Countermeasure efficacy of apigenin for silicon-ion-induced early damage in blood and bone marrow of exposed C57BL/6J mice.

We investigated the countermeasure efficacy of apigenin (AP), given as a diet supplement, for radiation-induced damage in the hematopoietic tissues collected on day 7 after a total-body exposure of male C57BL/6J mice to 0 or 0.5 Gy of 260 MeV/n silicon (28Si) ions. We gave food with AP at the concentration of 20 mg/kg body weight (bw) (AP20) or without AP (AP0) to mice before and after irradiation. There were four groups of mice (six mice in each): Group 1- Control, i.e. No Radiation (0 Gy) with AP0; Group 2 - Radiation (0.5 Gy) with AP0; Group 3 - No Radiation (0 Gy) with AP20; and Group 4 - Radiation (0.5 Gy) with AP20. The complete blood count (CBC) and differential blood count were performed for each mouse. In the same mouse, an anti-clastogenic activity of AP was evaluated using the in vivo blood-erythrocyte micronucleus (MN) assay. Further in each mouse, bone marrow (BM) cells were collected and used for measuring the levels of activated nuclear factor-kappa B (NF-κB), and pro-inflammatory cytokines (i.e. tumor necrotic factor-alpha (TNF-α), interleukin-1α (IL-1α), IL-1 beta (IL-1ß), and IL-6). We used the colony-forming unit assay (CFU-A) as a tool to study the countermeasure efficacy of AP against the harmful effects of 28Si ions on the proliferation of the hematopoietic stem/progenitor cells (HSPCs). Our results showed that AP is highly effective not only in the prevention of leukopenia and thrombocytopenia but also in the enhancement of erythropoiesis and the proliferation of HSPCs. We also observed the potent anti-clastogenic activity of AP given to mice as a diet supplement. Further, we found that AP is very effective in the suppression of activated NF-κB and pro-inflammatory cytokines, suggesting that AP given as a diet supplement protects mice from 28Si-ion-induced damage in the hematopoietic tissues of irradiated male C57BL/6J mice via its anti-inflammation activity.

Multi-omic Analysis of Non-human Primate Heart after Partial-body Radiation with Minimal Bone Marrow Sparing.

ABSTRACT: High-dose radiation exposure results in hematopoietic and gastrointestinal acute radiation syndromes followed by delayed effects of acute radiation exposure, which encompasses multiple organs, including heart, kidney, and lung. Here we sought to further characterize the natural history of radiation-induced heart injury via determination of differential protein and metabolite expression in the heart. We quantitatively profiled the proteome and metabolome of left and right ventricle from non-human primates following 12 Gy partial body irradiation with 2.5% bone marrow sparing over a time period of 3 wk. Global proteome profiling identified more than 2,200 unique proteins, with 220 and 286 in the left and right ventricles, respectively, showing significant responses across at least three time points compared to baseline levels. High-throughput targeted metabolomics analyzed a total of 229 metabolites and metabolite combinations, with 18 and 22 in the left and right ventricles, respectively, showing significant responses compared to baseline levels. Bioinformatic analysis performed on metabolomic and proteomic data revealed pathways related to inflammation, energy metabolism, and myocardial remodeling were dysregulated. Additionally, we observed dysregulation of the retinoid homeostasis pathway, including significant post-radiation decreases in retinoic acid, an active metabolite of vitamin A. Significant differences between left and right ventricles in the pathology of radiation-induced injury were identified. This multi-omic study characterizes the natural history and molecular mechanisms of radiation-induced heart injury in NHP exposed to PBI with minimal bone marrow sparing.

Effect of Radiation on the Essential Nutrient Homeostasis and Signaling of Retinoids in a Non-human Primate Model with Minimal Bone Marrow Sparing.

ABSTRACT: High-dose radiation exposure results in hematopoietic (H) and gastrointestinal (GI) acute radiation syndromes (ARS) followed by delayed effects of acute radiation exposure (DEARE), which include damage to lung, heart, and GI. Whereas DEARE includes inflammation and fibrosis in multiple tissues, the molecular mechanisms contributing to inflammation and to the development of fibrosis remain incompletely understood. Reports that radiation dysregulates retinoids and proteins within the retinoid pathway indicate that radiation disrupts essential nutrient homeostasis. An active metabolite of vitamin A, retinoic acid (RA), is a master regulator of cell proliferation, differentiation, and apoptosis roles in inflammatory signaling and the development of fibrosis. As facets of inflammation and fibrosis are regulated by RA, we surveyed radiation-induced changes in retinoids as well as proteins related to and targets of the retinoid pathway in the non-human primate after high dose radiation with minimal bone marrow sparing (12 Gy PBI/BM2.5). Retinoic acid was decreased in plasma as well as in lung, heart, and jejunum over time, indicating a global disruption of RA homeostasis after IR. A number of proteins associated with fibrosis and with RA were significantly altered after radiation. Together these data indicate that a local deficiency of endogenous RA presents a permissive environment for fibrotic transformation.

Long-acting PGE2 and Lisinopril Mitigate H-ARS.

Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.

Proteomic Evaluation of the Natural History of the Acute Radiation Syndrome of the Gastrointestinal Tract in a Non-human Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing Includes Dysregulation of the Retinoid Pathway.

Exposure to ionizing radiation results in injuries of the hematopoietic, gastrointestinal, and respiratory systems, which are the leading causes responsible for morbidity and mortality. Gastrointestinal injury occurs as an acute radiation syndrome. To help inform on the natural history of the radiation-induced injury of the partial body irradiation model, we quantitatively profiled the proteome of jejunum from non-human primates following 12 Gy partial body irradiation with 2.5% bone marrow sparing over a time period of 3 wk. Jejunum was analyzed by liquid chromatography-tandem mass spectrometry, and pathway and gene ontology analysis were performed. A total of 3,245 unique proteins were quantified out of more than 3,700 proteins identified in this study. Also a total of 289 proteins of the quantified proteins showed significant and consistent responses across at least three time points post-irradiation, of which 263 proteins showed strong upregulations while 26 proteins showed downregulations. Bioinformatic analysis suggests significant pathway and upstream regulator perturbations post-high dose irradiation and shed light on underlying mechanisms of radiation damage. Canonical pathways altered by radiation included GP6 signaling pathway, acute phase response signaling, LXR/RXR activation, and intrinsic prothrombin activation pathway. Additionally, we observed dysregulation of proteins of the retinoid pathway and retinoic acid, an active metabolite of vitamin A, as quantified by liquid chromatography-tandem mass spectrometry. Correlation of changes in protein abundance with a well-characterized histological endpoint, corrected crypt number, was used to evaluate biomarker potential. These data further define the natural history of the gastrointestinal acute radiation syndrome in a non-human primate model of partial body irradiation with minimal bone marrow sparing.

Photobiomodulation modulates the resolution of inflammation during acute lung injury induced by sepsis.

Sepsis is a big health problem and one of the most common causes of acute lung injury (ALI) leading to high mortality. Pro-resolving mediators play an important role in abrogating the inflammation and promoting tissue homeostasis restoration. ALI treatment is still a clinical health problem, so new therapies are needed. Here, we evaluated the effect of photobiomodulation treatment on the resolution process of ALI induced by lipopolysaccharide (LPS). Male Balb/c mice were submitted to LPS (ip) or vehicle and irradiated or not with light emitting diode (LED) 2 and 6 h after LPS or vehicle injection, and the parameters were investigated 3 and 7 days after the injections. Our results showed that after 3 days of LED treatment the blood and bronchoalveolar lavage (BAL) cells as well as interleukins (IL) including IL-6 and IL-17 were reduced. No differences were observed in the bone marrow cells, tracheal reactivity, and lipoxin A4 and resolvin E2. Indeed, after 7 days of LED treatment the bone marrow cells, lymphocytes, and lipoxin A4 were increased, while IL-6, IL-17, and IL-10 were decreased. No differences were observed in the blood cells and tracheal reactivity. Thus, our results showed that LED treatment attenuated ALI induced by sepsis by modulating the cell mobilization from their reserve compartments. In addition, we also showed later effects of the LED up to 7 days after the treatment. This study proposes photobiomodulation as therapeutic adjuvant to treat ALI.

Minimal uranium accumulation in lymphoid tissues following an oral 60-day uranyl acetate exposure in male and female C57BL/6J mice.

High levels of uranium (U) exist in soil, water, and air in the Southwestern United States due, in part, to waste generated from more than 160,000 abandoned hard rock mines located in this region. As a result, many people living in this region are chronically exposed to U at levels that have been linked to detrimental health outcomes. In an effort to establish a relevant in vivo mouse model for future U immunotoxicity studies, we evaluated the tissue distribution of U in immune organs; blood, bone marrow, spleen, and thymus, as well as femur bones, kidneys, and liver, following a 60-d drinking water exposure to uranyl acetate (UA) in male and female C57BL/6J mice. Following the 60-d exposure, there was low overall tissue retention of U (<0.01%) at both the 5 and the 50 ppm (mg/L) oral concentrations. In both male and female mice, there was limited U accumulation in immune organs. U only accumulated at low concentrations in the blood and bone marrow of male mice (0.6 and 16.8 ng/g, respectively). Consistent with previous reports, the predominant sites of U accumulation were the femur bones (350.1 and 399.0 ng/g, respectively) and kidneys (134.0 and 361.3 ng/g, respectively) of male and female mice. Findings from this study provide critical insights into the distribution and retention of U in lymphoid tissues following chronic drinking water exposure to U. This information will serve as a foundation for immunotoxicological assessments of U, alone and in combination with other metals.

Adjunctive laser-stimulated stem-cells therapy to primary reperfusion in acute myocardial infarction in humans: Safety and feasibility study.

BACKGROUND: Low-level laser therapy (LLLT) has photobiostimulatory effects on stem cells and may offer cardioprotection. This cell-based therapy may compliment primary percutaneous coronary intervention (PPCI) in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVE: In this randomized control trial, our primary objective was to determine the safety and feasibility of LLLT application to the bone marrow in patients with STEMI undergoing PPCI. METHODS: We randomly assigned patients undergoing PPCI to LLLT or non-laser therapy (NLT). In the LLLT group, 100 s of laser therapy was applied to the tibia bone prior to PPCI, as well as 24 and 72 h post-PPCI. In the control group, the power source was turned off. The primary outcome was the difference in door-to-balloon (D2B) time, and additional outcomes included differences in circulating cell counts, cardiac enzymes, and left-ventricular ejection fraction (LVEF) at pre-specified intervals post-PPCI. RESULTS: Twenty-four patients were randomized to LLLT (N = 12) or NLT (N = 12). No adverse effects of the treatment were detected. The D2B time was not significantly different between the groups (41 ± 8 vs 48 ± 1 min; P = 0.73). Creatinine Phosphokinase area under the curve, was lower after LLLT (22 ± 10) compared to NLT (49 ± 12), but this was not statistically significant (P = 0.08). Troponin-T was significantly lower after LLLT (2.7 ± 1.4 ng/mL) in comparison to NLT (5.2 ± 1.8 ng/mL. P < 0.05). At 9 months, LVEF improved in both groups without a significant difference between LLLT (55 ± 9%) and NLT (52 ± 9%; P = 0.90). CONCLUSION: LLLT is a safe and feasible adjunctive cell-based therapy to PPCI that may benefit ischemic myocardium.

Biophysical and biochemical roles of Moringa oleifera leaves as radioprotector.

It has been found that medicinal plants have chemical and/or therapeutic effects on different diseases related to oxidative damage. This work investigates the use of ethanolic Moringa oleifera leaves extract; as a protective and/or therapeutic agent against damage induced by high acute dose of ionizing radiation. Also, this study aims to explore the associations of electrical properties (relaxation time and DC conductivity of bone marrow) with biochemical markers (SOD, CAT and GSH) to detect and prognosticate radiation effects. Biophysical and biochemical data revealed that Moringa extract can improve the electrical properties of bone marrow and the antioxidants levels in the blood. They also showed that the feeding of Moringa leaves extract post irradiation is preferred to recover rapidly and continuously from radiation effects.

Cervical cancer treated with reduced-volume intensity-modulated radiation therapy base on Sedlis criteria (NCCN VS RTOG).

OBJECTIVE: This study aimed to evaluate the clinical efficacy of different target volumes in pelvic radiotherapy in postoperative treatment of cervical cancer based on the Sedlis criteria. METHODS: Patients who admitted to our department for post-operative radiotherapy of cervical cancer from December 2001 to December 2011 and met the Sedlis criteria were retrospectively analysed. The incidences of acute and late radiation injuries, and overall, disease-free and tumour-specific survival with reduced-volume pelvic and whole-pelvis radiotherapy were evaluated and compared. RESULTS: A total of 371 patients were included in the study, including 239 receiving whole-pelvis radiotherapy and 132 receiving reduced-volume pelvic radiotherapy. The volume of contours for mean PTV volumes, bilateral femoral heads and small intestine volumes in reduced-volume pelvic radiotherapy were lower than whole-pelvis radiotherapy; the results were similar to the V10, V20, V30, V40 and V45 for pelvic bone marrow and small intestine dose volume (both p < 0.05). The acute radiation injury observed in the two groups was mainly haematologic toxicity and upper and lower gastrointestinal symptoms. The incidences of acute radiation injury, and late radiation injury of gastrointestinal and urinary tracts were both significantly lower with reduced-volume pelvic radiotherapy than with whole-pelvis radiotherapy (both p < 0.05). Moreover, there was no significant difference in the incidence of lower extremity oedema, or 2-year or 5-year overall, disease-free or tumour-specific survival between groups (all p > 0.05). CONCLUSION: Reduced-volume pelvic radiotherapy could relieve acute and late radiation injuries, especially myelosuppression, and did not affect long-term survival. Advanced in knowledge: Our study shows that reduced-volume base on National Comprehensive Cancer Network 2016 is more fit for cervical cancer than others.

Beetroot (Beta vulgaris) rescues mice from γ-ray irradiation by accelerating hematopoiesis and curtailing immunosuppression.

CONTEXT: Beetroot [Beta vulgaris Linné (Chenopodiaceae)], a vegetable usually consumed as a food or a medicinal plant in Europe, has been reported to have antioxidant and anti-inflammatory properties. Since the lymphohematopoietic system is the most sensitive tissue to ionizing radiation, protecting it from radiation damage is one of the best ways to decrease detrimental effects from radiation exposure. OBJECTIVE: In this study, we evaluated the radio-protective effects of beetroot in hematopoietic stem cells (HSCs) and progenitor cells. MATERIALS AND METHODS: Beetroot extract was administered at a dose of 400 mg/mouse per os (p.o.) three times into C57BL/6 mice and, at day 10 after γ-ray irradiation, diverse molecular presentations were measured and compared against non-irradiated and irradiated mice with PBS treatments. Survival of beetroot-fed and unfed irradiated animal was also compared. RESULTS: Beetroot not only stimulated cell proliferation, but also minimized DNA damage of splenocytes. Beetroot also repopulated S-phase cells and increased Ki-67 or c-Kit positive cells in bone marrow. Moreover, beetroot-treated mice showed notable boosting of differentiation of HSCs into burst-forming units-erythroid along with increased production of IL-3. Also, beetroot-treated mice displayed enhancement in the level of hematocrit and hemoglobin as well as the number of red blood cell in peripheral blood. Beetroot diet improved survival rate of lethally exposed mice with a dose reduction factor (DRF) of 1.1. DISCUSSION AND CONCLUSION: These results suggest that beetroot has the potency to preserve bone marrow integrity and stimulate the differentiation of HSCs against ionizing radiation.

Radioprotective and Apoptotic Properties of a Combination of α-Tocopherol Acetate and Ascorbic Acid.

We studied radioprotective and apoptotic properties of a combination of α-tocopherol acetate and ascorbic acid. α-Tocopherol acetate (10 mg/kg body weight) or ascorbic acid (20 mg/kg) or combination of these agents in the same doses was orally administered to male rats at various terms before and after single whole-body exposure to γ-irradiation in the doses of 2 and 8 Gy. Irradiation increased the frequency of chromosome aberrations in bone marrow cells and plasma level of low-molecular-weight DNA. Vitamin combination administered before or after irradiation significantly reduced the frequency of chromosome aberrations by 2-2.5 times. Administration of this combination 10 min before irradiation 1.5-fold increased the content of low-molecular-weight DNA in blood plasma in comparison with the control animals exposed to radiation. The combination of α-tocopherol acetate and ascorbic acid produced radioprotective effects and enhanced apoptosis in irradiated cells.

Long-Term Bone Marrow Suppression During Postoperative Chemotherapy in Rectal Cancer Patients After Preoperative Chemoradiation Therapy.

PURPOSE/OBJECTIVE(S): To quantify ensuing bone marrow (BM) suppression during postoperative chemotherapy resulting from preoperative chemoradiation (CRT) therapy for rectal cancer. METHODS AND MATERIALS: We retrospectively evaluated 35 patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy for locally advanced rectal cancer. The pelvic bone marrow (PBM) was divided into ilium (IBM), lower pelvis (LPBM), and lumbosacrum (LSBM). Dose volume histograms (DVH) measured the mean doses and percentage of BM volume receiving between 5-40 Gy (i.e.: PBM-V5, LPBM-V5). The Wilcoxon signed rank tests evaluated the differences in absolute hematologic nadirs during neoadjuvant vs. adjuvant treatment. Logistic regressions evaluated the association between dosimetric parameters and ≥ grade 3 hematologic toxicity (HT3) and hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Receiver Operator Characteristic (ROC) curves were constructed to determine optimal threshold values leading to HT3. RESULTS: During OxF chemotherapy, 40.0% (n=14) and 48% (n=17) of rectal cancer patients experienced HT3 and HE, respectively. On multivariable logistic regression, increasing pelvic mean dose (PMD) and lower pelvis mean dose (LPMD) along with increasing PBM-V (25-40), LPBM-V25, and LPBM-V40 were significantly associated with HT3 and/or HE during postoperative chemotherapy. Exceeding ≥36.6 Gy to the PMD and ≥32.6 Gy to the LPMD strongly correlated with causing HT3 during postoperative chemotherapy. CONCLUSIONS: Neoadjuvant RT for rectal cancer has lasting effects on the pelvic BM, which are demonstrable during adjuvant OxF. Sparing of the BM during preoperative CRT can aid in reducing significant hematologic adverse events and aid in tolerance of postoperative chemotherapy.

Low-Level Laser Therapy to the Bone Marrow Reduces Scarring and Improves Heart Function Post-Acute Myocardial Infarction in the Pig.

OBJECTIVE: Cell therapy for myocardial repair is one of the most intensely investigated strategies for treating acute myocardial infarction (MI). The aim of the present study was to determine whether low-level laser therapy (LLLT) application to stem cells in the bone marrow (BM) could affect the infarcted porcine heart and reduce scarring following MI. METHODS: MI was induced in farm pigs by percutaneous balloon inflation in the left coronary artery for 90 min. Laser was applied to the tibia and iliac bones 30 min, and 2 and 7 days post-induction of MI. Pigs were euthanized 90 days post-MI. The extent of scarring was analyzed by histology and MRI, and heart function was analyzed by echocardiography. RESULTS: The number of c-kit+ cells (stem cells) in the circulating blood of the laser-treated (LT) pigs was 2.62- and 2.4-fold higher than in the non-laser-treated (NLT) pigs 24 and 48 h post-MI, respectively. The infarct size [% of scar tissue out of the left ventricle (LV) volume as measured from histology] in the LT pigs was 3.2 ± 0.82%, significantly lower, 68% (p < 0.05), than that (16.6 ± 3.7%) in the NLT pigs. The mean density of small blood vessels in the infarcted area was significantly higher [6.5-fold (p < 0.025)], in the LT pigs than in the NLT ones. Echocardiography (ECHO) analysis for heart function revealed the left ventricular ejection fraction in the LT pigs to be significantly higher than in the NLT ones. CONCLUSIONS: LLLT application to BM in the porcine model for MI caused a significant reduction in scarring, enhanced angiogenesis and functional improvement both in the acute and long term phase post-MI.

A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.

PURPOSE: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. METHODS AND MATERIALS: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). RESULTS: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. CONCLUSIONS: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

Radiation-induced hematopoietic myelosuppression and genotoxicity get significantly countered by active principles of Podophyllum hexandrum: A study in strain 'A' mice.

PURPOSE: To investigate the protective role of a novel formulation, prepared by a combination of three active principles isolated from Podophyllum hexandrum (G-002M), against radiation- mediated hematopoietic suppression and cytogenetic aberrations in lethally irradiated mice. MATERIALS AND METHODS: G-002M, a combination of podophyllotoxin, podophyllotoxin-ß-D glucoside and rutin, was administered intramuscularly in mice (- 1 h) to radiation (9 Gy) exposure. The animals were autopsied at different time intervals for further studies. RESULTS: Loss of bone marrow progenitor cells, altered myeloid/erythroid ratio, serum erythropoietin and pancytopenia in irradiated mice was found significantly (p < 0.001) ameliorated in G-002M pre-administered mice within 30 d. Bcl-2 (B-cell lymphoma 2) and BAX (Bcl-2-associated X) protein expression was also positively (p < 0.001) countered in these mice. Chromosomal aberrations in 30 d were found remarkably (p < 0.001) reduced in marrow of G-002M pretreated mice. Accelerated antioxidants, reduced DNA damage, stimulated lymphocyte proliferation and minimal cellular atrophy in spleen were some of the other key features observed in G-002M administered mice. CONCLUSIONS: Reduction in hematopoietic aplasia and chromosomal aberrations, besides, early recovery in bone marrow and spleen of G-002M pretreated mice, could be attributed to its free radical scavenging, DNA protecting and apoptotic proteins modulating ability against radiation.

Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy.

UNLABELLED: Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-(68)Ga-DOTAGA ((68)Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated. METHODS: Five patients with a history of prostate cancer were injected intravenously with 91-148 MBq of (68)Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. RESULTS: Injection of 150 MBq of (68)Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy). CONCLUSION: (68)Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by (18)F-FDG.

Low-level laser therapy to the mouse femur enhances the fungicidal response of neutrophils against Paracoccidioides brasiliensis.

Neutrophils (PMN) play a central role in host defense against the neglected fungal infection paracoccidioidomycosis (PCM), which is caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb). PCM is of major importance, especially in Latin America, and its treatment relies on the use of antifungal drugs. However, the course of treatment is lengthy, leading to side effects and even development of fungal resistance. The goal of the study was to use low-level laser therapy (LLLT) to stimulate PMN to fight Pb in vivo. Swiss mice with subcutaneous air pouches were inoculated with a virulent strain of Pb or fungal cell wall components (Zymosan), and then received LLLT (780 nm; 50 mW; 12.5 J/cm2; 30 seconds per point, giving a total energy of 0.5 J per point) on alternate days at two points on each hind leg. The aim was to reach the bone marrow in the femur with light. Non-irradiated animals were used as controls. The number and viability of the PMN that migrated to the inoculation site was assessed, as well as their ability to synthesize proteins, produce reactive oxygen species (ROS) and their fungicidal activity. The highly pure PMN populations obtained after 10 days of infection were also subsequently cultured in the presence of Pb for trials of protein production, evaluation of mitochondrial activity, ROS production and quantification of viable fungi growth. PMN from mice that received LLLT were more active metabolically, had higher fungicidal activity against Pb in vivo and also in vitro. The kinetics of neutrophil protein production also correlated with a more activated state. LLLT may be a safe and non-invasive approach to deal with PCM infection.

NEW APPLICATIONS OF ADAPTOGENS TO REDUCE RADIATION SIDE EFFECTS.

One of the live medical issues today is to find medication to prevent adverse effects of ionizing radiation on the immune and hematopoietic systems. In Yakutia where in most of its regions the overall environmental situation is getting worse due to the development of natural deposits including radioactive deposits, this problem remains vital. The purpose of this work is to study radioprotective properties of adaptogens in the case of the hematopoietic system under irradiation. The studies were conducted on certain groups of hybrid mice. We used the methods of radiation exposure by a radiological apparatus RUM-25 on hybrid mice followed by studying the cellularity of bone marrow, spleen and thymus. The functional activity of all compartments of early hematopoiesis (bone marrow hematopoiesis) was identified by the exogenous colony forming method. The study found that the extracts of reindeer and moose antlers have a stimulating effect on the functional activity of the hematopoietic precursors in response to radiation. The study medication stimulates regeneration processes in the thymus and bone marrow after irradiation. Further, the adaptogens stimulatory effect on CFU functional activity was identified. The most pronounced effect has the extracts of reindeer antlers "Epsorin".

Radioprotective effects of dragon's blood and its extracts on radiation-induced myelosuppressive mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Dragon׳s blood, a traditional Chinese herb, has been used to "panacea of blood activating" and its major biological activity appears to be from phenolic compounds. In this study, our research aims to examine the effects of Dragon׳s blood (DB) and its extracts (DBE) on radiation-induced myelosuppressive mice. MATERIALS AND METHODS: Adult BALB/C mice were exposed to the whole body irradiation with 4 Gy (60)Co γ-rays. DB and DBE were respectively administered orally for 5 constitutive days prior to irradiation treatment. The radioprotective effects and relevant mechanisms of DB and DBE in radiation-induced bone marrow injury were investigated by ex vivo examination. RESULTS: We found that the administration of DB and DBE significantly increased the numbers of peripheral blood cells and colony forming unit of bone marrow-derived stem/progenitor cells. Interestingly, compared with the irradiation group, the administration of DB and DBE significantly decreased the levels of the inflammatory cytokines such as IL-6, TNF-α and IFN-γ and oxidative stress injury such as SOD, CAT, GSH, MDA in serum of mice. Furthermore, DBE markedly improved the morphology of bone marrow histopathology. CONCLUSIONS: Our data suggest that DB and DBE effectively attenuate radiation-induced damage in bone marrow, which is likely associated with the anti-oxidative and anti-inflammatory properties of DB and DBE.