pınarbası, Mine Altunbek, Fidan Seker-Polat, Ahmet Cingöz, Serdar Onur Aydın, Mehmet Kahraman, Mustafa Culha, Ihsan Solaroglu, Tugba Bagcı-Önder
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to a group of the tumor necrosis factor (TNF) gene superfamily, which initiates apoptosis in cancer cells through interaction with the death receptors DR4 and DR5 [3,4]. Binding of TRAIL to death receptors triggers caspase-8-dependent death signaling in a mitochondrial-independent manner (extrinsic apoptotic pathway) by activating caspase-3, −6, and −7 [5]. Activation of caspase-8 also leads to the cleavage of Bidx, thereby promoting the mitochondria-dependent pathway (intrinsic apoptotic pathway) via activation of caspase-9 [6,7]. TRAIL is identified as an attractive chemotherapeutic agent as it selectively induces cancer cells without affecting the normal cells [8]. However, short half-life, poor solubility, inefficient delivery and resistance through a variety of mechanisms of TRAIL in cancer cells are the major limitations for the clinical applicability [9]. Qi et al. showed that glioma stem cells exhibit resistance to the apoptotic effect of TRAIL [10]. Therefore, novel TRAIL sensitizing agents are required to enhance the apoptotic effect of TRAIL for the improved clinical applications.
Co-delivery of doxorubicin and TRAIL plasmid by modified PAMAM dendrimer in colon cancer cells, in vitro and in vivo evaluation
Published in Drug Development and Industrial Pharmacy, 2019
Elham Pishavar, Mohammad Ramezani, Maryam Hashemi
However, TRAIL has potential to induce apoptosis in cancer cells selectively but its therapies application in cancers has been limited due to short half-life, the presence of resistant cancer cell and its inefficient in vivo delivery [59]. Different parameters could influence the in vivo toxicity of drug or gene carriers including chemical structures, surface and terminal groups, size, biodistribution and their metabolism [22]. In this research, in vivo antitumor activity assessment of the conjugates indicated that M-PAMAM G5/TRAIL could inhibit the growth of tumor efficiently without significant alterations in the morphologies of major organs. The increased anti-tumor effect and non-observed toxicity of M-PAMAM G5/TRAIL in various organs could be attributed to the hydrophobic modifications and conjugation of PEG to the dendrimer structure.