Eight Weeks of Intermittent Exercise in Hypoxia, with or without a Low-Carbohydrate Diet, Improves Bone Mass and Functional and Physiological Capacity in Older Adults with Type 2 Diabetes.

In an increasingly aging and overweight population, osteoporosis and type 2 diabetes (T2DM) are major public health concerns. T2DM patients experience prejudicial effects on their bone health, affecting their physical capacity. Exercise in hypoxia (EH) and a low-carbohydrate diet (LCD) have been suggested for therapeutic benefits in T2DM, improving bone mineral content (BMC) and glycemic control. This study investigated the effects of EH combined with an LCD on body composition and functional and physiologic capacity in T2DM patients. Older T2DM patients (n = 42) were randomly assigned to the following groups: (1) control group: control diet + exercise in normoxia; (2) EH group: control diet + EH; (3) intervention group: LCD + EH. Cardiopulmonary tests (BRUCE protocol), body composition (DEXA), and functional capacity (6MWT, handgrip strength) were evaluated. Body mass index (kg/m2) and body fat (%) decreased in all groups (p < 0.001). BMC (kg) increased in all groups (p < 0.001) and was significantly higher in the EH and EH + LCD groups (p < 0.001). VO2peak improved in all groups (p < 0.001), but more so in the hypoxia groups (p = 0.019). Functional capacity was increased in all groups (p < 0.001), but more so in the EH group in 6MWT (p = 0.030). EH with and without an LCD is a therapeutic strategy for improving bone mass in T2DM, which is associated with cardiorespiratory and functional improvements.

Combined low-carbohydrate diet and long-term exercise in hypoxia in type 2 diabetes: A randomized controlled trial protocol to assess glycemic control, cardiovascular risk factors and body composition.

Background: Cardiovascular disease is the leading cause of mortality associated with diabetes, which is characterized by chronic hyperglycemia. Low-carbohydrate diet has gained popularity as an intervention in patients with type 2 diabetes mellitus, acting to improve glycemic profile and serum lipids. In its turn, exercise in hypoxia induces specific adaptations, mostly modulated via hypoxia-induced transcription factor signaling cascade, which increases with exposure to altitude, and promotes angiogenesis, glycogen supply, glucose tolerance, and raises GLUT-4 expression. Aim: Given that hyperglycemia decreases HIF-1α and it is better controlled when following a low-carbohydrate diet, this study aims to examine the hypothesis that a combination of both low-carbohydrate diet and chronic exercise in hypoxia in type 2 diabetes mellitus is associated with improved glycemic control and cardiovascular parameters, whose protocol is described. Methods: Patients with type 2 diabetes mellitus (n = 48) will be recruited and randomized into one of the three groups: (a) Control group: Control diet (low-fat and moderate-carbohydrate diet) + exercise in normoxia; (2) exercise in hypoxia group: Control diet + exercise in hypoxia; (3) intervention group: Low-carbohydrate diet (low-carbohydrate and high-fat diet) + exercise in hypoxia. Before and after 8 weeks of interventions, cardiopulmonary tests (Bruce protocol), body composition and blood pressure will be evaluated. Blood samples will be collected to measure hypoxia-induced transcription factor, C-reactive protein, glycemic and lipid profiles. Summary: This will be the first trial to examine the isolated and combined effect of chronic exercise in hypoxia and low-carbohydrate diet in type 2 diabetes mellitus. This trial will help to fill a significant research gap, guide future research and contribute to the combined nutrition and exercise approach to type 2 diabetes mellitus.

Pharmacological and Non-Pharmacological Agents versus Bovine Colostrum Supplementation for the Management of Bone Health Using an Osteoporosis-Induced Rat Model.

Osteoporosis is defined by loss of bone mass and deteriorated bone microarchitecture. The present study compared the effects of available pharmacological and non-pharmacological agents for osteoporosis [alendronate (ALE) and concomitant supplementation of vitamin D (VD) and calcium (Ca)] with the effects of bovine colostrum (BC) supplementation in ovariectomized (OVX) and orchidectomized (ORX) rats. Seven-month-old rats were randomly allocated to: (1) placebo-control, (2) ALE group (7.5 µg/kg of body weight/day/5 times per week), (3) VD/Ca group (VD: 35 µg/kg of body weight/day/5 times per week; Ca: 13 mg/kg of body weight/day/3 times per week), and (4) BC supplementation (OVX: 1.5 g/day/5 times per week; ORX: 2 g/day/5 times per week). Following four months of supplementation, bone microarchitecture, strength and bone markers were evaluated. ALE group demonstrated significantly higher Ct.OV, Ct.BMC, Tb.Th, Tb.OV and Tb.BMC and significantly lower Ct.Pr, Tb.Pr, Tb.Sp, Ct.BMD and Tb.BMD, compared to placebo (p < 0.05). BC presented significantly higher Ct.Pr, Ct.BMD, Tb.Pr, Tb.Sp, and Tb.BMD and significantly lower Ct.OV, Ct.BMC, Tb.Th, Tb.OV and Tb.BMC compared to ALE in OVX rats (p < 0.05). OVX rats receiving BC experienced a significant increase in serum ALP and OC levels post-supplementation (p < 0.05). BC supplementation may induce positive effects on bone metabolism by stimulating bone formation, but appear not to be as effective as ALE.

The Role of ROS as a Double-Edged Sword in (In)Fertility: The Impact of Cancer Treatment.

Tumor cells are highly resistant to oxidative stress resulting from the imbalance between high reactive oxygen species (ROS) production and insufficient antioxidant defenses. However, when intracellular levels of ROS rise beyond a certain threshold, largely above cancer cells' capacity to reduce it, they may ultimately lead to apoptosis or necrosis. This is, in fact, one of the molecular mechanisms of anticancer drugs, as most chemotherapeutic treatments alter redox homeostasis by further elevation of intracellular ROS levels or inhibition of antioxidant pathways. In traditional chemotherapy, it is widely accepted that most therapeutic effects are due to ROS-mediated cell damage, but in targeted therapies, ROS-mediated effects are mostly unknown and data are still emerging. The increasing effectiveness of anticancer treatments has raised new challenges, especially in the field of reproduction. With cancer patients' life expectancy increasing, many aiming to become parents will be confronted with the adverse effects of treatments. Consequently, concerns about the impact of anticancer therapies on reproductive capacity are of particular interest. In this review, we begin with a short introduction on anticancer therapies, then address ROS physiological/pathophysiological roles in both male and female reproductive systems, and finish with ROS-mediated adverse effects of anticancer treatments in reproduction.

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice.

Pd2Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd2Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd2Spm (5 mg/kg/day) or cisplatin (2 mg/kg/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd2Spm was observed in MDA-MB-231 cells (IC50 values of 7.3-8.3 µM), with at least 10-fold lower activity in MCF-12A cells (IC50 values of 89.5-228.9 µM). Pd2Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd2Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd2Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd2Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.

A Neuroprotective Bovine Colostrum Attenuates Apoptosis in Dexamethasone-Treated MC3T3-E1 Osteoblastic Cells.

Glucocorticoid-induced osteoporosis (GIO) is one of the most common secondary forms of osteoporosis. GIO is partially due to the apoptosis of osteoblasts and osteocytes. In addition, high doses of dexamethasone (DEX), a synthetic glucocorticoid receptor agonist, induces neurodegeneration by initiating inflammatory processes leading to neural apoptosis. Here, a neuroprotective bovine colostrum against glucocorticoid-induced neuronal damage was investigated for its anti-apoptotic activity in glucocorticoid-treated MC3T3-E1 osteoblastic cells. A model of apoptotic osteoblastic cells was developed by exposing MC3T3-E1 cells to DEX (0-700 µM). Colostrum co-treated with DEX was executed at 0.1-5.0 mg/mL. Cell viability was measured for all treatment schedules. Caspase-3 activation was assessed to determine both osteoblast apoptosis under DEX exposure and its potential prevention by colostrum co-treatment. Glutathione reduced (GSH) was measured to determine whether DEX-mediated oxidative stress-driven apoptosis is alleviated by colostrum co-treatment. Western blot was performed to determine the levels of p-ERK1/2, Bcl-XL, Bax, and Hsp70 proteins upon DEX or DEX plus colostrum exposure. Colostrum prevented the decrease in cell viability and the increase in caspase-3 activation and oxidative stress caused by DEX exposure. Cells, upon colostrum co-treated with DEX, exhibited higher levels of p-ERK1/2 and lower levels of Bcl-XL, Bax, and Hsp70. Our data support the notion that colostrum may be able to reduce DEX-induced apoptosis possibly via the activation of the ERK pathway and modulation of the Hsp70 system. We provided preliminary evidence on how bovine colostrum, as a complex and multi-component dairy product, in addition to its neuroprotective action, may affect osteoblastic cell survival undergoing apoptosis.

Bovine Colostrum Supplementation Improves Bone Metabolism in an Osteoporosis-Induced Animal Model.

Osteoporosis is characterized by bone loss. The present study aims to investigate the effects of bovine colostrum (BC) on bone metabolism using ovariectomized (OVX) and orchidectomized (ORX) rat models. Twenty-seven-week-old Wistar Han rats were randomly assigned as: (1) placebo control, (2) BC supplementation dose 1 (BC1: 0.5 g/day/OVX, 1 g/day/ORX), (3) BC supplementation dose 2 (BC2: 1 g/day/OVX, 1.5 g/day/ORX) and (4) BC supplementation dose 3 (BC3: 1.5 g/day/OVX, 2 g/day/ORX). Bone microarchitecture, strength, gene expression of VEGFA, FGF2, RANKL, RANK and OPG, and bone resorption/formation markers were assessed after four months of BC supplementation. Compared to the placebo, OVX rats in the BC1 group exhibited significantly higher cortical bone mineral content and trabecular bone mineral content (p < 0.01), while OVX rats in the BC3 group showed significantly higher trabecular bone mineral content (p < 0.05). ORX rats receiving BC dose 2 demonstrated significantly higher levels of trabecular bone mineral content (p < 0.05). Serum osteocalcin in the ORX was pointedly higher in all BC supplementation groups than the placebo (BC1: p < 0.05; BC2, BC3: p < 0.001). Higher doses of BC induced significantly higher relative mRNA expression of OPG, VEGFA, FGF2 and RANKL (p < 0.05). BC supplementation improves bone metabolism of OVX and ORX rats, which might be associated with the activation of the VEGFA, FGF2 and RANKL/RANK/OPG pathways.

Associations between nutrition, energy expenditure and energy availability with bone mass acquisition in dance students: a 3-year longitudinal study.

Three years of study showed that female and male vocational dancers displayed lower bone mass compared to controls, at forearm, lumbar spine and femoral neck. Energy intake was found to positively predict bone mass accruals only in female dancers at femoral neck. Vocational dancers can be a risk population to develop osteoporosis. PURPOSE: To determine whether risk factors normally associated with low bone mass in athletic populations (i.e. nutrition intake, energy expenditure and energy availability) are significant predictors of bone mass changes in vocational dance students. METHODS: The total of 101 vocational dancers (63 females, 12.8 ± 2.2 years; 38 males, 12.7 ± 2.2 years) and 115 age-matched controls (68 females, 13.0 ± 2.1 years; 47 males, 13.0 ± 1.8 years) were monitored for 3 consecutive years. Bone mass parameters were measured annually at impact sites (femoral neck, FN; lumber spine, LS) and non-impact site (forearm) using DXA. Nutrition (3-day record), energy expenditure (accelerometer), energy availability and IGF-1 serum concentration (immunoradiometric assays) were also assessed. RESULTS: Female and male vocational dancers had consistently reduced bone mass at all anatomical sites (p < 0.001) than controls. IGF-1 did not differ between male vocational dancers and controls, but female dancers showed it higher than controls. At baseline, calcium intake was significantly greater in female vocational dancers than controls (p < 0.05). Male vocational dancers' fat and carbohydrate intakes were significantly lower than matched controls (p < 0.001 and p < 0.05, respectively). Energy availability of both female and male vocational dancers was within the normal range. A significant group effect was found at the FN regarding energy intake (p < 0.05) in female dancers. No significant predictors were found to explain bone mass differences in males. CONCLUSION: Our 3-year study revealed that both female and male vocational dancers displayed lower bone mass compared to controls, at both impact and non-impact sites. The aetiology of these findings may be grounded on factors different than those usually considered in athletic populations.

Sulfated Oligomers of Tyrosol: Toward a New Class of Bioinspired Nonsaccharidic Anticoagulants.

Sulfated phenolic polymers have extensively been investigated as anticoagulant agents in view of their higher bioavailability and resistance to degradation compared to heparins, allowing for increased half-lives. In this frame, we report herein the preparation of sulfated derivatives of tyrosol, one of the most representative phenolic constituents of extra virgin olive oil, by different approaches. Mild sulfation of OligoTyr, a mixture of tyrosol oligomers, that has been reported to possess antioxidant properties and osteogenic activity, afforded OligoTyrS I in good yields. Elemental analysis, NMR, and MALDI-MS investigation provided evidence for an almost complete sulfation at the OH on the phenylethyl chain, leaving the phenolic OH free. Peroxidase/H2O2 oxidation of tyrosol sulfated at the alcoholic group (TyrS) also provided sulfated tyrosol oligomers (OligoTyrS II) that showed on structural analysis highly varied structural features arising likely from the addition of oxygen, derived from water or hydrogen peroxide, to the intermediate quinone methides and substantial involvement of the phenolic OH group in the oligomerization. In line with these characteristics, OligoTyrS I proved to be more active than OligoTyrS II as antioxidant in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) assays and as anticoagulant in the classical clotting times, mainly in prolonging the activated partial thromboplastin time (APTT). After intraperitoneal administration in mice, OligoTyrS I was also able to significantly decrease the weight of an induced thrombus. Data from chromogenic coagulation assays showed that the anticoagulant effect of OligoTyrS I was not dependent on antithrombin or factor Xa and thrombin direct inhibition. These results clearly highlight how some structural facets of even closely related phenol polymers may be critical in dictating the anticoagulant activity, providing the key for the rationale design of active synthetic nonsaccharidic anticoagulant agents alternative to heparin.

Endocrine parameters in association with bone mineral accrual in young female vocational ballet dancers.

Less is known on bone mass gains in dancers involved in vocational dance training. The present study found that, as young vocational dancers progress on their professional training, their bone health remains consistently lower compared to non-exercising controls. Endocrine mechanisms do not seem to explain these findings. PURPOSE: Little is known on bone mass development in dancers involved in vocational training. The aim of the present study was to model bone mineral content (BMC) accruals and to determine whether circulating levels of oestrogens, growth hormone (GH), and insulin-like growth factor I (IGF-1) explain differences in bone mass gains between vocational dance students and matched controls. METHODS: The total of 67 vocational female dancers (VFDs) and 68 aged-matched controls (12.1 ± 1.9 years and 12.7 ± 2.0 years at baseline, respectively) were followed for two consecutive years (34 VFD and 31 controls remained in the study for the full duration). BMC was evaluated annually at impact [femoral neck (FN); lumbar spine (LS)] and non-impact sites (forearm) using DXA. Anthropometry, age at menarche (questionnaire), and hormone serum concentrations (immunoradiometric assays) were also assessed for the same period. RESULTS: VFD demonstrated consistently reduced body weight (p < 0.001) and BMC at all three anatomical sites (p < 0.001) compared to controls throughout the study period. Menarche, body weight, GH, and IGF-1 were significantly associated with bone mass changes over time (p < 0.05) but did not explain group differences in BMC gains at impact sites (p > 0.05). However, body weight did explain the differences between groups in terms of BMC gains at the forearm (non-impact site). CONCLUSION: Two consecutive years of vocational dance training revealed that young female dancers demonstrate consistently lower bone mass compared to controls at both impact and non-impact sites. The studied endocrine parameters do not seem to explain group differences in terms of bone mass gains at impact sites.

The Antitumor Activity of a Lead Thioxanthone is Associated with Alterations in Cholesterol Localization.

The search for novel anticancer small molecules and strategies remains a challenge. Our previous studies have identified TXA1 (1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H- thioxanthen-9-one) as a hit compound, with in vitro antitumor potential by modulating autophagy and apoptosis in human tumor cell lines. In the present study, the mechanism of action and antitumor potential of the soluble salt of this molecule (TXA1.HCl) was further investigated using in vitro and mouse xenograft tumor models of NSCLC. Our results showed that TXA1.HCl affected steroid biosynthesis, increased RagD expression, and caused abnormal cellular cholesterol localization. In addition, TXA1.HCl treatment presented no toxicity to nude mice and significantly reduced the growth of human NSCLC cells xenografts in mice. Overall, this work provides new insights into the mechanism of action of TXA1, which may be relevant for the development of anticancer therapeutic strategies, which target cholesterol transport.

Bone mass of female dance students prior to professional dance training: A cross-sectional study.

BACKGROUND: Professional dancers are at risk of developing low bone mineral density (BMD). However, whether low BMD phenotypes already exist in pre-vocational dance students is relatively unknown. AIM: To cross-sectionally assess bone mass parameters in female dance students selected for professional dance training (first year vocational dance students) in relation to aged- and sex-matched controls. METHODS: 34 female selected for professional dance training (10.9yrs ±0.7) and 30 controls (11.1yrs ±0.5) were examined. Anthropometry, pubertal development (Tanner) and dietary data (3-day food diary) were recorded. BMD and bone mineral content (BMC) at forearm, femur neck (FN) and lumbar spine (LS) were assessed using Dual-Energy X-Ray Absorptiometry. Volumetric densities were estimated by calculating bone mineral apparent density (BMAD). RESULTS: Dancers were mainly at Tanner pubertal stage I (vs. stage IV in controls, p<0.001), and demonstrated significantly lower body weight (p<0.001) and height (p<0.01) than controls. Calorie intake was not different between groups, but calcium intake was significantly greater in dancers (p<0.05). Dancers revealed a significantly lower BMC and BMD values at all anatomical sites (p<0.001), and significantly lower BMAD values at the LS and FN (p<0.001). When adjusted for covariates (body weight, height, pubertal development and calcium intake), dance students continued to display a significantly lower BMD and BMAD at the FN (p<0.05; p<0.001) at the forearm (p<0.01). CONCLUSION: Before undergoing professional dance training, first year vocational dance students demonstrated inferior bone mass compared to controls. Longitudinal models are required to assess how bone health-status changes with time throughout professional training.

Prevalence of low bone mineral density in female dancers.

BACKGROUND AND OBJECTIVE: While some authors report that dancers have reduced bone mineral density (BMD) and increased risk of osteoporosis, others have stressed the positive effects of dance training on developing healthy BMD. Given the existing controversy, the aim of this systematic review was to examine the best evidence-based information available in relation to female dancers. METHODS: Four databases (Web of Science, PubMed, EBSCO, Scopus) and two dance science journals (Journal of Dance Medicine and Science and Medical Problems of Performing Artists) were searched for relevant material using the keywords "dance", "ballet", "BMD", "bone density", "osteoporosis" and "female athlete triad syndrome". A total of 257 abstracts were screened using selected inclusion (studies involving bone measurements in dancers) and exclusion (editorials, opinion papers, chapters in books, narrative reviews and non-English language papers) criteria according to PRISMA guidelines. Following the above screening, a total of 108 abstracts were identified as potentially relevant. After the exclusion of conference proceedings, review papers, studies focusing only in male dancers and studies in which dancers' information were combined with other athletes, the eligible papers were subsequently assessed using the GRADE system and grouped according to: (1) prevalence of low BMD and associated factors, (2) incidence of low BMD and risk factors, (3) prevention/treatment of low BMD in dancers, and (4) other studies. RESULTS: Of the 257 abstracts that were initially screened, only 35 studies were finally considered. Only one of these 35 was of high quality, while the remaining 34 were of relatively low quality. Seven studies reported prevalence of low BMD and associated factors, 10 reported associated factors with no prevalence data, while one reported prevalence with no associated factors data. One study cited risk factors, while another one elaborated on the treatment of low BMD in dancers. The remaining 15 studies were classified as "other studies". CONCLUSIONS: It remains unclear whether low BMD is prevalent in female dancers. The present review highlights the need for high-quality BMD research in this area.

Biochemical impact of soccer: an analysis of hormonal, muscle damage, and redox markers during the season.

This study aimed to analyze changes in performance, muscle function, and stress-related biochemical markers in professional soccer players (n = 14) at 4 timepoints (3 for performance and 4 for stress-related biochemical markers) during the soccer season [Formula: see text] preseason (E1), midseason (E2), end of the season (E3) [Formula: see text] and after the end of the recovery period (E4). Performance in 5- and 30-m sprints, countermovement jump, and agility, and maximal isokinetic knee extension and knee flexion strength were measured (E1 to E3). We observed increased in-season levels of myoglobin (E2 > E1 and E4; p < 0.05), a higher testosterone/cortisol ratio (T/C), and increased levels of creatine kinase (CK), C-reactive protein, superoxide dismutase (SOD), protein sulfhydryls (-SH), and malondialdehyde (E2 and E3 > E1 and E4; p < 0.05). Lower cortisol concentrations (E3 < E1 and E4; p < 0.05) and glutathione reductase activity (E3 < E2 and E4; p < 0.05) were observed at the end of the season. T/C, CK, SOD, -SH, and malondialdehyde decreased during the off-season, and cortisol and glutathione reductase increased (E3 < E4; p < 0.05). Agility increased in E2 and E3 (p < 0.01). Significant correlations were found during the season between hormonal and muscle function parameters (r = 0.56-0.86; p < 0.05). In addition, in E2, significant associations were observed between match-accumulated time (MATE2; minutes played by each player during the competition period), performance, and hormonal and redox parameters (r = 0.456-0.615; p < 0.05). In conclusion, this study shows that soccer players face significant changes in biomarkers of physiologic strain (muscle damage and oxidative stress-related markers) during the season, but values return to normal during the off-season. Additionally, MAT influences physical, hormonal, and oxidative stress-related parameters in professional soccer players.

Neuromuscular function, hormonal and redox status and muscle damage of professional soccer players after a high-level competitive match.

The main aim was to analyse the impact of an official match on hormonal and redox status, muscle damage and inflammation and neuromuscular function. Seven high-level male soccer players from the same team performed an official match and data were collected 72 h before, 24, 48 and 72 h post-match. Plasma testosterone/cortisol ratio (T/C), creatine kinase (CK), superoxide dismutase (SOD), glutathione peroxidase (GPX) and reductase (GR) activities, myoglobin (Mb), C-reactive protein (CRP), uric acid (UA), protein sulfhydryls (-SH), malondialdehyde (MDA) concentrations and total antioxidant status (TAS) were measured. Sprint, jump and change of direction performance, and maximal isokinetic knee extension and flexion were obtained as neuromuscular functional parameters. Cortisol increased and T/C decreased until 48 h recovery (P < 0.05). Mb, CRP and -SH (P < 0.05) increased at 24 h and CK, TAS, SOD and MDA (P < 0.05) increased up to 48 h recovery. GR increased and GPX decreased at 24 h recovery (P < 0.05). Jump performance decreased 24 h post-match (P < 0.05), but no significant alterations in sprint, change of direction and muscle strength were observed. In conclusion, an official match resulted in changes in plasma biomarkers until 48 h of recovery period, without major impact on performance.

Primary cardiac sarcoma after breast cancer.

Primary cardiac sarcomas are rare tumours carrying poor prognosis. Postradiation sarcoma has been reported in patients with breast, cervical and head and neck cancers. We report a case of a 56-year-old woman with stage IIA breast cancer diagnosed in 1997, submitted to mastectomy, adjuvant chemotherapy, radiotherapy and hormonotherapy. Pulmonary metastasis were detected in 2008 and treated with chemotherapy and hormonotherapy, being in complete remission since August 2009. She was admitted in December 2009 with a 3-week history of fever, dyspnoea, polyarthralgias and leg oedema. An echocardiography showed a mass in the left atrium. She was submitted to a surgical tumour resection and the histology revealed a sarcoma of intermediate degree of differentiation. Chemoradiation therapy was started and she remains alive after 3 years, without tumour regrowth or metastasis. This case is a therapeutic challenge, because the previous therapies for breast cancer hampered the options for extra chemoradiation therapy.

Influence of dietary supplementation with dextrin or oligofructose on the hepatic redox balance in rats.

We assessed the impact of oligofructose (OFS) and dextrin (DEX) as diet supplements on hepatic redox state. Rats were fed either a 10% OFS or a 10% DEX supplemented diet for 9 wk. In the DEX diet group, the levels of hepatic protein carbonylation were decreased by 63%. Total glutathione and reduced glutathione (GSH) contents were reduced in the OFS and DEX diet groups by around 20%. DEX supplementation significantly reduced oxidized glutathione (GSSG) levels resulting in a 33% increase in the GSH/GSSG ratio. The activity of the hepatic antioxidant enzymes was not changed by either OFS or DEX supplementation. OFS supplementation caused a decrease in serum levels of triglycerides (36%), cholesterol (24%), HDL (16%) and LDL (17%). DEX supplementation only reduced triglycerides (32%) and urea (22%). Both diets increased serum levels of acetate by fivefold and propionate by twofold, but DEX diet decreased butyrate levels by 75%. Due to their different composition/structure these two dietary fibers affected metabolism in different ways. Diet supplementation with 10% DEX can potentially improve host health, by protecting the liver from protein carbonylation and by improving GSH/GSSG ratio and diet supplementation with 10% OFS can improve the lipid profile.

Polysulfated xanthones: multipathway development of a new generation of dual anticoagulant/antiplatelet agents.

A multipathway strategy was used to evaluate the in vitro and in vivo antithrombotic effects of a new synthetic family of sulfated small molecules. Polysulfated xanthonosides showed highly effective anticoagulation effects in vitro, both in plasma (clotting times) and in whole human blood (thromboelastography), as well as in vivo (ip administration, mice). Physicochemical properties were assessed for mangiferin heptasulfate (7), which showed high solubility and stability in water and in human plasma and no putative hepatotoxicity in vivo. Mangiferin heptasulfate (7) was found to be a direct inhibitor of FXa, while persulfated 3,6-(O-ß-glucopyranosyl)xanthone (13) acted as a dual inhibitor of FXa (directly and by antithrombin III activation). By impedance aggregometry, compounds 7 and 13 exhibited the antiplatelet effect by inhibition of both arachidonic acid and ADP-induced platelet aggregation. Dual anticoagulant/antiplatelet agents, such as sulfated xanthonosides 7 and 13, are expected to lead to a new therapeutic approach for the treatment of both venous and arterial thrombosis.

Dual anticoagulant/antiplatelet persulfated small molecules.

A new series of persulfated compounds was synthesized and assayed for in vitro anticoagulant and antiplatelet activities, which may be useful in the treatment of both venous and arterial thrombosis. Persulfation of polyphenolic components of wine, coumarins and other structurally diverse small molecules was achieved with triethylamine-sulphur trioxide adduct. The derivatives were highly effective in increasing the APTT, being trans-resveratrol 3-ß-D-glucopyranoside persulfate (15) the most potent (APTT2=1.5×10(-4) M), and were able to completely block the clotting process at the highest concentration. Compound 15 showed good stability in human plasma and anticoagulation effects in whole blood. trans-Resveratrol 3-ß-D-glucopyranoside persulfate (15) and a series of polysulfated oligoflavonoids (1-4) also exhibited antiplatelet activity by inhibition of arachidonic acid and ADP-induced platelet aggregation.

Flavonoids with an oligopolysulfated moiety: a new class of anticoagulant agents.

Polysulfated (oligo)flavonoids were synthesized and assayed for their in vitro and in vivo anticoagulant activities. The approach was based on molecular hybridization of two classes of anticoagulants, sulfated polysaccharides and sulfated flavonoids. The synthesis was optimized using microwave-assisted sulfation with triethylamine-sulfur trioxide. The obtained polysulfated flavonosides were highly effective in increasing clotting times and able to completely block the clotting process, in contrast to their corresponding aglycones. The thromboelastography proved that polysulfated flavonosides possess good whole blood anticoagulation activity. The following structure-activity relationships were found: 3-O-rutinosides (10, 13) were direct inhibitors of FXa, while 7-O-rutinosides (7, 8) showed inhibition of FXa by ATIII activation. Furthermore, compounds 7 and 13 were stable in plasma and active in vivo and preliminary toxicity studies would lead us to rule out acute side effects. From the overall results, the polysulfated flavonosides showed the potential as new effective and safe agents for anticoagulant therapy.