scholarly journals Prophylactic neuroprotection against stroke: Low-dose, prolonged treatment with deferoxamine or deferasirox establishes prolonged neuroprotection independent of HIF-1 function

2011 ◽  
Vol 31 (6) ◽  
pp. 1412-1423 ◽  
Author(s):  
Yanxin Zhao ◽  
David A Rempe
Keyword(s):  
High Risk ◽  
Stroke Volume ◽  
Low Dose ◽  
Chronic Administration ◽  
Iron Chelator ◽  
Prolonged Treatment ◽  
Clinical Use ◽  
High Doses ◽  
Dependent Mechanism

Prophylactic neuroprotection against stroke could reduce stroke burden in thousands of patients at high risk of stroke, including those with recent transient ischemic attacks (TIAs). Prolyl hydroxylase inhibitors (PHIs), such as deferoxamine (DFO), reduce stroke volume when administered at high doses in the peristroke period, which is largely mediated by the hypoxia-inducible transcription factor (HIF-1). Yet, in vitro experiments suggest that PHIs may also induce neuroprotection independent of HIF-1. In this study, we examine chronic, prophylactic, low-dose treatment with DFO, or another iron chelator deferasirox (DFR), to determine whether they are neuroprotective with this paradigm and mediate their effects through a HIF-1-dependent mechanism. In fact, prophylactic administration of low-dose DFO or DFR significantly reduces stroke volume. Surprisingly, DFO remained neuroprotective in mice haploinsufficient for HIF-1 (HIF-1 +/ –) and transgenic mice with conditional loss of HIF-1 function in neurons and astrocytes. Similarly, DFR was neuroprotective in HIF-1 +/ mice. Neither DFO nor DFR induced expression of HIF-1 targets. Thus, low-dose chronic administration of DFO or DFR induced a prolonged neuroprotective state independent of HIF-1 function. As DFR is an orally administered and well-tolerated medication in clinical use, it has promise for prophylaxis against stroke in patients at high risk of stroke.

scholarly journals Toll-Like Receptor Signaling in Airborne Burkholderia thailandensis Infection

2009 ◽  
Vol 77 (12) ◽  
pp. 5612-5622 ◽  
Author(s):  
T. Eoin West ◽  
Thomas R. Hawn ◽  
Shawn J. Skerrett
Keyword(s):  
Low Dose ◽  
Inflammatory Responses ◽  
High Dose ◽  
Tlr Signaling ◽  
Necrosis Factor Alpha ◽  
Airborne Infection ◽  
Essential Components ◽  
High Doses

ABSTRACT Melioidosis is a tropical disease endemic in southeast Asia and northern Australia caused by the gram-negative soil saprophyte Burkholderia pseudomallei. Although infection is often systemic, the lung is frequently involved. B. thailandensis is a closely related organism that at high doses causes lethal pneumonia in mice. We examined the role of Toll-like receptors (TLRs), essential components of innate immunity, in vitro and in vivo during murine B. thailandensis pneumonia. TLR2, TLR4, and TLR5 mediate NF-κB activation by B. thailandensis in transfected HEK293 or CHO cells. In macrophages, TLR4 and the adaptor molecule MyD88, but not TLR2 or TLR5, are required for tumor necrosis factor alpha production induced by B. thailandensis. In low-dose airborne infection, TLR4 is needed for early, but not late, bacterial containment, and MyD88 is essential for control of infection and host survival. TLR2 and TLR5 are not necessary to contain low-dose infection. In high-dose airborne infection, TLR2 deficiency confers a slight survival advantage. Lung and systemic inflammatory responses are induced by low-dose inhaled B. thailandensis independently of individual TLRs or MyD88. These findings suggest that redundancy in TLR signaling or other MyD88-dependent pathways may be important in pneumonic B. thailandensis infection but that MyD88-independent mechanisms of inflammation are also activated. TLR signaling in B. thailandensis infection is substantially comparable to signaling induced by virulent B. pseudomallei. These studies provide additional insights into the host-pathogen interaction in pneumonic Burkholderia infection.

scholarly journals Tumor-derived biomimetic nanozyme with immune evasion ability for synergistically enhanced low dose radiotherapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chunyu Huang ◽  
Zeming Liu ◽  
Mingzhu Chen ◽  
Liang Du ◽  
Chunping Liu ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Low Dose ◽  
Immune Escape ◽  
Redox Homeostasis ◽  
Low Dose Radiotherapy ◽  
Tumor Tissues ◽  
High Doses ◽  
Intracellular Hydrogen Peroxide

AbstractHigh doses of radiation can cause serious side effects and efficient radiosensitizers are urgently needed. To overcome this problem, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for enhanced low-dose radiotherapy (RT). CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH-OXD) and peroxidase (POD) activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2 Gy) can provide a substantial suppression of tumor proliferation. This is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes. Graphical Abstract

scholarly journals Acute Low-Dose Hydralazine-Induced Lupus Pneumonitis

2017 ◽  
Vol 2017 ◽  
pp. 1-4
Author(s):  
Sarah K. Holman ◽  
Donique Parris ◽  
Sarah Meyers ◽  
Jason Ramirez
Keyword(s):  
Low Dose ◽  
Inflammatory Cells ◽  
Chest Ct ◽  
Prolonged Treatment ◽  
Drug Induced ◽  
Asthma Exacerbations ◽  
High Doses ◽  
Diagnostic Work ◽  
Work Up ◽  
Restrictive Pattern

A 35-year-old female was started on hydralazine 10 mg orally three times a day for treatment of postpartum hypertension. Three months later, after multiple unsuccessful courses of prednisone and antibiotics for presumed pneumonia and asthma exacerbations, her respiratory symptoms progressed in severity and she developed resting hypoxia. Previous diagnostic work-up included spirometry with a restrictive pattern, chest CT showing bilateral basilar consolidation, negative BAL, and nonspecific findings on lung biopsy of mild inflammatory cells. Review of systems was positive for arthralgia, lymphadenopathy, paresthesia, and fatigue that began four weeks after starting hydralazine. A clinical diagnosis of hydralazine-induced lupus (HIL) with pneumonitis was made. Antihistone antibodies were positive supporting a diagnosis of HIL. Management included cessation of hydralazine and a prolonged steroid taper. Within days, patient began improving symptomatically. Six weeks later, CT chest showed complete resolution of infiltrates. Genetic testing revealed she was heterozygous for N-acetyltransferase 2 (intermediate acetylator). Drug-induced lupus should be considered in patients with lupus-like symptoms taking medications with a known association. While the majority of HIL cases occur with high doses and prolonged treatment, cases of low-dose HIL have been reported in patients who are slow acetylators.

scholarly journals Tumor-Derived Biomimetic Nanozyme With Immune Evasion Ability For Synergistically Enhanced Low Dose Radiotherapy

2021 ◽  
Author(s):  
Chunyu Huang ◽  
Zeming Liu ◽  
Mingzhu Chen ◽  
Liang Du ◽  
Yongfa Zheng ◽  
...  
Keyword(s):  
High Performance ◽  
Low Dose ◽  
Immune Escape ◽  
Redox Homeostasis ◽  
Low Dose Radiotherapy ◽  
Tumor Tissues ◽  
High Doses ◽  
Intracellular Hydrogen Peroxide

Abstract High doses of radiation can cause serious side effects and drug resistance, high-performance radiosensitizers are urgently needed. To overcome this issue, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for use in combination with low-dose RT. CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH) and peroxidase activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2Gy) can provide a substantial suppression of tumor proliferation. To summarize, this is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes.

scholarly journals Low-Dose Pesticides Alter Primary Human Bone Marrow Mesenchymal Stem/Stromal Cells through ALDH2 Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5699
Author(s):  
Amélie Foucault ◽  
Noémie Ravalet ◽  
Joevin Besombes ◽  
Frédéric Picou ◽  
Nathalie Gallay ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Low Dose ◽  
Low Doses ◽  
Aldehyde Dehydrogenase 2 ◽  
Primitive Hematopoiesis ◽  
In Vitro Effects ◽  
High Doses ◽  
Chlorpyrifos Ethyl ◽  
The Impact

(1) Background: The impact of occupational exposure to high doses of pesticides on hematologic disorders is widely studied. Yet, lifelong exposure to low doses of pesticides, and more particularly their cocktail effect, although poorly known, could also participate to the development of such hematological diseases as myelodysplastic syndrome (MDS) in elderly patients. (2) Methods: In this study, a cocktail of seven pesticides frequently present in water and food (maneb, mancozeb, iprodione, imazalil, chlorpyrifos ethyl, diazinon and dimethoate), as determined by the European Food Safety Authority, were selected. Their in vitro effects at low-doses on primary BM-MSCs from healthy volunteers were examined. (3) Results: Exposure of normal BM-MSCs to pesticides for 21 days inhibited cell proliferation and promoted DNA damage and senescence. Concomitantly, these cells presented a decrease in aldehyde dehydrogenase 2 (ALDH2: mRNA, protein and enzymatic activity) and an increase in acetaldehyde levels. Pharmacological inhibition of ALDH2 with disulfiram recapitulated the alterations induced by exposure to low doses of pesticides. Moreover, BM-MSCs capacity to support primitive hematopoiesis was significantly altered. Similar biological abnormalities were found in primary BM-MSCs derived from MDS patients. (4) Conclusions: these results suggest that ALDH2 could participate in the pathophysiology of MDS in elderly people long exposed to low doses of pesticides.

Pomalidomide (CC4047) Plus Low-Dose Dexamethasone As Therapy for Relapsed Multiple Myeloma

2009 ◽  
Vol 27 (30) ◽  
pp. 5008-5014 ◽  
Author(s):  
Martha Q. Lacy ◽  
Suzanne R. Hayman ◽  
Morie A. Gertz ◽  
Angela Dispenzieri ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Low Dose ◽  
Progression Free Survival ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
High Risk Disease ◽  
Grade 3

Purpose Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma. Patients and Methods Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group. Results Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease. Conclusion The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.

scholarly journals Inhibition of the iron-catalysed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine

1979 ◽  
Vol 184 (2) ◽  
pp. 469-472 ◽  
Author(s):  
J M C Gutteridge ◽  
R Richmond ◽  
B Halliwell
Keyword(s):  
Lipid Peroxidation ◽  
Ascorbic Acid ◽  
Acetic Acid ◽  
Hydroxyl Radicals ◽  
Iron Chelator ◽  
Clinical Use ◽  
Membrane Phospholipids ◽  
Iron Salt ◽  
Iron Salts

The peroxidation of membrane phospholipids induced in vitro by ascorbic acid or by dialuric acid (hydroxybarbituric acid) does not occur in the absence of traces of metal ions. Peroxidation induced by adding iron salts to phospholipids can either be promoted or inhibited by the chelators EDTA, diethylenetriaminepenta-acetic acid and bathophenanthrolinesulphonate, depending on the ratio [chelator]/[iron salt]. The iron chelator desferrioxamine inhibits peroxidation at all concentrations tested, and it also inhibits the iron-catalysed formation of hydroxyl radicals (OH.) from superoxide (O2-.). Since desferrioxamine is approved for clinical use, it might prove a valuable tool in the treatment of inflammation, poisoning by autoxidizable molecules and radiation damage.

Prolonged Treatment of Ultra-Low Dose Chondroitinase ABC Improves Matrix Production in Engineered Cartilage

2013 ◽  
Author(s):  
Grace D. O’Connell ◽  
Victoria Cui ◽  
Robert J. Nims ◽  
Adam B. Nover ◽  
Gerard A. Ateshian ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Low Dose ◽  
Prolonged Treatment ◽  
Load Bearing ◽  
Functional Load ◽  
Diarthrodial Joints ◽  
Equilibrium Modulus ◽  
Matrix Production ◽  
Engineered Cartilage

Articular cartilage is the load bearing soft tissue of diarthrodial joints, and mechanical loading maintains the integrity of the tissue. The predominant extracellular matrix constituents, proteoglycans and collagen, allow cartilage to support the high compressive and tensile loads experienced in diurnal loading. Our laboratory has been successful in cultivating engineered cartilage constructs with a compressive equilibrium modulus and glycosaminglycan (GAG) content near native values [1, 2]. Many approaches to cultivating engineered cartilage have been limited by low collagen production in vitro, an impediment for attaining native functional load-bearing properties [3].

scholarly journals Requirements for Identification of Low Dose and Non-Linear Mutagenic Responses to Ionising Radiation

Dose-Response ◽  
2007 ◽  
Vol 5 (4) ◽  
pp. dose-response.0 ◽  
Author(s):  
Pamela J. Sykes ◽  
Tanya K. Day
Keyword(s):  
Low Dose ◽  
Threshold Model ◽  
Dose Range ◽  
Cellular Transformation ◽  
Low Dose Radiation ◽  
Spontaneous Frequency ◽  
High Doses ◽  
Dose Radiation

Cancer results from multiple changes in gene expression that can occur both genetically and epigenetically. High doses of radiation can lead to mutations and cancer. At high doses the number of mutations caused by radiation is essentially linear with dose. Low dose radiation induced protective responses observed for cancer in vivo and cellular transformation in vitro would predict that hormetic responses would also be observed in mutation assays. Although there are a large number of different mutation assays available, very few are able to detect changes in mutation frequency in response to very low doses of DNA damaging agents. The easiest way to cope with this lack of data in the low dose range is to invoke a linear-no-threshold model for risk assessment. The reasons for the lack of data are discussed. In order to identify hormetic mutation responses, assays need to have a spontaneous frequency that is high enough to enable a reduction below spontaneous frequency to be detected in a feasible number of scored cells and also need to be able to identify both genetic and epigenetic changes. The pKZ1 chromosomal inversion assay fits the criteria for detecting hormetic responses to low dose radiation.

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