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Advanced Science (Weinheim,... Jun 2020The manifestation of acute kidney injury (AKI) is associated with poor patient outcomes, with treatment options limited to hydration or renal replacement therapies. The...
The manifestation of acute kidney injury (AKI) is associated with poor patient outcomes, with treatment options limited to hydration or renal replacement therapies. The onset of AKI is often associated with a surfeit of reactive oxygen species. Here, it is shown that selenium-doped carbon quantum dots (SeCQDs) have broad-spectrum antioxidant properties and prominent renal accumulation in both healthy and AKI mice. Due to these properties, SeCQDs treat or prevent two clinically relevant cases of AKI induced in murine models by either rhabdomyolysis or cisplatin using only 1 or 50 µg per mouse, respectively. The attenuation of AKI in both models is confirmed by blood serum measurements, kidney tissue staining, and relevant biomarkers. The therapeutic efficacy of SeCQDs exceeds amifostine, a drug approved by the Food and Drug Administration that also acts by scavenging free radicals. The findings indicate that SeCQDs show great potential as a treatment option for AKI and possibly other ROS-related diseases.
PubMed: 32596126
DOI: 10.1002/advs.202000420 -
BMC Cancer Jun 2022Concurrent chemoradiotherapy (CCRT) has become the cornerstone of treatment for patients with locally advanced non-small cell lung cancer (LA-NSCLC). The aim of this... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Concurrent chemoradiotherapy (CCRT) has become the cornerstone of treatment for patients with locally advanced non-small cell lung cancer (LA-NSCLC). The aim of this study was to compare the efficacies and toxicities of different CCRT regimens in the treatment of LA-NSCLC by adopting a network meta-analysis (NMA).
METHODS
An exhaustive search of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted to identify relevant studies from inception to October 1, 2020. Direct and indirect evidence was combined to calculate the odds radios (ORs) and 95% confidence intervals (CIs), as well as to plot the surface under the cumulative ranking (SUCRA) curves. Cluster analyses were adopted to compare the efficacies and toxicities of different CCRT regimens according to the similarity of 2 variables. Publication bias was detected by comparison-adjusted funnel plots.
RESULTS
Twenty-two studies were enrolled in this NMA, including 18 regimens: CCRT (cisplatin + etoposide), CCRT (carboplatin + paclitaxel), CCRT (pemetrexed + carboplatin), CCRT (pemetrexed + cisplatin), CCRT (docetaxel + cisplatin), CCRT (S-1 + cisplatin), CCRT (mitomycin + vindesine + cisplatin), CCRT (cisplatin + vinorelbine), CCRT (cisplatin), CCRT (etoposide + cisplatin + amifostine), RT, CCRT (5-FU), CCRT (paclitaxel + cisplatin), CCRT (irinotecan + carboplatin), CCRT (nedaplatin), CCRT (carboplatin + etoposide), CCRT (paclitaxel), and CCRT (carboplatin). The results indicated that the regimens with CCRT (cisplatin + etoposide), CCRT (carboplatin + paclitaxel), CCRT (pemetrexed + cisplatin), CCRT (S-1 + cisplatin), and CCRT (cisplatin + vinorelbine) had relatively better efficacies compared with other regimens. As for toxicities of different CCRT regimens, the CCRT (carboplatin + paclitaxel), CCRT (pemetrexed + cisplatin), and CCRT (docetaxel + cisplatin) were relatively lower.
CONCLUSIONS
Our study demonstrated that CCRT (pemetrexed + cisplatin) and CCRT (carboplatin + paclitaxel) might be the best options for the treatment of LA-NSCLC, and CCRT (pemetrexed + cisplatin) had the highest 3-year overall survival (OS) rate.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Cisplatin; Docetaxel; Etoposide; Humans; Irinotecan; Lung Neoplasms; Network Meta-Analysis; Paclitaxel; Pemetrexed; Vinorelbine
PubMed: 35725420
DOI: 10.1186/s12885-022-09717-8 -
Analytical Biochemistry Mar 2021PrC-210 is a direct-acting ROS-scavenger. It's active when administered orally, IV, or topically; it has none of the nausea/emesis nor hypotension side effects that have...
PrC-210 is a direct-acting ROS-scavenger. It's active when administered orally, IV, or topically; it has none of the nausea/emesis nor hypotension side effects that have precluded human amifostine use. PrC-210 confers 100% survival to mice and rats that received an otherwise 100% lethal radiation dose and 36% reduction of ischemia-reperfusion-induced mouse myocardial infarct damage, and thus is a viable candidate to prevent human ROS-induced ischemia-reperfusion and ionizing radiation toxicities. We report the first assay for the pharmacologically active PrC-210 thiol in blood. PrC-210 has no double-bonds nor light absorption, so derivatizing the thiol with a UV-absorbing fluorochrome enables quantification. This assay: i) is done on the benchtop; it's read with a fluorescence plate reader, ii) provides linear product formation through 60 min, iii) quantifies μM to low mM rodent blood levels of PrC-210 that confer complete radioprotection, iv) accurately reflects PrC-210 thiol formation of mixed disulfides with other thiols in blood, and v) shows excellent between-day assay outcome with very low standard deviation and coefficient of variation. A fluorescence assay quantifying formation of a PrC-210 thiol-bimane adduct enables measurement of blood PrC-210 thiol. A blood assay will help in the development of PrC-210 for use in the human clinical setting.
Topics: Animals; Biological Assay; Diamines; Fluorescence; Free Radical Scavengers; Hydrogen-Ion Concentration; Mice; Pyrazoles; Radiation-Protective Agents; Rats; Reactive Oxygen Species; Sulfhydryl Compounds
PubMed: 33417842
DOI: 10.1016/j.ab.2021.114100 -
Advances in Therapy May 2020We prospectively tested in a phase II study high-dose aracytin and idarubicin plus amifostine as induction regimen in 149 patients with acute myeloid leukaemia (AML)...
Feasibility and Outcome of a Phase II Study of Intensive Induction Chemotherapy in 91 Elderly Patients with AML Evaluated Using a Simplified Multidimensional Geriatric Assessment.
INTRODUCTION
We prospectively tested in a phase II study high-dose aracytin and idarubicin plus amifostine as induction regimen in 149 patients with acute myeloid leukaemia (AML) aged ≥ 60 years, evaluated by a simplified multidimensional geriatric assessment (MGA).
METHODS
Ninety-one fully or partially fit patients (61%) were allocated to intensive chemotherapy and 58 (39%) frail patients to best supportive care (BSC). Intensively treated patients, showing early death and complete response (CR) rate respectively of 5.5% and 73.6%, received 61 consolidations, followed by autologous transplant (ASCT), stem cell transplantation (SCT) or gemtuzumab ozogamicin, depending on mobilization outcome and donor availability.
RESULTS
The 8-year overall survival (OS) of these patients was 20.4%, with median duration of 11.4 months significantly superior to the 1.5 months of BSC arm (p < 0.001). Hyperleukocytosis and cytogenetics were predictors of survival with a relative risk of 1.8 in patients with poor karyotype without hyperleukocytosis (p = 0.02) and 3 in those with hyperleukocytosis (≥ 50,000/μl) (p = 0.002).
CONCLUSION
MGA allowed tailored post-consolidation in 53.8% of patients after high-dose aracytin induction, with long-term survival doubling that reported in the literature after standard-dose cytarabine regimens.
TRIAL REGISTRATION
The study was registered with the Umin Clinical Trial Registry (www.umin.ac.jp/ctr), number R000014052.
Topics: Aged; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Feasibility Studies; Female; Gemtuzumab; Geriatric Assessment; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Outcome Assessment, Health Care; Survival Analysis
PubMed: 32297279
DOI: 10.1007/s12325-020-01310-4 -
Transplantation and Cellular Therapy Oct 2022Bone marrow (BM) transplantation has been used to treat malignant and nonmalignant BM-related disorders. Although an effective strategy, the procedure is associated with...
Vascular Cell Adhesion Molecule 1-Mediated Targeting of Human Hematopoietic Stem Cells to Bone Marrow Is Effective in Conferring Regeneration and Survival in Lethally Irradiated Mice.
Bone marrow (BM) transplantation has been used to treat malignant and nonmalignant BM-related disorders. Although an effective strategy, the procedure is associated with numerous complications, including graft rejection and nonspecific stem cell distribution. Avoidance of immune graft rejection has downsized the quantity of available stem cells, whereas nonspecific distribution necessitates the infusion of increased stem cell doses. A dual-purpose approach is needed to reduce the stem cell dose for transplantation. This used cell encapsulation and BM targeting to increase the quantity of transplanted stem cells reaching the BM. Cells were encapsulated with different biomaterials-chitosan (CS), polyallylamine hydrochloride (PAH), polystyrene sulfonate (PSS), and liposomes-and assessed for interaction with immune system components. The biomaterials were conjugated with vascular cell adhesion molecule 1 (VCAM1), a peptide that binds to BM-specific cell surface molecule, and evaluated for a successful transplantation. Encapsulated cells showed reduced interaction with antibody and cytokine without adverse effects on viability. Constitutive expression of VCAM1 was found to be specific on human bone marrow endothelial cells and was used for targeting by conjugating VCAM1-binding peptide to encapsulated cells. Peptide-conjugated-encapsulated stem cell formulations transplanted in irradiated mice with or without treatment with radioprotectant amifostine showed an increased percentage of cells reaching bone marrow. Post-transplantation survival along with blood count of neutrophils, platelets, and leukocytes was also enhanced for VCAM1-binding peptide-conjugated formulations with 100% survival demonstrated by peptide-conjugated CS/PSS/CS encapsulation formulation in irradiated mice for 4 weeks. Encapsulated cells retained their viability with increased shielding to the immune system, ensuring that graft rejection can be avoided. Transplanted encapsulated stem cells were distributed in a higher percentage to BM when conjugated to VCAM1-binding peptide, which could enable the use of lower stem cell doses. The peptide-conjugated CS/PSS/CS encapsulation system conferred 100% survival in irradiated mice, with increased regeneration demonstrating the ability to treat radiation-exposed victims.
Topics: Amifostine; Animals; Biocompatible Materials; Bone Marrow; Chitosan; Cytokines; Endothelial Cells; Hematopoietic Stem Cells; Humans; Liposomes; Mice; Vascular Cell Adhesion Molecule-1
PubMed: 35850428
DOI: 10.1016/j.jtct.2022.07.012 -
Metabolites Sep 2021Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related...
Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.
PubMed: 34564443
DOI: 10.3390/metabo11090627 -
Annals of Translational Medicine Dec 2019Fast and reliable biomarkers are needed to distinguish whether individuals were exposed or not to radiation and assess radiation dose, and to predict the severity of...
BACKGROUND
Fast and reliable biomarkers are needed to distinguish whether individuals were exposed or not to radiation and assess radiation dose, and to predict the severity of radiation damage in a large-scale radiation accident. Serum amyloid A1 (SAA1) is a protein induced by multiple factors including inflammatory. Therefore, this study aimed at exploring the role of SAA1 in the radiation dose estimation and lethality prediction after radiation.
METHODS
C57BL/6J female mice were exposed to total body irradiation (TBI) at different doses and time points and amifostine, a drug used to reduce the side effects of radiotherapy, was injected before irradiation. Patients with nasopharyngeal carcinoma subjected to radiotherapy were used as the irradiation model in humans.
RESULTS
A moderate SAA1 increase was observed at 6 hours in serum samples from irradiated mice at all doses used, with a peak at 12 hours, then decreased to day 3 after exposure. A second SAA1 increase was observed from day 5 to 7, which was associated to subsequent lethality. Treatment with amifostine before irradiation could prevent mice death and inhibit the second SAA1 increase. SAA1 increase after radiation was confirmed in human serum of nasopharyngeal carcinoma patients after radiotherapy.
CONCLUSIONS
Serum SAA1 levels could represent a biomarker for radiation dose estimation and its second increase might be a useful lethality indicator after radiation in a mouse model.
PubMed: 32042731
DOI: 10.21037/atm.2019.12.27 -
Dose-response : a Publication of... 2020The parotid glands are damaged by oxidative stress and a series of pathophysiological changes after irradiation. Rosmarinic acid (RA) is a natural antioxidant that...
The parotid glands are damaged by oxidative stress and a series of pathophysiological changes after irradiation. Rosmarinic acid (RA) is a natural antioxidant that provides a radioprotective effect against harmful damage from ionizing radiation. The present study aims to explore the protective effects of RA on radiation-induced parotid gland injury and its underlying mechanism. Sprague-Dawley rats were irradiated with 15 Gy X-ray and treated with different concentrations of RA (30, 60, and 120 mg/kg) or amifostine (AMI, 250 mg/kg). Saliva secretion function, oxidative stress, apoptosis, the inflammatory response, and fibrosis were determined by the measurement of the salivary flow rate, enzyme-linked immunosorbent assay, transferase-mediated DUTP Nick end labeling, Western blot, quantitative real time polymerase chain reaction, and hematoxylin and eosin staining. Here, we show that RA treatment significantly attenuated reactive oxygen species by a direct hindrance effect and the indirect activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nicotinamide adenine dinucleotide phosphate oxidase 4 signaling. Rosmarinic acid not only reduced apoptosis by inhibiting p53/jun N-terminal kinase activation but also reduced parotid gland tissue fibrosis by downregulating inflammatory factor levels. Compared to AMI, RA has the obvious advantages of late efficacy and convenient usage. Moreover, 60 mg/kg is the minimum effective dose of RA. Therefore, RA can potentially be applied as a therapeutic radioprotective agent to treat radiation-induced parotid gland injury in the future.
PubMed: 32127788
DOI: 10.1177/1559325820907782 -
Biomolecules Mar 2023The radiation protection strategy with chemical agents has long been based on an antioxidative approach consisting in reducing the number of radical oxygen and nitrogen...
Molecular Influence of the ATM Protein in the Treatment of Human Cells with Different Radioprotective Drugs: Comparisons between Antioxidative and Pro-Episkevic Strategies.
The radiation protection strategy with chemical agents has long been based on an antioxidative approach consisting in reducing the number of radical oxygen and nitrogen species responsible for the formation of the radiation-induced (RI) DNA damage, notably the DNA double-strand breaks (DSB), whose subset participates in the RI lethal effect as unrepairable damage. Conversely, a DSB repair-stimulating strategy that may be called the "pro-episkevic" approach (from the ancient Greek , meaning repair) can be proposed. The pro-episkevic approach directly derives from a mechanistic model based on the RI nucleoshuttling of the ATM protein (RIANS) and contributes to increase the number of DSB managed by NHEJ, the most predominant DSB repair and signaling pathway in mammalians. Here, three radioresistant and three radiosensitive human fibroblast cell lines were pretreated with antioxidative agents (N-acetylcysteine or amifostine) or to two pro-episkevic agents (zoledronate or pravastatin or both (ZOPRA)) before X-ray irradiation. The fate of the RI DSB was analyzed by using γH2AX and pATM immunofluorescence. While amifostine pretreatment appeared to be the most efficient antioxidative process, ZOPRA shows the most powerful radiation protection, suggesting that the pro-episkevic strategy may be an alternative to the antioxidative one. Additional investigations are needed to develop some new drugs that may elicit both antioxidative and pro-episkevic properties and to quantify the radiation protection action of both types of drugs applied concomitantly.
Topics: Animals; Humans; Ataxia Telangiectasia Mutated Proteins; Radiation-Protective Agents; DNA Breaks, Double-Stranded; Antioxidants; Amifostine; DNA Repair; Mammals
PubMed: 36979459
DOI: 10.3390/biom13030524 -
Atherosclerosis Dec 2019We have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced...
BACKGROUND AND AIMS
We have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice.
METHODS
LDL was incubated with sphingomyelinase, which increased its average particle diameter from 26 to 170 nm, and was then incubated for up to 7 days with human monocyte-derived macrophages. LDL receptor-deficient mice were fed a Western diet (19-22 per group) and some given cysteamine in their drinking water at a dose equivalent to that used in cystinosis patients. The extent of atherosclerosis in the aortic root and the rest of the aorta was measured.
RESULTS
Confocal microscopy revealed lipid accumulation in lysosomes in the cultured macrophages. Large amounts of ceroid were produced, which colocalised with the lysosomal marker LAMP2. The antioxidants cysteamine, butylated hydroxytoluene, amifostine and its active metabolite WR-1065, inhibited the production of ceroid. Cysteamine at concentrations well below those expected to be present in lysosomes inhibited the oxidation of LDL by iron ions at lysosomal pH (pH 4.5) for prolonged periods. Finally, we showed that the extent of atherosclerotic lesions in the aortic root and arch of mice was significantly reduced by cysteamine.
CONCLUSIONS
These results support our hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide a novel therapy for this disease.
Topics: Animals; Antioxidants; Aorta; Aortic Diseases; Atherosclerosis; Cysteamine; Disease Models, Animal; Female; Foam Cells; Humans; Hydrogen-Ion Concentration; Lipoproteins, LDL; Lysosomes; Mice, Knockout; Oxidation-Reduction; Plaque, Atherosclerotic; Receptors, LDL; Sphingomyelin Phosphodiesterase; THP-1 Cells
PubMed: 31629988
DOI: 10.1016/j.atherosclerosis.2019.09.019