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Modulation of Classical Multidrug Resistance and Drug Resistance in General
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
High expression of the major vault protein (MVP), also known as lung resistance protein (LRP), is associated with intracellular drug sequestration and resistance to anthracyclines in cellular models (77). This protein is expressed in some AMLs, and may contribute to clinical drug resistance in that disease (78,79).
Orthostatic Intolerance Syndrome, Vasoregulatory Asthenia and Other Hyperadrenergic States
Published in David Robertson, Italo Biaggioni, Disorders of the Autonomic Nervous System, 2019
The role of MVP in the pathophysiology of this syndrome also remains unclear. Even though most publications stress the association between this syndrome and the presence of MVP, it is now evident that patients with normal mitral valves may present with symptomatology that is indistinguishable from patients with MVP-D. This issue is complicated further by preliminary reports indicating that normal subjects may develop echocardiographic signs of MVP when subjected to volume depletion. If this is true in patients with MVP-D, it opens the possibility that hypovolemia may be the primary phenomenon that produces a “functional” prolapse of the mitral valve. In our experience, more often than not, patients are referred with the diagnosis of MVP only to find equivocal signs of prolapse on re-examination of the echocardiogram. Taylor et aL studied 78 patients with MVP-D and 40 patients with identical symptomatology but without MVP, and compared them to a group of asymptomatic MVP patients and normal controls. No differences (in symptoms, hemodynamic responses to autonomic stimuli, or plasma catecholamines) were found between MVP-D and patients with orthostatic intolerance without MVP (Taylor et al., 1989). As a group, patients with MVP-D were slightly more sensitive to the tachycardic response to isoproterenol than patients without MVP (Taylor et al., 1989). It remains to be determined if patients with dysautonomia unrelated to MVP can be differentiated from MVP-D by the degree of β-adrenoreceptor hypersensitivity, by differences in upright cardiac output or by alterations in plasma volume.
Characteristics, Events, and Stages in Tumorigenesis
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Overall, EVs range in size from 30 nm to 1 mm [850, 853]. The diverse combinations of the content within EVs also contributes to their heterogeneity. An exact classification of EVs does not seem to exist, possibly due to their heterogeneity, overlap, and the lack of study [845, 849, 854–857]. Regardless, there are three prominent types which have been discussed in the literature and include exosomes (~10–150 nm), microvesicles (MVEs) (~150–1000 nm), and apoptotic bodies or apoptotic blebs (~1000–5000 nm) [830, 836, 837, 839, 841, 851, 854, 857, 858]. In addition, based on their size and the mechanisms involved in their generation, EVs can also be divided into two broad subfamilies, such as relatively ‘large vesicles' (from 200 nm to 1–2 µm in diameter) and ‘smaller vesicles' (from 30 to 150 nm in diameter) [835]. The other reported extracellular vesicles and particles (exosome independent or nonvesicle) are small EVs (∼40–150 nm) (such as Arrestin-domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs)); medium EVs (mEVs) (150–1000 nm); oncosomes or large oncosomes (∼1–10 μm released via vesicle budding and membrane scission and from amoeboid-like invasive tumor cells); larger MVEs such as amphisomes or nuecleosomes; exomeres (nonvesicular (NV) fractions obtained from high-resolution density gradient nonmembranous nanoparticles (≤35–50 nm), rich in metabolism related proteins like glycolysis and mTORC1 pathway components); nanovesicles; Argonaute 1–4 or AGO 1–4 proteins (miRNA-processing proteins that can transport as NV particles; Argonaute-bound micro-RNAs); major vault protein (large 41 nm by 72.5 nm ribonucleoprotein cytoplasmic particles); ectosomes (100–500 nm or 90–120 nm), and small exosomes (Exo-S) (60–80 nm); migrasomes (≤3000 nm, formed during cell migration); platelet-derived microparticles (~130–500 nm; also referred to as ‘platelet dust' released with platelet activation); prostasomes (50–500 nm, membrane-surrounded particles found only in prostatic fluid and seminal plasma); tolerosomes (released by intestinal epithelial, serum factor); epididymosomes (acquisition of new sperm proteins); dexosomes (released from dendritic cells); synaptic vesicles (released from neurons); and others that include promininosomes, texosomes, and archaeosomes [463, 464, 768, 828, 830, 831, 836, 837, 841–843, 849, 858–892]. Transport of bioactive cargos between cells is carried out by both MVs and exosomes [859, 893]. EVs may bud from the plasma membrane (ectosomal vesicles) or endosomal compartment (endosomes) [849].
An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders
Published in Expert Opinion on Investigational Drugs, 2019
The COX-enzyme may be valuable in pharmacoresistant or drug-resistant epilepsy cases. Celecoxib restored the efficacy of phenobarbital (a standard barbiturate) in a pharmacoresistant animal model of epilepsy [82]. After the treatment with celecoxib, both responder and nonresponder rats showed significant improvement in SRS pattern with phenobarbital administration [82]. Zibell and colleagues have demonstrated an increase in the BBB efflux transporter P-glycoproteins during a seizure activity involving NMDA glutamatergic signaling and COX-2 mechanism [83]. This mechanism restricts the penetration of antiepileptic drugs and therefore limits its efficacy. Celecoxib has been found to block seizures induced upregulation of P-glycoproteins in rat brain capillaries [83]. Celecoxib has also been shown to reduce the expression of major vault protein (MVT) in the SE animal model [84]. MVT is a vesicular drug transporter protein that participates in multidrug resistance seen in intractable epilepsy patients [85]. Therefore, inhibition of COX-2 enzyme could theoretically prevent pharmacoresistance. Another significant finding of Schlichtiger and colleague’s study is an increase in seizure activity while these rats were administered with celecoxib per se treatment [82].
Association of Elongation Factor Tu GTP-binding Domain-containing 2 Gene (EFTUD2) Polymorphism with the Risk of Hepatitis B Virus Infection
Published in Immunological Investigations, 2022
Anran Tian, Yuwen Li, Haozhi Fan, Pingping Hu, Ruirui Xu, Hui Yuan, Jinyuan Cai, Wen Zhang, Ming Yue, Jun Li, Chen Dong, Chuanlong Zhu
Numerous SNP sites have also been associated with hepatitis C virus (HCV) infection. In cirrhotic patients with HCV, rs13105517 of Toll-like receptor 2 (TLR2) and rs10116253 of TLR4 were found to be associated with the outcomes of HCV infection (Neamatallah et al. 2020); moreover, rs1041981 affects the chronicity of HCV infection (Yue et al. 2021). We previously identified EFTUD2 as a novel anti-HCV immunomodulator (Zhu et al. 2015a). EFTUD2 regulates its downstream regulators through gene splicing on melanoma differentiation-associated protein 5 (MDA5) to activate interferon regulatory factor 3 (IRF3) for an antiviral effect (Zhu et al. 2015b). EFTUD2 is a component of the U5 small nuclear ribonucleoprotein that controls the process of pre-mRNA splicing, together with the other spliceosome (Wahl et al. 2009). De Arras et al. used EFTUD2 small interfering RNA (siRNA) to show that the knockdown of EFTUD2 in mouse macrophages inhibits the production of IL-6. Inhibition of EFTUD2 by siRNA reduces the level of the proinflammatory cytokine TNF-α (De Arras et al. 2014). EFTUD2, also known as Snu114, is closely related to spliceosome remodeling and also participates in spliceosome activation (Bartels et al. 2002). Studies have indicated that EFTUD2 modulates the innate immune response by selectively splicing myeloid differentiation factor 88 (MyD88), a key signal receptor involved in several TLR signaling pathways (De Arras et al. 2014). Major vault protein (MVP) is a virus-induced protein that is synthesized to regulate type I IFN production. The HBV surface antigen (HBsAg) and e antigen (HBeAg) have been shown to inhibit the binding of MVP with MyD88, thus restricting the downstream IFN pathway (Tan et al. 2018).