Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P‐glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To ...address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT‐11) and a NO‐releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp‐mediated MDR reversal agent. The site‐specific drug release and the NO‐reduced Pgp‐mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell‐killing threshold, eventually inducing its antitumor activity. These results reveal that this pH‐responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.
Two is better than one: A carrier system is developed that can generate NO bubbles in the acidic environment of tumor tissues to trigger localized drug release (specifically irinotecan, denoted CPT‐11) and to reverse Pgp‐mediated multidrug resistance (Pgp=P‐glycoprotein). The combined system enhances intracellular drug accumulation in cancer cells so that the concentration exceeds the therapeutic threshold, eventually leading to antitumor activity.
Inflammation is associated with many diseases, in which activated inflammatory cells produce various reactive oxygen species (ROS), including H2O2. This work proposes an ultrasensitive ROS-responsive ...hollow microsphere (HM) carrier that contains an anti-inflammatory drug, an acid precursor consisting of ethanol and FeCl2, and sodium bicarbonate (SBC) as a bubble-generating agent. In cases of inflamed osteoarthritis, the H2O2 at low concentration diffuses through the HMs to oxidize their encapsulated ethanol in the presence of Fe2+ by the Fenton reaction, establishing an acidic milieu. In acid, SBC decomposes to form CO2 bubbles, disrupting the shell wall of the HMs and releasing the anti-inflammatory drug to the problematic site, eventually protecting against joint destruction. These results reveal that the proposed HMs may uniquely exploit biologically relevant concentrations of H2O2 and thus be used for the site-specific delivery of therapeutics in inflamed tissues.
In the absence of adequate oxygen, cancer cells that are grown in hypoxic solid tumors resist treatment using antitumor drugs (such as doxorubicin, DOX), owing to their attenuated intracellular ...production of reactive oxygen species (ROS). Hyperbaric oxygen (HBO) therapy favorably improves oxygen transport to the hypoxic tumor tissues, thereby increasing the sensitivity of tumor cells to DOX. However, the use of HBO with DOX potentiates the ROS-mediated cytotoxicity of the drug toward normal tissues. In this work, we hypothesize that regional oxygen treatment by an implanted oxygen-generating depot may enhance the cytotoxicity of DOX against malignant tissues in a highly site-specific manner, without raising systemic oxygen levels. Upon implantation close to the tumor, the oxygen-generating depot reacts with the interstitial medium to produce oxygen in situ, effectively shrinking the hypoxic regions in the tumor tissues. Increasing the local availability of oxygen causes the cytotoxicity of DOX that is accumulated in the tumors to be significantly enhanced by the elevated production of ROS, ultimately allaying the hypoxia-induced DOX resistance in solid malignancies. Importantly, this enhancement of cytotoxicity is limited to the site of the tumors, and this feature of the system that is proposed herein is unique.
Benzyl isothiocyanate (BITC), a member of isothiocyanates (ITCs), has been shown to induce cell death in many human cancer cells, but there is no further report to show BITC suppresses glioblastoma ...multiforme cells in vivo. In the present study, we investigate the effects of BITC on the inhibition of GBM 8401/luc2 cell generated tumor on athymic nude mice. We established a luciferase expressing stable clone named as GBM 8401/luc2. Thirty male mice were inoculated subcutaneously with GBM 8401/luc2 cells to generate xenograft tumor mice model. Group I was treated with 110 μL phosphate‐buffered solution plus 10 μL dimethyl sulfoxide, Group II‐III with BITC (5 or 10 μmol/100 μL/day, relatively). Mice were given oral treatment of BITC by gavage for 21 days. Results showed that BITC did not affect the body weights. After anesthetized, the photons emitted from mice tumor were detected with Xenogen IVIS imaging system 200 and higher dose of BITC have low total photon flux than that of lower dose of BITC. Results also showed that higher dose of BITC have low total tumor volumes and weights than that of low dose of BITC. Isolated tumors were investigated by immunohistochemical analysis and results showed that BITC at both dose of treatment weakly stained with anti‐MCL1 and ‐XIAP. However, both dose of BITC treatments have strong signals of caspase‐3 and Bax. Overall, these data demonstrated that BITC suppressed tumor properties in vivo. Overall, based on these observations, BITC can be used against human glioblastoma multiforme in the future.
A unique feature of cancer cells is to convert glucose into lactate to produce cellular energy, even under the presence of oxygen. Called aerobic glycolysis The Warburg Effect it has been extensively ...studied and the concept of aerobic glycolysis in tumor cells is generally accepted. However, it is not clear if aerobic glycolysis in tumor cells is fixed, or can be reversed, especially under therapeutic stress conditions. Here, we report that mTOR, a critical regulator in cell proliferation, can be relocated to mitochondria, and as a result, enhances oxidative phosphorylation and reduces glycolysis. Three tumor cell lines (breast cancer MCF-7, colon cancer HCT116 and glioblastoma U87) showed a quick relocation of mTOR to mitochondria after irradiation with a single dose 5 Gy, which was companied with decreased lactate production, increased mitochondrial ATP generation and oxygen consumption. Inhibition of mTOR by rapamycin blocked radiation-induced mTOR mitochondrial relocation and the shift of glycolysis to mitochondrial respiration, and reduced the clonogenic survival. In irradiated cells, mTOR formed a complex with Hexokinase II HK II, a key mitochondrial protein in regulation of glycolysis, causing reduced HK II enzymatic activity. These results support a novel mechanism by which tumor cells can quickly adapt to genotoxic conditions via mTOR-mediated reprogramming of bioenergetics from predominantly aerobic glycolysis to mitochondrial oxidative phosphorylation. Such a "waking-up" pathway for mitochondrial bioenergetics demonstrates a flexible feature in the energy metabolism of cancer cells, and may be required for additional cellular energy consumption for damage repair and survival. Thus, the reversible cellular energy metabolisms should be considered in blocking tumor metabolism and may be targeted to sensitize them in anti-cancer therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The petrogenesis of adakites holds important clues to the formation of the continental crust and copper ± gold porphyry mineralization. However, it remains highly debated as to whether adakites form ...by slab melting, by partial melting of the lower continental crust, or by fractional crystallization of normal arc magmas. Here, we show that to form adakitic signature, partial melting of a subducting oceanic slab would require high pressure at depths of >50 km, whereas partial melting of the lower continental crust would require the presence of plagioclase and thus shallower depths and additional water. These two types of adakites can be discriminated using geochemical indexes. Compiled data show that adakites from circum-Pacific regions, which have close affinity to subduction of young hot oceanic plate, can be clearly discriminated from adakites from the Dabie Mountains and the Tibetan Plateau, which have been attributed to partial melting of continental crust, in Sr/Y-versus-La/Yb diagram. Given that oceanic crust has copper concentrations about two times higher than those in the continental crust, whereas the high oxygen fugacity in the subduction environment promotes the release of copper during partial melting, slab melting provides the most efficient mechanism to concentrate copper and gold; slab melts would be more than two times greater in copper (and also gold) concentrations than lower continental crust melts and normal arc magmas. Thus, identification of slab melt adakites is important for predicting exploration targets for copper- and gold-porphyry ore deposits. This explains the close association of ridge subduction with large porphyry copper deposits because ridge subduction is the most favorable place for slab melting.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Kaempferol is a natural flavonoid. Previous studies have reported that kaempferol has anti‐proliferation activities and induces apoptosis in many cancer cell lines. However, there are no reports on ...human osteosarcoma. In this study, we investigate the anti‐cancer effects and molecular mechanisms of kaempferol in human osteosarcoma cells. Our results demonstrate that kaempferol significantly reduces cell viabilities of U‐2 OS, HOB and 143B cells, especially U‐2 OS cells in a dose‐dependent manner, but exerts low cytotoxicity on human fetal osteoblast progenitor hFOB cells. Comet assay, DAPI staining and DNA gel electrophoresis confirm the effects of DNA damage and apoptosis in U‐2 OS cells. Flow cytometry detects the increase of cytoplasmic Ca2+ levels and the decrease of mitochondria membrane potential. Western blotting and fluorogenic enzymatic assay show that kaempferol treatment influences the time‐dependent expression of proteins involved in the endoplasmic reticulum stress pathway and mitochondrial signaling pathway. In addition, pretreating cells with caspase inhibitors, BAPTA or calpeptin before exposure to kaempferol increases cell viabilities. The anti‐cancer effects of kaempferol in vivo are evaluated in BALB/cnu/nu mice inoculated with U‐2 OS cells, and the results indicate inhibition of tumor growth. In conclusion, kaempferol inhibits human osteosarcoma cells in vivo and in vitro.
Acute respiratory distress syndrome (ARDS) involves dysregulated immune-inflammatory responses, characterized by severe oxidative stress and high mortality. Metabolites modulating the inflammatory ...and immune responses may play a central role in the pathogenesis of ARDS. Most biogenic amines may induce the production of reactive oxygen species, oxidative stress, mitochondrial dysfunction, and programmed cell death. We conducted a prospective study on metabolic profiling specific to the amino acids and biogenic amines of 69 patients with ARDS. Overall, hospital mortality was 52.2%. Between day 1 and day 7 after ARDS onset, plasma kynurenine levels and the kynurenine/tryptophan ratio were significantly higher among non-survivors than in survivors (all p < 0.05). Urine metabolic profiling revealed a significantly higher prevalence of tryptophan degradation and higher concentrations of metabolites downstream of the kynurenine pathway among non-survivors than among survivors upon ARDS onset. Cox regression models revealed that plasma kynurenine levels and the plasma kynurenine/tryptophan ratio on day 1 were independently associated with hospital mortality. The activation of the kynurenine pathway was associated with mortality in patients with ARDS. Metabolic phenotypes and modulating metabolic perturbations of the kynurenine pathway could perhaps serve as prognostic markers or as a target for therapeutic interventions aimed at reducing oxidative stress and mortality in ARDS.
Casticin, a polymethoxyflavone, present in natural plants, has been shown to have biological activities including anti‐cancer activities. Herein, we investigated the anti‐oral cancer activity of ...casticin on SCC‐4 cells in vitro. Viable cells, cell cycle distribution, apoptotic cell death, reactive oxygen species (ROS) production, and Ca2+ production, levels of ΔΨm and caspase activity were measured by flow cytometric assay. Cell apoptosis associated protein expressions were examined by Western blotting and confocal laser microscopy. Results indicated that casticin induced cell morphological changes, DNA condensation and damage, decreased the total viable cells, induced G2/M phase arrest in SCC‐4 cells. Casticin promoted ROS and Ca2+ productions, decreases the levels of ΔΨm, promoted caspase‐3, ‐8, and ‐9 activities in SCC‐4 cells. Western blotting assay demonstrated that casticin affect protein level associated with G2/M phase arrest and apoptosis. Confocal laser microscopy also confirmed that casticin increased the translocation of AIF and cytochrome c in SCC‐4 cells. In conclusion, casticin decreased cell number through G2/M phase arrest and the induction of cell apoptosis through caspase‐ and mitochondria‐dependent pathways in SCC‐4 cells.
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