Heterogeneous uptake of hydroperoxyl radicals (HO2)
onto aerosols has been proposed to be a significant sink of HOx, hence
impacting the atmospheric oxidation capacity. Accurate calculation of the
...HO2 uptake coefficient γHO2 is key to
quantifying the potential impact of this atmospheric process. Laboratory
studies show that γHO2 can vary by orders of
magnitude due to changes in aerosol properties, especially aerosol soluble
copper (Cu) concentration and aerosol liquid water content (ALWC). In this
study we present a state-of-the-art model called MARK to simulate both gas-
and aerosol-phase chemistry for the uptake of HO2 onto Cu-doped
aerosols. Moreover, a novel parameterization of HO2 uptake was
developed that considers changes in relative humidity (RH) and condensed-phase
Cu ion concentrations and which is based on a model optimization using
previously published and new laboratory data included in this
work. This new parameterization will be applicable to wet aerosols, and it
will complement current IUPAC recommendations. The new parameterization is
as follows (the explanations for symbols are in the Appendix): 1γHO2=1αHO2+3×υHO24×106×RdHcorrRT×(5.87+3.2×ln(ALWC/PM+0.067))×PM-0.2×Cu2+eff0.65+υHO2l4RTHorgDorgε. All parameters used in the paper are summarized in Table A1. Using this new
equation, field data from a field campaign were used to evaluate the impact
of the HO2 uptake onto aerosols on the ROx (= OH + HO2 + RO2) budget. Highly variable values for HO2 uptake were
obtained for the North China Plain (median value < 0.1).
Protein-based targeted toxins play an increasingly important role in targeted tumor therapies. In spite of their high intrinsic toxicity, their efficacy in animal models is low. A major reason for ...this is the limited entry of the toxin into the cytosol of the target cell, which is required to mediate the fatal effect. Target receptor bound and internalized toxins are mostly either recycled back to the cell surface or lysosomally degraded. This might explain why no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date although more than 500 targeted toxins have been developed within the last decades. To overcome the problem of insufficient endosomal escape, a number of strategies that make use of diverse chemicals, cell-penetrating or fusogenic peptides, and light-induced techniques were designed to weaken the membrane integrity of endosomes. This review focuses on glycosylated triterpenoids as endosomal escape enhancers and throws light on their structure, the mechanism of action, and on their efficacy in cell culture and animal models. Obstacles, challenges, opportunities, and future prospects are discussed.
Triterpenoidal saponins are synthesized in the roots of
L. The same plant is also a source for the toxin Saporin, which is a ribosome-inactivating protein. Triterpenoidal saponins are known to ...increase the cytotoxicity of Saporin by modulating its intracellular trafficking. Here, we investigated if the combinatorial effects elicited by purified saponins and Saporin can be applied to increase the therapeutic efficacy of the immunotoxin Saporin-Rituximab. First, saponins were purified by high-performance liquid chromatography. Thereafter, their intrinsic cytotoxicity was evaluated on Ramos cells with no observed effect up to 5 µg/mL, however, saponins increased the cytotoxicity of Saporin, while no influence was observed on its
-glycosidase activity. Saporin-Rituximab bound to CD20 in Ramos cells and, in the absence of saponins, had a GI
(concentration inhibiting cell growth to 50 %) of 7 nM. However, in the presence of a nontoxic concentration of saponins, the GI
of Saporin-Rituximab was 0.01 nM, a nearly 700-fold increase in efficacy. Moreover, two further immunotoxins, namely Saporin-anti-CD22 and Saporin-anti-CD25, were tested in combination with saponins yielding enhancement factors of 170-fold and 25-fold, respectively. All three receptors are present in Ramos cells and the differences in cytotoxicity enhancement may be explained by the differing expression levels of the cellular receptors. The application of purified saponins from
L. is therefore a new strategy to potentially improve the cytotoxicity and therapeutic efficacy of Rituximab-immunotoxins for the treatment of B-cell lymphoma.
Saponins in tumor therapy Bachran, Christopher; Bachran, Silke; Sutherland, Mark ...
Mini reviews in medicinal chemistry,
06/2008, Volume:
8, Issue:
6
Journal Article
Peer reviewed
Saponins are plant glycosides with favorable anti-tumorigenic properties. Several saponins inhibit tumor cell growth by cell cycle arrest and apoptosis with IC50 values of up to 0.2 microM. We ...discuss diverse groups of saponins (dioscins, saikosaponins, julibrosides, soy saponins, ginseng saponins and avicins) investigated in relation to tumor therapy and focus on cellular and systemic mechanisms of tumor cell growth inhibition both in vitro and in vivo. The review also describes saponins in combination with conventional tumor treatment strategies, which result in improved therapeutic success. Some combinations of saponins and anti-tumorigenic drugs induce synergistic effects with potentiated growth inhibition.
Saponins are plant metabolites that possess multidirectional biological activities, among these is antitumor potential. The mechanisms of anticancer activity of saponins are very complex and depend ...on various factors, including the chemical structure of saponins and the type of cell they target. The ability of saponins to enhance the efficacy of various chemotherapeutics has opened new perspectives for using them in combined anticancer chemotherapy. Co-administration of saponins with targeted toxins makes it possible to reduce the dose of the toxin and thus limit the side effects of overall therapy by mediating endosomal escape. Our study indicates that the saponin fraction CIL1 of
L. can improve the efficacy of the EGFR-targeted toxin dianthin (DE). We investigated the effect of cotreatment with CIL1 + DE on cell viability in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, on proliferation in a crystal violet assay (CV) and on pro-apoptotic activity using Annexin V/7 Actinomycin D (7-AAD) staining and luminescence detection of caspase levels. Cotreatment with CIL1 + DE enhanced the target cell-specific cytotoxicity, as well as the antiproliferative and proapoptotic properties. We found a 2200-fold increase in both the cytotoxic and antiproliferative efficacy of CIL1 + DE against HER14-targeted cells, while the effect on control NIH3T3 off-target cells was less profound (6.9- or 5.4-fold, respectively). Furthermore, we demonstrated that the CIL1 saponin fraction has a satisfactory in vitro safety profile with a lack of cytotoxic and mutagenic potential.
This paper presents determinations of reactive uptake coefficients for N2O5, γ(N2O5), on aerosols from nighttime aircraft measurements of ozone, nitrogen oxides, and aerosol surface area on the NOAA ...P‐3 during Second Texas Air Quality Study (TexAQS II). Determinations based on both the steady state approximation for NO3 and N2O5 and a plume modeling approach yielded γ(N2O5) substantially smaller than current parameterizations used for atmospheric modeling and generally in the range 0.5–6 × 10−3. Dependence of γ(N2O5) on variables such as relative humidity and aerosol composition was not apparent in the determinations, although there was considerable scatter in the data. Determinations were also inconsistent with current parameterizations of the rate coefficient for homogenous hydrolysis of N2O5 by water vapor, which may be as much as a factor of 10 too large. Nocturnal halogen activation via conversion of N2O5 to ClNO2 on chloride aerosol was not determinable from these data, although limits based on laboratory parameterizations and maximum nonrefractory aerosol chloride content showed that this chemistry could have been comparable to direct production of HNO3 in some cases.
Hydroxyl (OH) and peroxy radicals (HO2 and RO2)
were measured in the Pearl River Delta, which is one of the most polluted
areas in China, in autumn 2014. The radical observations were complemented
by ...measurements of OH reactivity (inverse OH lifetime) and a comprehensive
set of trace gases including carbon monoxide (CO), nitrogen oxides (NOx=NO, NO2) and volatile organic compounds (VOCs). OH reactivity was in
the range from 15 to 80 s−1, of which about 50 % was
unexplained by the measured OH reactants. In the 3 weeks of the
campaign, maximum median radical concentrations were 4.5×106 cm−3
for OH at noon and 3×108 and
2.0×108 cm−3 for HO2 and RO2, respectively, in
the early afternoon. The completeness of the daytime radical measurements
made it possible to carry out experimental budget analyses for all radicals
(OH, HO2, and RO2) and their sum (ROx). The maximum loss rates for
OH, HO2, and RO2 reached values between 10 and 15 ppbv h−1
during the daytime. The largest fraction of this can be attributed to radical
interconversion reactions while the real loss rate of ROx remained below
3 ppbv h−1. Within experimental uncertainties, the destruction rates of HO2
and the sum of OH, HO2, and RO2 are balanced by their respective
production rates. In case of RO2, the budget could be closed by
attributing the missing OH reactivity to unmeasured VOCs. Thus, the
presumption of the existence of unmeasured VOCs is supported by RO2
measurements. Although the closure of the RO2 budget is greatly
improved by the additional unmeasured VOCs, a significant imbalance in the
afternoon remains, indicating a missing RO2 sink. In case of OH, the
destruction in the morning is compensated by the quantified OH sources from
photolysis (HONO and O3), ozonolysis of alkenes, and OH recycling
(HO2+NO). In the afternoon, however, the OH budget indicates a
missing OH source of 4 to 6 ppbv h−1. The diurnal variation of the missing OH
source shows a similar pattern to that of the missing RO2 sink so that
both largely compensate each other in the ROx budget. These observations
suggest the existence of a chemical mechanism that converts RO2 to OH
without the involvement of NO, increasing the RO2 loss rate during the daytime
from 5.3 to 7.4 ppbv h−1 on average. The photochemical net ozone
production rate calculated from the reaction of HO2 and RO2 with
NO yields a daily integrated amount of 102 ppbv ozone, with daily integrated
ROx primary sources being 22 ppbv in this campaign. The produced ozone can
be attributed to the oxidation of measured (18 %) and unmeasured (60 %)
hydrocarbons, formaldehyde (14 %), and CO (8 %). An even larger
integrated net ozone production of 140 ppbv would be calculated from the
oxidation rate of VOCs with OH if HO2 and all RO2 radicals
react with NO. However, the unknown RO2 loss (evident in the RO2
budget) causes 30 ppbv less ozone production than would be expected from the
VOC oxidation rate.
Targeted tumor therapy can provide the basis for the inhibition of tumor growth. However, a number of toxin-based therapeutics lack efficacy because of insufficient endosomal escape after being ...internalized by endocytosis. To address this problem, the potential of glycosylated triterpenoids, such as SO1861, as endosomal escape enhancers (EEE) for superparamagnetic iron oxide nanoparticle (SPION)-based toxin therapy was investigated. Herein, two different SPION-based particle systems were synthesized, each selectively functionalized with either the targeted toxin, dianthin-epidermal growth factor (DiaEGF), or the EEE, SO1861. After applying both particle systems in vitro, an almost 2000-fold enhancement in tumor cell cytotoxicity compared to the monotherapy with SPION-DiaEGF and a 6.7-fold gain in specificity was observed. Thus, the required dose of the formulation was appreciably reduced, and the therapeutic window widened.
Pulsed cavity ring-down spectroscopy is a highly sensitive method for direct absorption spectroscopy that has been applied to in situ detection of NO3, N 2O5 and NO2 in the atmosphere from a variety ...of platforms, including ships, aircraft, and towers. In this paper, we report the development of schemes to significantly improve the accuracy of these measurements. This includes the following: (1) an overall improvement in the inlet transmission efficiencies (92 ± 2% for NO3 and 97 ± 1% for N2O5) achieved primarily through a reduction in the inlet residence time; and (2) the development of a calibration procedure that allows regular determination of these efficiencies in the field by addition of NO3 or N2O5 to the inlet from a portable source followed by conversion of NO3 to NO2. In addition, the dependence of the instrument’s sensitivity and accuracy to a variety of conditions encountered in the field, including variations in relative humidity, aerosol loading, and VOC levels, was systematically investigated. The rate of degradation of N2O5 transmission efficiency on the inlet and filter system due to the accumulation of inorganic aerosol was determined, such that the frequency of filter changes required for accurate measurements could be defined. In the absence of aerosol, the presence of varying levels of relative humidity and reactive VOC were found to be unimportant factors in the instrument’s performance. The 1 σ accuracy of the NO3, N2O5, and NO2 measured with this instrument are −9/+12, −8/+11, ± 6%, respectively, where the ∓ signs indicate that the actual value is low/high relative to the measurement. The largest contribution to the overall uncertainty is now due to the NO3 absorption cross section rather than the inlet transmission efficiency.
The first wintertime in situ
measurements of hydroxyl (OH), hydroperoxy (HO2) and organic peroxy
(RO2) radicals
(ROx=OH+HO2+RO2) in combination
with observations of total reactivity of OH radicals, ...kOH in
Beijing are presented. The field campaign “Beijing winter finE particle
STudy – Oxidation, Nucleation and light Extinctions” (BEST-ONE) was
conducted at the suburban site Huairou near Beijing from January to
March 2016. It aimed to understand oxidative capacity during wintertime and
to elucidate the secondary pollutants' formation mechanism in the North China
Plain (NCP). OH radical concentrations at noontime ranged from 2.4×106cm-3 in severely polluted air (kOH∼27s-1) to 3.6×106cm-3 in relatively clean
air (kOH∼5s-1). These values are nearly 2-fold
larger than OH concentrations observed in previous winter campaigns in
Birmingham, Tokyo, and New York City. During this campaign, the total primary
production rate of ROx radicals was dominated by the
photolysis of nitrous acid accounting for 46 % of the identified primary
production pathways for ROx radicals. Other important
radical sources were alkene ozonolysis (28 %) and photolysis of
oxygenated organic compounds (24 %). A box model was used to simulate the
OH, HO2 and RO2 concentrations based on the observations
of their long-lived precursors. The model was capable of reproducing the
observed diurnal variation of the OH and peroxy radicals during clean days
with a factor of 1.5. However, it largely underestimated HO2 and
RO2 concentrations by factors up to 5 during pollution episodes.
The HO2 and RO2 observed-to-modeled ratios increased with
increasing NO concentrations, indicating a deficit in our understanding of
the gas-phase chemistry in the high NOx regime. The OH
concentrations observed in the presence of large OH reactivities indicate
that atmospheric trace gas oxidation by photochemical processes can be highly
effective even during wintertime, thereby facilitating the vigorous formation
of secondary pollutants.
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