Radioprotective Effect of Nigella Sativa Oil on Heart Tissues of Rats Exposed to Irradition

Abstract Background Various studies are ongoing related to the radioprotective agents. Herbal preparations are currently becoming popular because of their beneficial effects with fewer side effects compared to the synthetic/semi-synthetic medicines, and Nigella sativa oil (NSO) is only one of them. Objective To investigate NSO for its antioxidant effects on the heart tissue of rats exposed to ionizing radiation (IR). Methods Thirty six male albino Wistar rats, divided into four groups, were designated to group I (IR plus NSO group) that received both 5 Gray of gamma IR to total cranium and NSO; group II (IR alone group) that received IR plus saline, group III (control group of NSO) that received saline and did not receive NSO or IR; group IV (control group) that received only sham IR. Alterations in Total antioxidant status (TAS) and Total oxidant status (TOS), Oxidative stres index (OSI), Sulhydryl group (SH), Lipid hydroperoxide (LOOH), Paraoxonase (PON) levels, Arylesterase (ARE) and Ceruloplasmin (CER) activities in homogenized heart tissue of rats were measured by biochemical methods. Results In heart tissue of the rats in the IR alone group (group II) LOOH, TOS and OSI levels were found to be higher, ARE activity and TAS level were found to be lower than all of the other groups (p < 0.01). These results also support that IR increases oxidative stress and NSO's protective effect. Conclusion NSO would reduce the oxidative damage in the irradiated heart tissue in the experimental rat model.

Resveratrol administration prevents radiation-related changes in metabolic profiles of hearts 20 weeks after irradiation of mice with a single 2 Gy dose.

We aimed to evaluate whether resveratrol affects radiation-induced changes in metabolite profiles of the mouse heart. Hearts were irradiated in vivo with a single 2 Gy dose during the resveratrol administration and metabolite profiles of heart tissue were analyzed by the untargeted HR-MAS NMR approach twenty weeks after irradiation. The administration of resveratrol mitigated the radiation-induced decline in the content of choline-containing compounds and unsaturated lipids, which might reflect the stabilization of cell membrane structure against radiation-related damage. Results obtained with this mouse model suggest that the resveratrol supplementation may prevent metabolic changes related to radiation-induced damage in the heart.

Reducing Cardiac Radiation Dose From Breast Cancer Radiation Therapy With Breath Hold Training and Cognitive Behavioral Therapy.

The delivery of radiation therapy shares many of the challenges encountered in imaging procedures. As in imaging, such as MRI, organ motion must be reduced to a minimum, often for lengthy time periods, to effectively target the tumor during imaging-guided therapy while reducing radiation dose to nearby normal tissues. For patients, radiation therapy is frequently a stress- and anxiety-provoking medical procedure, evoking fear from negative perceptions about irradiation, confinement from immobilization devices, claustrophobia, unease with equipment, physical discomfort, and overall cancer fear. Such stress can be a profound challenge for cancer patients' emotional coping and tolerance to treatment, and particularly interferes with advanced radiation therapy procedures where active, complex and repetitive high-level cooperation is often required from the patient.In breast cancer, the most common cancer in women worldwide, radiation therapy is an indispensable component of treatment to improve tumor control and outcome in both breast-conserving therapy for early-stage disease and in advanced-stage patients. High technological complexity and high patient cooperation is required to mitigate the known cardiac toxicity and mortality from breast cancer radiation by reducing the unintended radiation dose to the heart from left breast or left chest wall irradiation. To address this, radiation treatment in daily deep inspiration breath hold (DIBH), to create greater distance between the treatment target and the heart, is increasingly practiced. While holding the promise to decrease cardiac toxicity, DIBH procedures often augment patients' baseline stress and anxiety reaction toward radiation treatment. Patients are often overwhelmed by the physical and mental demands of daily DIBH, including the nonintuitive timed and sustained coordination of abdominal thoracic muscles for prolonged breath holding.While technologies, such as DIBH, have advanced to millimeter-precision in treatment delivery and motion tracking, the "human factor" of patients' ability to cooperate and perform has been addressed much less. Both are needed to optimally deliver advanced radiation therapy with minimized normal tissue effects, while alleviating physical and cognitive distress during this challenging phase of breast cancer therapy.This article discusses physical training and psychotherapeutic integrative health approaches, applied to radiation oncology, to leverage and augment the gains enabled by advanced technology-based high-precision radiation treatment in breast cancer. Such combinations of advanced technologies with training and cognitive integrative health interventions hold the promise to provide simple feasible and low-cost means to improve patient experience, emotional outcomes and quality of life, while optimizing patient performance for advanced imaging-guided treatment procedures - paving the way to improve cardiac outcomes in breast cancer survivors.

Interior photon counting computed tomography for quantification of coronary artery calcium: pre-clinical phantom study.

Computed tomography (CT) is the reference method for cardiac imaging, but concerns have been raised regarding the radiation dose of CT examinations. Recently, photon counting detectors (PCDs) and interior tomography, in which the radiation beam is limited to the organ-of-interest, have been suggested for patient dose reduction. In this study, we investigated interior PCD-CT (iPCD-CT) for non-enhanced quantification of coronary artery calcium (CAC) using an anthropomorphic torso phantom and ex vivo coronary artery samples. We reconstructed the iPCD-CT measurements with filtered back projection (FBP), iterative total variation (TV) regularization, padded FBP, and adaptively detruncated FBP and adaptively detruncated TV. We compared the organ doses between conventional CT and iPCD-CT geometries, assessed the truncation and cupping artifacts with iPCD-CT, and evaluated the CAC quantification performance of iPCD-CT. With approximately the same effective dose between conventional CT geometry (0.30 mSv) and interior PCD-CT with 10.2 cm field-of-view (0.27 mSv), the organ dose of the heart was increased by 52.3% with interior PCD-CT when compared to CT. Conversely, the organ doses to peripheral and radiosensitive organs, such as the stomach (55.0% reduction), were often reduced with interior PCD-CT. FBP and TV did not sufficiently reduce the truncation artifact, whereas padded FBP and adaptively detruncated FBP and TV yielded satisfactory truncation artifact reduction. Notably, the adaptive detruncation algorithm reduced truncation artifacts effectively when it was combined with reconstruction detrending. With this approach, the CAC quantification accuracy was good, and the coronary artery disease grade reclassification rate was particularly low (5.6%). Thus, our results confirm that CAC quantification can be performed with the interior CT geometry, that the artifacts are effectively reduced with suitable interior reconstruction methods, and that interior tomography provides efficient patient dose reduction.

Impact of zinc oxide nanoparticles on thioredoxin-interacting protein and asymmetric dimethylarginine as biochemical indicators of cardiovascular disorders in gamma-irradiated rats.

Nanoparticle is a microscopic particle that has been existed in a wide range of biotechnological purposes. Zinc oxide nanoparticles (ZnO-NPs) have fewer environmental hazards and have shown positive impacts in the medical field. This work aimed to observe the effects of low and high doses of ZnO-NPs on heart injury induced by ionizing radiation (IR). Animals were irradiated by 8 Gy of gamma rays and ZnO-NPs (10 and 300 mg/Kg/day) were orally delivered to rats 1 hour after irradiation. Animals were dissected on 15th day postirradiation. Data showed that the oxidative damage resulted from radiation exposure, appeared by marked increments in the malondialdehyde (MDA) content and the level and protein expression of thioredoxin-interacting protein (TXNIP) with a noticeable decline in the level and expression of thioredoxin 1 (Trx-1) and thioredoxin reductase (TrxR), as well as glutathione (GSH) level and the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Moreover, radiation-induced inflammation, manifested by a noticeable elevation in the level of tumor necrotic factor-alpha (TNF-α), interleukin-18 (IL-18), and C-reactive protein (CRP). Additionally, endothelial dysfunction marked with a high level of asymmetric dimethylarginine (ADMA), total nitrite/nitrate (NOx), intercellular adhesion molecule 1 (ICAM-1), homocysteine (Hcy), creatine kinase (CK-MB), cardiac troponin-I (cTn-I), and lactate dehydrogenase (LDH). In addition, a decrease of zinc (Zn) level in the cardiac tissue was recorded. ZnO-NPs treatment (10 mg/kg) mitigated the oxidative stress and inflammation effects on the cardiovascular tissue through the positive modulations in the studied parameters. In contrast, ZnO-NPs treatment (300 mg/kg) induced cardiovascular toxicity of normal rats and elevated the deleterious effects of radiation. In conclusion, ZnO-NPs at a low dose could mitigate the adverse effects on cardiovascular tissue induced by radiation during its applications, while the high dose showed morbidity and mortality in normal and irradiated rats.

Effects of Nutritional Intervention on the Survival of Patients with Cardiopulmonary Failure Undergoing Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND/AIM: This study aimed to examine the effects of nutritional intervention on the prognosis of patients with cardiopulmonary failure undergoing extracorporeal membrane oxygenation (ECMO) therapy in Taiwan. MATERIALS AND METHODS: An institutional review board-approved retrospective study was conducted on patients receiving ECMO therapy in the intensive care unit of the China Medical University Hospital, Taiwan, from January 2013 to December 2013. The study included 102 patients with cardiopulmonary failure receiving ECMO therapy. RESULTS: The data indicated that higher survival rates were closely related to lower age and APACHE II scores among the patients. In addition, compared to patients who deceased, those who survived had a higher total calorie intake. Most patients could tolerate bolus feeding and polymeric formulas. Furthermore, patients who underwent nutritional therapy with nutritional goals greater than 80% achieved a better outcome and lower mortality than other patients. CONCLUSION: Early nutritional intervention could benefit patients undergoing ECMO, and those who reached the delivery goal of 80% had significantly better outcomes than other patients. Enteral feeding can begin early and was well tolerated by patients receiving ECMO therapy. Following individual nutrition goals is critical for better outcomes, and this analysis might be useful in establishing individualized nutrition goals for oriental population when caring for critically ill patients.

Effects of Preparatory Coaching and Home Practice for Deep Inspiration Breath Hold on Cardiac Dose for Left Breast Radiation Therapy.

AIMS: Deep inspiration breath hold (DIBH) reduces cardiac radiation exposure by creating cardiac-chest wall separation in breast cancer radiotherapy. DIBH requires sustaining chest wall expansion for up to 40 s and involves complex co-ordination of thoraco-abdominal muscles, which may not be intuitive to patients. We investigated the effect of in-advance preparatory DIBH coaching and home practice on cardiac doses. MATERIALS AND METHODS: Successive patients from 1 February 2015 to 31 December 2016 with left-sided breast cancer who underwent tangential field radiotherapy utilising the DIBH technique were included. The study cohort consisted of patients treated by a physician who routinely provided DIBH coaching and home practice instructions at least 5 days before simulation. The control group included non-coached patients under another physician's care. Minimum, maximum and mean cardiac doses and V5, V10 and V30 from DIBH and free breathing simulation computed tomography scans were obtained from the planning system. DIBH and free breathing cardiac doses and volume exposures were compared between the coached and non-coached groups using the two-sample t-test, Fisher's exact test and the Mann-Whitney U-test. RESULTS: Twenty-seven coached and 42 non-coached patients were identified. The DIBH maximum cardiac dose was lower in coached patients at 13.1 Gy compared with 19.4 Gy without coaching (P = 0.004). The percentage cardiac volume exposure in DIBH was lower in coached patients; the DIBH V10 was 0.5% without coaching and 0.1% with coaching (P = 0.005). There was also a trend towards lower DIBH V5 in the coached group compared with the non-coached group (1.2% versus 1.9%, P = 0.071). No significant differences in patient cardiopulmonary comorbidity factors that might influence cardiac doses were found between the groups. CONCLUSIONS: Our results suggest that cardiac dose sparing can potentially be further improved with a 5 day regimen of preparatory DIBH coaching and in-advance home practice before simulation. These hypothesis-generating findings should be confirmed in a larger study.

Melanin nanoparticles: Antioxidant activities and effects on γ-ray-induced DNA damage in the mouse.

The radioprotective and antioxidant activities of melanin nanoparticles (MNP) were investigated in Chinese hamster ovary (CHO) cells in vitro and BALB/C mice in vivo. The endpoints measured were cell viability, superoxide dismutase (SOD) enzyme activity, malondialdehyde (MDA) levels, DNA damage (comet assay), and histopathological examination of tissues. Irradiated groups showed decreased SOD activity and increased MDA levels. Irradiation caused a 3-10-fold increase in comet parameters such as % tail DNA. Treatment with MNP protected cells from DNA damage and death, restored SOD activity, and decreased MDA production. Synthetic MNPs have both antioxidant and radioprotective activities.

Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms.

A wide search for ischemic preconditioning (IPC) mechanisms of cardioprotection identified the light elicited circadian rhythm protein Period 2 (Per2) to be cardioprotective. Studies on cardiac metabolism found a key role for light elicited Per2 in mediating metabolic dependence on carbohydrate metabolism. To profile Per2 mediated pathways following IPC of the mouse heart, we performed a genome array and identified 352 abundantly expressed and well-characterized Per2 dependent micro RNAs. One prominent result of our in silico analysis for cardiac Per2 dependent micro RNAs revealed a selective role for miR-21 in the regulation of hypoxia and metabolic pathways. Based on this Per2 dependency, we subsequently found a diurnal expression pattern for miR-21 with higher miR-21 expression levels at Zeitgeber time (ZT) 15 compared to ZT3. Gain or loss of function studies for miR-21 using miRNA mimics or miRNA inhibitors and a Seahorse Bioanalyzer uncovered a critical role of miR-21 for cellular glycolysis, glycolytic capacity, and glycolytic reserve. Exposing mice to intense light, a strategy to induce Per2, led to a robust induction of cardiac miR-21 tissue levels and decreased infarct sizes, which was abolished in miR-21-/- mice. Similarly, first translational studies in humans using intense blue light exposure for 5 days in healthy volunteers resulted in increased plasma miR-21 levels which was associated with increased phosphofructokinase activity, the rate-limiting enzyme in glycolysis. Together, we identified miR-21 as cardioprotective downstream target of Per2 and suggest intense light therapy as a potential strategy to enhance miR-21 activity and subsequent carbohydrate metabolism in humans.

Changes of microRNA-1, -15b and -21 levels in irradiated rat hearts after treatment with potentially radioprotective drugs.

The aim of this study was to measure expression levels of microRNAs (miRNAs) (miRNA-1, -15b and -21) in the rat myocardium after a single dose of ionizing radiation (6-7 Gy/min, total 25 Gy). The rats were treated with selected drugs (Atorvastatin, acetylsalicylic acid (ASA), Tadalafil, Enbrel) for six weeks after irradiation. MiRNAs levels were measured by RT-qPCR. Irradiation down-regulated miRNA-1 in irradiated hearts. In Tadalafil- and Atorvastatin-treated groups, miRNA-1 expression levels were further decreased compared with irradiated controls. However, Enbrel increased miRNA-1 level in irradiated hearts similarly to that in non-irradiated untreated group. Increase of miRNA-15b is pro-apoptotic in relationship with ischemia. Irradiation caused down-regulation of miRNA-15b. Administration of ASA in the irradiated group resulted in the increase of miRNA-15b expression compared to non-treated controls without irradiation. After Enbrel administration, miRNA-15b levels were overexpressed compared to non-treated normal group. MiRNA-21 belongs to the most markedly up-regulated miRNAs in response to cardiogenic stress. MiRNA-21 was increased nearly 2-fold compared to non-treated hearts whereas Tadalafil reduced miRNA-21 levels (about 40 %). Our study suggests that Enbrel and Tadalafil changed miRNAs expression values of the irradiated rats to the values of non-irradiated controls, thus they might be helpful in mitigation of radiation-induced toxicity.

Chronic intermittent hypobaric hypoxia attenuates radiation induced heart damage in rats.

AIMS: Radiation-induced heart damage (RIHD) is becoming an increasing concern for patients and clinicians due to the use of radiotherapy for thoracic tumor. Chronic intermittent hypobaric hypoxia (CIHH) preconditioning has been documented to exert a cardioprotective effect. Here we hypothesized that CIHH was capable of attenuating functional and structural damage in a rat model of RIHD. MAIN METHODS: Male adult Sprague-Dawley rats were randomly divided into 4 groups: control, radiation, CIHH and CIHH plus radiation. Cardiac function was measured using Langendorff perfusion in in vitro rat hearts. Cardiac fibrosis, oxidative stress and endoplasmic reticulum stress (ERS) was assessed by quantitative analysis of protein expression. KEY FINDINGS: No significant difference between any two groups was observed in baseline cardiac function as assessed by left ventricular end diastolic pressure (LVEDP), left ventricular developing pressure (LVDP) and the derivative of left ventricular pressure (±LVdp/dt). When challenged by ischemia/reperfusion, LVEDP was increased but LVDP and ±LVdp/dt was decreased significantly in radiation group compared with controls, accompanied by an enlarged infarct size and decreased coronary flow. Importantly, CIHH dramatically improved radiation-induced damage of cardiac function and blunted radiation-induced cardiac fibrosis in the perivascular and interstitial area. Furthermore, CIHH abrogated radiation-induced increase in malondialdehyde and enhanced total superoxide dismutase activity, as well as downregulated expression levels of ERS markers like GRP78 and CHOP. SIGNIFICANCE: CIHH pretreatment alleviated radiation-induced damage of cardiac function and fibrosis. Such a protective effect was closely associated with suppression of oxidative stress and ERS responses.

Cardiovascular Disease Risk in a Large, Population-Based Cohort of Breast Cancer Survivors.

PURPOSE: To conduct a large, population-based study on cardiovascular disease (CVD) in breast cancer (BC) survivors treated in 1989 or later. METHODS AND MATERIALS: A large, population-based cohort comprising 70,230 surgically treated stage I to III BC patients diagnosed before age 75 years between 1989 and 2005 was linked with population-based registries for CVD. Cardiovascular disease risks were compared with the general population, and within the cohort using competing risk analyses. RESULTS: Compared with the general Dutch population, BC patients had a slightly lower CVD mortality risk (standardized mortality ratio 0.92, 95% confidence interval [CI] 0.88-0.97). Only death due to valvular heart disease was more frequent (standardized mortality ratio 1.28, 95% CI 1.08-1.52). Left-sided radiation therapy after mastectomy increased the risk of any cardiovascular event compared with both surgery alone (subdistribution hazard ratio (sHR) 1.23, 95% CI 1.11-1.36) and right-sided radiation therapy (sHR 1.19, 95% CI 1.04-1.36). Radiation-associated risks were found for not only ischemic heart disease, but also for valvular heart disease and congestive heart failure (CHF). Risks were more pronounced in patients aged <50 years at BC diagnosis (sHR 1.48, 95% CI 1.07-2.04 for left- vs right-sided radiation therapy after mastectomy). Left- versus right-sided radiation therapy after wide local excision did not increase the risk of all CVD combined, yet an increased ischemic heart disease risk was found (sHR 1.14, 95% CI 1.01-1.28). Analyses including detailed radiation therapy information showed an increased CVD risk for left-sided chest wall irradiation alone, left-sided breast irradiation alone, and internal mammary chain field irradiation, all compared with right-sided breast irradiation alone. Compared with patients not treated with chemotherapy, chemotherapy used ≥1997 (ie, anthracyline-based chemotherapy) increased the risk of CHF (sHR 1.35, 95% CI 1.00-1.83). CONCLUSION: Radiation therapy regimens used in BC treatment between 1989 and 2005 increased the risk of CVD, and anthracycline-based chemotherapy regimens increased the risk of CHF.

Opsin spectral sensitivity determines the effectiveness of optogenetic termination of ventricular fibrillation in the human heart: a simulation study.

KEY POINTS: Optogenetics-based defibrillation, a theoretical alternative to electrotherapy, involves expression of light-sensitive ion channels in the heart (via gene or cell therapy) and illumination of the cardiac surfaces (via implanted LED arrays) to elicit light-induced activations. We used a biophysically detailed human ventricular model to determine whether such a therapy could terminate fibrillation (VF) and identify which combinations of light-sensitive ion channel properties and illumination configurations would be effective. Defibrillation was successful when a large proportion (> 16.6%) of ventricular tissue was directly stimulated by light that was bright enough to induce an action potential in an uncoupled cell. While illumination with blue light never successfully terminated VF, illumination of red light-sensitive ion channels with dense arrays of implanted red light sources resulted in successful defibrillation. Our results suggest that cardiac expression of red light-sensitive ion channels is necessary for the development of effective optogenetics-based defibrillation therapy using LED arrays. ABSTRACT: Optogenetics-based defibrillation has been proposed as a novel and potentially pain-free approach to enable cardiomyocyte-selective defibrillation in humans, but the feasibility of such a therapy remains unknown. This study aimed to (1) assess the feasibility of terminating sustained ventricular fibrillation (VF) via light-induced excitation of opsins expressed throughout the myocardium and (2) identify the ideal (theoretically possible) opsin properties and light source configurations that would maximise therapeutic efficacy. We conducted electrophysiological simulations in an MRI-based human ventricular model with VF induced by rapid pacing; light sensitisation via systemic, cardiac-specific gene transfer of channelrhodopsin-2 (ChR2) was simulated. In addition to the widely used blue light-sensitive ChR2-H134R, we also modelled theoretical ChR2 variants with augmented light sensitivity (ChR2+), red-shifted spectral sensitivity (ChR2-RED) or both (ChR2-RED+). Light sources were modelled as synchronously activating LED arrays (LED radius: 1 mm; optical power: 10 mW mm-2 ; array density: 1.15-4.61 cm-2 ). For each unique optogenetic configuration, defibrillation was attempted with two different optical pulse durations (25 and 500 ms). VF termination was only successful for configurations involving ChR2-RED and ChR2-RED+ (for LED arrays with density ≥ 2.30 cm-2 ), suggesting that opsin spectral sensitivity was the most important determinant of optogenetic defibrillation efficacy. This was due to the deeper penetration of red light in cardiac tissue compared with blue light, which resulted in more widespread light-induced propagating wavefronts. Longer pulse duration and higher LED array density were associated with increased optogenetic defibrillation efficacy. In all cases observed, the defibrillation mechanism was light-induced depolarisation of the excitable gap, which led to block of reentrant wavefronts.

The effects of electromagnetic radiation (2450 MHz wireless devices) on the heart and blood tissue: role of melatonin.

OBJECTIVE: This study was designed to investigate the effects of 2450 MHz EMR on the heart and blood in rat and possible ameliorating effects of melatonin. MATERIAL AND METHOD: Thirty-two female Wistar Albino rats were randomly grouped (by eight in each group) as follows:  Group I: cage-control group (dimethysulfoxide (DMSO), 10mg/kg/day i.p. without stress and EMR. Group II: sham-control rats stayed in restrainer without EMR and DMSO (10mg/kg/day i.p.). Group III: rats exposed to 2450 MHz EMR. Group IV: treated group rats exposed to 2450 MHz EMR+melatonin (MLT) (10mg/kg/day i.p.). RESULTS: In the blood tissue, there was no significant difference between the groups in respect of erythrocytes GSH, GSH-Px activity, plasma LP level and vitamin A concentration (p > 0.05). However, in the Group IV, erythrocytes' LP levels (p < 0.05) were observed to be significantly decreased while plasma vitamin C, and vitamin E concentrations (p < 0.05) were found to be increased when compared to Group III. In the heart tissues, MDA and NO levels significantly increased in group III compared with groups I and II (p < 0.05). Contrary to these oxidant levels, CAT and SOD enzyme activities decreased significantly in group III compared with groups I and II (p 0.05). Besides, MLT treatment lowered the MDA and NO levels compared with group III. DISCUSSION: In conclusion, these results demonstrated that contrary to its effect on the heart, the wireless (2450 MHz) devices cause slight oxidative-antioxidative changes in the blood of rats, and a moderate melatonin supplementation may play an important role in the antioxidant system (plasma vitamin C and vitamin E). However, further investigations are required to clarify the mechanism of action of the applied 2450 MHz EMR exposure (Tab. 3, Fig. 1, Ref. 49).

Method for Correction of Consequences of Radiation-Induced Heart Disease using Low-Intensity Electromagnetic Emission under Experimental Conditions.

Effects of successive exposure to ionizing irradiation and low-intensity broadband red light on electrical activity of the heart and myocardium microstructure were studied in rats. Lowintensity red light corrected some ECG parameters, in particular, it normalized QT and QTc intervals and voltage of R and T waves. Changes in ECG parameters were followed by alterations in microstructure of muscle fi laments in the myocardium of treatment group animals comparing to control group.

A safety study of a novel photosensitizer, sinoporphyrin sodium, for photodynamic therapy in Beagle dogs.

Sinoporphyrin sodium (DVDMS) is a novel hematoporphyrin-like photosensitizer developed for photodynamic therapy (PDT), an effective therapeutic modality for tumor treatment; however, the safety of photosensitizer-based PDT is always of great concern. The purpose of the current study was to investigate the potential repeated-dose toxicity and describe the toxicokinetic process of DVDMS-based PDT in Beagle dogs. The dogs were randomly allocated to six groups, and then were administrated a DVDMS preparation intravenously at dose levels of 0, 1, 3, 9, 1 and 9 mg per kg body weight, respectively; then, the latter two groups were illuminated 24 h later with a 630 nm laser for 10 min, once every seven days for 5 weeks. During the study period, clinical signs, mortality, body weight, food consumption, body temperature, ophthalmoscopy, hematology, serum biochemistry, urinalysis, electrocardiograms, toxicokinetics, organ weights, gross anatomy and histopathology were examined. After the administration, no deaths were observed; however, the dogs that received PDT showed skin swelling and ulceration, indicating that DVDMS-PDT induced a phototoxic effect. DVDMS led to an increase in blood coagulation in dogs in the 9 mg kg(-1) group and in the two PDT groups on Day 35, whereas it induced a decrease in dogs in the 3 mg kg(-1) group and in the two PDT groups on Day 49. The toxicokinetic study showed that the systematic exposure of DVDMS in dogs occurred in a dose-dependent manner, and DVDMS did not accumulate in blood plasma. The DVDMS-based PDT group showed no obvious treatment-related pathological changes; however, slight or mild brown-and-yellow pigmentation of DVDMS (or its metabolite) was observed to deposit in the liver, spleen, local lymph nodes and marrow of dogs in the mid- and high-dose groups, as well as the high-dose PDT group. In females, the absolute and relative spleen weights increased in dogs in the 9 mg kg(-1) DVDMS groups with and without PDT during the treatment and recovery period, respectively. The target organs are presumed to be the liver and immune organs (spleen, bone marrow and lymph nodes), while all of the responses were slight. Based on the results above, the no-observed-adverse-effect level (NOAEL) was considered to be 1 mg kg(-1), and DVDMS-PDT appeared to be a safe and promising anti-tumor therapy in the clinic.

Coronary calcium score in 12-year breast cancer survivors after adjuvant radiotherapy with low to moderate heart exposure - Relationship to cardiac radiation dose and cardiovascular risk factors.

BACKGROUND/PURPOSE: We explored the relation between coronary artery calcium (CAC) and cardiac radiation doses in breast cancer survivors (BCS) treated with radiotherapy (RT). Additionally, we examined the impact of other risk factors and biomarkers of coronary artery disease (CAD). MATERIALS AND METHODS: 236 BCS (median age 51years [range 30-70], median observation time 12years [9.2-15.7]), treated with 4-field RT of 50GY, were included and examined in 2004 (T1), 2007 (T2) and 2011 (T3) with clinical examination, blood tests and questionnaires. At T3, cardiac computed tomography was performed with quantification of CAC using Agatston score (AS). For 106 patients cardiac dose volume histograms were available. RESULTS: The cohort-based median of the mean cardiac dose was 2.5 (range 0.5-7.0) Gy. There was no correlation between measures of cardiac dose and AS. AS was correlated with high cholesterol at T1/T2 (p=0.022), high proBNP at T1/T2 (p<0.022) and T3 (p<0.022) and high HbA1c at T3 (p=0.022). In addition, a high AS was significantly associated with hypertension (p=0.022). Age (p<0.001) and cholesterol at T1/T2 (p=0.001) retained significant associations in multivariate analysis. CONCLUSIONS: Traditional, modifiable risk factors of CAD correlate with CAC and may be important for the long term risk of CAD after RT. With low to moderate cardiac radiation exposure, a contribution of radiation dose to CAC could not be demonstrated.

Amelioration of cardiac function and activation of anti-inflammatory vasoactive peptides expression in the rat myocardium by low level laser therapy.

Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation.

Effect of black grape juice against heart damage from acute gamma TBI in rats.

The aim of this study was to evaluate the potential positive effect of black grape juice (BGJ) on lipid peroxidation considering Total Body Irradiation (TBI) in Wistar rats. As a potential feasible means of evaluation in situ, blood serum lactate dehydrogenase (LDH) levels were evaluated as a marker for heart damage from acute radiation syndrome (ARS). Twenty rats were divided into four groups, two of them being irradiated by gamma-rays from a Co-60 source. Animals were treated by gavage with 2 mL per day of BGJ or placebo for one week before and 4 days after 6 Gy whole body gamma-irradiation, when they were euthanasiated. LDH on serum and lipid peroxidation on heart tissue were evaluated. High concentration of metabolites from lipid peroxidation in heart, and high LDH level on serum were found only in gamma-irradiated group given placebo, mainly at the first 24 h after radiation. Phytochemical analysis of BGJ was performed by determining total phenolics, flavonoids, and tannins followed by a high-performance liquid chromatography (HPLC/DAD) analysis, which showed resveratrol as the major constituent. Results suggest that BGJ is a good protective candidate compound against heart damage from ARS and its effects suggest its use as a radiomodifier.

Protective effect of hesperidin, a citrus flavanoglycone, against γ-radiation-induced tissue damage in Sprague-Dawley rats.

The present study was designed to evaluate the radioprotective effect of hesperidin, a citrus flavanoglycone, against γ-radiation-induced cellular damage in the liver, heart, and kidney of rats. Whole-body γ-radiation exposure (5 Gy) of healthy adult rats resulted in cellular damage and oxidative stress manifested as increased levels of serum marker enzymes, lipid peroxidation, and fibrosis in the tissues, accompanied by depletion of cellular glutathione and abnormal alteration in the levels of lysosomal enzymes. Treatment with hesperidin (50 and 100 mg/kg, p.o.) for 7 days was found to offer significant protection against γ-radiation-induced toxicity in the tissues, which was evident by the improved status of most of the parameters investigated. Further, the histological examination of periodic acid-Schiff-stained tissue sections of animals treated with hesperidin following radiation exposure showed minimal necrotic damage with a recovery pattern in a dose-dependent manner compared with radiation-exposed animals. The results of our study show that administration of hesperidin offers effective protection against γ-radiation-induced cellular damage and oxidative stress in rats.