Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as ...the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
Background and purpose: Apremilast is an orally administered phosphodiesterase‐4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory ...effects of apremilast on pro‐inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis.
Experimental approach: Apremilast was tested in vitro against endotoxin‐ and superantigen‐stimulated PBMC, bacterial peptide and zymosan‐stimulated polymorphonuclear cells, immunonoglobulin and cytokine‐stimulated NK cells, and ultraviolet B light‐activated keratinocytes. Apremilast was orally administered to beige‐severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed.
Key results: Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon‐γ and tumour necrosis factor (TNF)‐α, and interleukins (IL)‐2, IL‐12 and IL‐23. Production of TNF‐α by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF‐α, human leukocyte antigen‐DR and intercellular adhesion molecule‐1 in the lesioned skin.
Conclusions and implications: Apremilast displayed a broad pattern of anti‐inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF‐α, IL‐12 and IL‐23 production, as well as NK and keratinocyte responses by this phosphodiesterase‐4 inhibitor suggests a novel approach to the treatment of psoriasis.
The incidence of symptomatic radiation induced lung pneumonitis (RILP), a major dose limiting side effect of thoracic radiotherapy, is in the range of 15-40%. Therapeutic options for the prevention ...and treatment of RILP are limited. Hence there is a need for developing novel radioprotectors to prevent RILP which can be patient compliant. This study sought to evaluate the efficacy of oral 3,3′-diselenodipropionic acid (DSePA), a novel selenocystine derivative to prevent RILP. C3H/HeJ (pneumonitis responding) mice received a single dose of 18 Gy, whole thorax irradiation and a subset were treated with DSePA orally (2.5 mg/kg), three times per week beginning 2 h post irradiation and continued till 6 months. DSePA delayed onset of grade ≥ 2 RILP by 45 days compared to radiation control (~105 versus ~60 days). It also reversed the severity of pneumonitis in 3/10 radiation treated mice leading to significant improvement in asymptomatic survival compared to radiation control (~180 versus ~102 days). DSePA significantly (p < 0.05) reduced the radiation-mediated infiltration of polymorphonuclear neutrophils (PMN) and elevation in levels of cytokines such as IL1-β, ICAM-1, E-selectin, IL-17 and TGF-β in the bronchoalveolar lavage fluid. Moreover DSePA lowered PMN-induced oxidants, maintained glutathione peroxidase activity and suppressed NF-kB/IL-17/G-CSF/neutrophil axis in the lung of irradiated mice. Additionally, this compound did not protect A549 (lung cancer) derived xenograft tumor from radiation exposure in SCID mice. DSePA offers protection to normal lung against RILP without affecting radiation sensitivity of tumors. It has the potential to be developed as an oral agent for preventing RILP.
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•Oral DSePA delays the onset of radiation pneumonitis (grade ≥ 2) by 45 days.•Oral DSePA reverses the severity of pneumonitis in 3/10 radiation treated mice.•DSePA lowers PMN-induced oxidants, maintaines glutathione peroxidase activity in lung.•DSePA suppresses the NF-kB/IL-17/G-CSF/neutrophil axis implicated in RILP.•DSePA doesn't protect lung cancer cells from radiation exposure.
In the past two decades, high-amplitude electromagnetic outbursts have been detected from dormant galaxies and often attributed to the tidal disruption of a star by the central black hole
. X-ray ...emission from the Seyfert 2 galaxy GSN 069 (2MASX J01190869-3411305) at a redshift of z = 0.018 was first detected in July 2010 and implies an X-ray brightening by a factor of more than 240 over ROSAT observations performed 16 years earlier
. The emission has smoothly decayed over time since 2010, possibly indicating a long-lived tidal disruption event
. The X-ray spectrum is ultra-soft and can be described by accretion disk emission with luminosity proportional to the fourth power of the disk temperature during long-term evolution. Here we report observations of quasi-periodic X-ray eruptions from the nucleus of GSN 069 over the course of 54 days, from December 2018 onwards. During these eruptions, the X-ray count rate increases by up to two orders of magnitude with an event duration of just over an hour and a recurrence time of about nine hours. These eruptions are associated with fast spectral transitions between a cold and a warm phase in the accretion flow around a low-mass black hole (of approximately 4 × 10
solar masses) with peak X-ray luminosity of about 5 × 10
erg per second. The warm phase has kT (where T is the temperature and k is the Boltzmann constant) of about 120 electronvolts, reminiscent of the typical soft-X-ray excess, an almost universal thermal-like feature in the X-ray spectra of luminous active nuclei
. If the observed properties are not unique to GSN 069, and assuming standard scaling of timescales with black hole mass and accretion properties, typical active galactic nuclei with higher-mass black holes can be expected to exhibit high-amplitude optical to X-ray variability on timescales as short as months or years
.
SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised ...patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ~6-fold increase in remdesivir IC
but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.
Schematic of the procedure for preparation of extractant impregnated polymeric beads.
•The PC88A EIMPBs were synthesized and characterized by FTIR, TGA and SEM.•The physiochemical strength of these ...beads was found to be excellent.•The synthesized beads show a great potential for effective removal of Am (III).•The sorption kinetics and sorption isotherms explain the mechanism of extraction.•The synthesized EIMPBs have good reusability up to 10 successive cycles.
The removal of Am (III) ions from aqueous solutions was studied by solid-liquid extraction using indigenously synthesized Extractant Impregnated Macroporous Polymeric Beads (EIMPBs). These beads were prepared by an in situ phase inversion method using polyethersulfone (PES) as base polymer and 2-ethylhexyl phosphonic acid mono-2-ethylhexyl ester (PC88A) as an extractant. The synthesized EIMPBs were characterized by FTIR, TGA and SEM techniques. The batch equilibration study using these beads for the uptake of Am (III) was carried out as a function of parameters, like pH, equilibration time, Am (III) concentration, etc. The blank polymeric beads, without PC88A, have shown negligible sorption of Am (III) under the experimental conditions. The experimental data on the sorption behavior of Am (III) on the polymeric beads fitted well in the pseudo-second-order kinetics model. The synthesized polymeric beads exhibited very good sorption capacity for Am (III) at pH 3. The reusability of the beads was also ascertained by repetitive sorption/desorption of Am (III) up to 10 cycles of operation, without any significant change in their sorption characteristics.
To determine the effect of dexamethasone on the antimyeloma effects of lenalidomide, we tested in vitro proliferation, tumor suppressor gene expression, caspase activity, cell cycling, and apoptosis ...levels in a series of multiple myeloma (MM) and plasma cell leukemia cell lines treated with lenalidomide and dexamethasone, alone or in combination. The effect of dexamethasone on the immunomodulatory activities of lenalidomide such as T cell and natural killer (NK) cell activation was measured via interleukin IL-2 production, and interferon-gamma and granzyme B production respectively. Lenalidomide inhibited proliferation in most cell lines tested, and this effect was enhanced by dexamethasone. This effect was observed in MM cells containing the high-risk cytogenetic abnormalities t(4;14), t(14;16), del17p, del13, and hypodiploidy. Mechanistically, lenalidomide plus dexamethasone synergistically induced expression of the tumor suppressor genes Egr1, Egr2, Egr3, p15, p21, and p27 in MM cell lines and MM patient cells. The combination activated caspases 3, 8, and 9; and induced cell cycle arrest and apoptosis. Lenalidomide alone increased T cell production of IL-2, and NK cell production of interferon-gamma and granzyme B. Notably, dexamethasone antagonized these immunostimulatory effects of lenalidomide in a dose-dependent manner. These data further elucidate the mechanism of action of lenalidomide and dexamethasone in MM, and suggest that use of low-dose dexamethasone with lenalidomide may retain the antiproliferative effect of lenalidomide while permitting greater immunomodulatory effects of this combination regimen.
Chronic diseases have been treated using the phytochemical concepts of ethnomedicinal plant-derived herbal products. Terminalia arjuna, a significant ethnomedicinal plant, was revisited and ...reconnoitred for antioxidant, free radical scavenging, and DNA nicking inhibiting activity under H
conditions using 21 solvent extracts. Ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid, and nitrous oxide scavenging (%) were found to have a strong positive association and interaction (PCA 1 explains 84.54% variation) with ethanol bark (Etoh-AB) (Meoh-AF). TPC (144.67-1794 µg/mL GAE) and TFC (2.5-34 µM Fe(II)/g were highest in Etoh-AB. In a pattern of combined solvent extracts, Etoh-AB had the highest antioxidant capacity, accompanied by Etoh-AL ≥ Meoh-AB ≥ Dw-AF. With R
= 0.94, the DNA nicking inhibition behaviour parameters relative front, relative quantity, band (%), and lane (%) formed a positive significant (p < 0.01) connection. For the first time, we show that Etoh-AB nicks supercoiled, circular plasmid DNA in a way that is comparable to normal antioxidants. Normal antioxidants with the ability to prevent DNA nicking include Butylated hydroxy anisole < Butylated hydroxy toluene < ascorbic acid < and Gallic acid. Gallic acid (m/z 170.0208 g/mol) and Ellagic acid (m/z 302.0063 g/mol were present in high concentrations in solvent extracts. 0.48 mg was found to be the effective concentration for inhibiting relative DNA nicking. The current study is the first of its kind to show that steroid concentrations are higher in bark fractions of acetone, ethanol, and methanol. Furthermore, T. arjuna solvent extracts provide a wealth of information on phytochemical profiling, antioxidant ability, and DNA nicking inhibition, which may be useful for exploring the natural way and further research to develop a remedy against geriatric chronic disease. Despite the fact that ethanol is very close to methanol in terms of solvent toxicity, the current study identified it as the preferred solvent. Thus, the current research revisits previous studies and explores the potentiality of non-polar and polar aprotic and polar protic solvent systems, which lend credence to bioactive compounds that may be useful in isolating and formulating safe and cost effective herbal medicament for livestocks and aquaculture, and drugs for deoxygenerative human diseases, and can also be investigated further to instil environmental frugality.
Hepatitis E virus (HEV) causes an acute, self-limiting hepatitis. The disease takes a severe form in pregnant women, leading to around 30% mortality. Zinc is an essential micronutrient that plays a ...crucial role in multiple cellular processes. Our earlier findings demonstrated the antiviral activity of zinc salts against HEV infection. Zinc oxide (ZnO) and its nanostructures have attracted marked interest due to their unique characteristics. Here we synthesized ZnO nanoparticles ZnO(NP) and tetrapod-shaped ZnO nanoparticles ZnO(TP) and evaluated their antiviral activity. Both ZnO(NP) and ZnO(TP) displayed potent antiviral activity against hepatitis E and hepatitis C viruses, with the latter being more effective. Measurement of cell viability and intracellular reactive oxygen species levels revealed that both ZnO(NP) and ZnO(TP) are noncytotoxic to the cells even at significantly higher doses, compared to a conventional zinc salt (ZnSO
4
). Our study paves the way for evaluation of the potential therapeutic benefit of ZnO(TP) against HEV and HCV.
With their location in the perisinusoidal space of Disse, hepatic stellate cells (HSCs) communicate with all of the liver cell types both by physical association (cell body as well as cytosolic ...processes penetrating into sinusoids through the endothelial fenestrations) and by producing several cytokines and chemokines. Bacterial lipopolysaccharide (LPS), circulating levels of which are elevated in liver diseases and transplantation, stimulates HSCs to produce increased amounts of cytokines and chemokines. Although recent research provides strong evidence for the role of HSCs in hepatic inflammation and immune regulation, the number of HSC-elaborated inflammatory and immune regulatory molecules may be much greater then known at the present time. Here we report time-dependent changes in the gene expression profile of inflammatory and immune-regulatory molecules in LPS-stimulated rat HSCs, and their validation by biochemical analyses. LPS strongly up-regulated LPS-response elements (TLR2 and TLR7) but did not affect TLR4 and down-regulated TLR9. LPS also up-regulated genes in the MAPK, NFκB, STAT, SOCS, IRAK and interferon signaling pathways, numerous CC and CXC chemokines and IL17F. Interestingly, LPS modulated genes related to TGFβ and HSC activation in a manner that would limit their activation and fibrogenic activity. The data indicate that LPS-stimulated HSCs become a major cell type in regulating hepatic inflammatory and immunological responses by altering expression of numerous relevant genes, and thus play a prominent role in hepatic pathophysiology including liver diseases and transplantation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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