[Predictive factors for mandibular osteoradionecrosis after irradiation of head and neck cancers]. / Facteurs prédictifs de l'ostéoradionécrose mandibulaire après irradiation des cancers des voies aérodigestives supérieures.

The identification of the different risk factors for mandibular osteoradionecrosis (ORN) must be done before and after the management of patients with head and neck cancer. Various clinical criteria for this severe radiation-induced complication are related to the patient (intrinsic radiosensitivity, malnutrition associated with thin weight loss, active smoking intoxication, microcapillary involvement, precarious oral status, hyposalivation) and/or related to the disease (oral cavity, large tumor size, tumor mandibular invasion). Therapeutic risk factors are also associated with a higher risk of ORN (primary tumor surgery, concomitant radio-chemotherapy, post-irradiation dental avulsion, preventive non-observance with the absence of stomatological follow-up and daily installation of gutters fluoride and, non-observance curative healing treatments). Finally, various dosimetric studies have specified the parameters in order to target the dose values distributed in the mandible, which increases the risk of ORN. An mean mandibular dose greater than 48-54Gy and high percentages of mandibular volume receiving 40 to 60Gy appear to be discriminating in the risk of developing an ORN.

AhR and IDO1 in pathogenesis of Covid-19 and the "Systemic AhR Activation Syndrome:" a translational review and therapeutic perspectives.

Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.

Potential Protective Effect of Dietary Intake of Non-α-Tocopherols on Cellular Aging Markers Mediated by Tumor Necrosis Factor-α in Prediabetes: A Cross-Sectional Study of Chinese Adults.

It remains unknown how different glucose tolerance status affects the relationships between dietary intake of different tocopherol isoforms (α-, ß-, γ-, and δ-tocopherol) and cellular aging, oxidative stress, and inflammatory markers. The authors conducted a cross-sectional study among 582 Chinese adults with different glucose tolerance status to explore the association between dietary intake of different tocopherol isoforms and cellular aging, oxidative stress, and inflammatory markers. The inverse correlations between non-α-tocopherols and tumor necrosis factor-alpha (TNF-α) varied substantially across different glucose tolerance status, with the strongest observed in prediabetes (r = -0.33 for ß-/γ-tocopherol, r = -0.37 for δ-tocopherol, p < 0.01), followed by normal glucose tolerance (NGT). While such correlations were abolished in established diabetes. Furthermore, within prediabetes, the strongest inverse correlations between non-α-tocopherols and TNF-α were observed in impaired fasting glucose (IFG) (r = -0.42 for ß-/γ-tocopherol, r = -0.55 for δ-tocopherol, p < 0.01), while such correlations were significantly attenuated in individuals with impaired glucose tolerance (IGT) and IFG+IGT. And mediation model analysis displayed that TNF-α mediated the protective effect of non-α-tocopherols on leukocyte telomere length and mitochondrial DNA copy number, which was uniquely observed in prediabetes, while such mediation effect was statistically nonsignificant in NGT and established diabetes. In conclusion, our findings indicate that dietary intake of non-α-tocopherols might protect against cellular aging markers mediated by TNF-α in prediabetes. Individuals with prediabetes, especially for IFG, might benefit from increasing dietary intake of non-α-tocopherol in alleviating inflammation and cellular aging, which might provide a new dietary avenue for delaying diabetes onset.

Nutrient stability in mould-infested feed and mitigating effect of dietary supplemental vitamins in brown laying hens.

A 10-week study was conducted to assess the impact of mould infestation on nutrient stability of feed and the mitigating effect of supplemental tocopherol, retinol or a multivitamin on performance and hepatic histology of ISA Brown laying chickens. Two batches of corn were obtained: the aflasafe corn used in preparing control diet and corn with physical evidence of mould used in preparing diets 2 to 5 containing no supplemental vitamin, tocopherol, retinol or a branded multivitamin supplementations respectively. One hundred and fifty (150) laying chickens used were completely randomized into five dietary treatments with three replicates of 10 birds each. Results showed that there was gross instability in the nutrients of mouldy maize. The activities of the fungi depleted both protein and lipid contents by 11.54% and 12.72% respectively while crude fibre content rose by 31.7%. There was substantial drop in both retinol and tocopherol while aflatoxin content rose to 267 µg in mouldy corn and 118 µg in the mouldy diets. Feed intake was significantly (P < 0.05) reduced and consequently depressed (P < 0.05) egg production and feed efficiency. Egg quality differs (P < 0.05) in shell thickness and yolk colour. Proliferation of biliary duct epithelium, hepatic degeneration, cellular infiltration, hyper-cellularity or dilation of the sinusoidal spaces characterized livers of birds on mouldy corn diets while supplementation with vitamins subverted mycosis and aflatoxicosis as evidenced by normal-to-mild congestion of hepatocytes. It was concluded that mould contamination in feed compromised feed nutritive values, reduced bird performance and adversely impaired the liver of the experimental birds while tocopherol, retinol or a multivitamin supplementation relapses the damaging potential of mould and mycotoxin differently.

Randomised trial of chronic supplementation with a nutraceutical mixture in subjects with non-alcoholic fatty liver disease.

A mixture of natural ingredients, namely, DHA, phosphatidylcholine, silymarin, choline, curcumin and d-α-tocopherol, was studied in subjects with non-alcoholic fatty liver disease (NAFLD). Primary endpoints were serum levels of hepatic enzymes, and other parameters of liver function, the metabolic syndrome and inflammation were the secondary endpoints. The coagulation-fibrinolysis balance was also thoroughly investigated, as NAFLD is associated with haemostatic alterations, which might contribute to increased cardiovascular risk of this condition. The present study involved a double-blind, randomised, multicentre controlled trial of two parallel groups. Subjects with NAFLD (18-80 years, either sex) received the active or control treatment for 3 months. All assays were performed on a total of 113 subjects before and at the end of supplementation. The hepatic enzymes aspartate aminotransferase (AST), alanine aminotransferase and γ-glutamyl transpeptidase decreased from 23·2 to 3·7 % after treatment, only the AST levels reaching statistical significance. However, no differences were found between control and active groups. Metabolic and inflammatory variables were unchanged, except for a slight (less than 10 %) increase in cholesterol and glucose levels after the active treatment. Coagulation-fibrinolytic parameters were unaffected by either treatment. In conclusion, chronic supplementation with the mixture of dietary compounds was well tolerated and apparently safe in NAFLD subjects. The trial failed to demonstrate any efficacy on relevant physiopathological markers, but its protocol and results may be useful to design future studies with natural compounds.

New trends in adjunctive treatment and diagnosis in medication-related osteonecrosis of the jaw: A 10-year review.

Medication-related osteonecrosis of the jaw (MRONJ) is a major disease under study for over the last twenty years. Different classifications have been proposed and many therapies for the different stages have been applied. The evolution of treatments lead to an increasingly conservative approach. Numerous adjuvant treatments have been proposed in the last decade. All these complementary treatments have been proposed mainly to resolve or reduce the painful stress, predominantly caused by bacterial infection, simplifying the wound healing process and improving patients' compliance. Nowadays "secondary" treatments, such as autologous platelet concentrates (APCs, more specifically PRP, PRGF or PRF), hyperbaric oxygen (HBO), Auto/tetracycline fluorescence-guided bone surgery (AF-GBS/TF-GBS), medical drugs like teriparatide or the combination between pentoxifylline and tocopherol, fluorodeoxyglucose positron emission tomography (FDG-PET), laser and/or low-laser therapy and ozone therapy are more or less well documented and known considering their clinical effectiveness. The aim of the present review is the evaluation of the quantity and quality of scientific studies concerning this specific topic.

Challenges threaten, opportunity awaits hyperbaric medicine and the head and neck cancer patient.

Over the past four decades, hyperbaric oxygen (HBO2) therapy has played a prominent role in both the prevention and treatment of mandibular osteoradionecrosis (ORN). It has done so on the strength of laboratory observations and clinical reports, yet only limited efficacy data. This dual role has come under increasing scrutiny in the modern radiotherapy (RT) and surgical eras. The ability to spare healthy "non-target" tissue has markedly improved since the two-dimensional planning and delivery techniques in use when HBO2's prophylactic value was first demonstrated. A recent study failed to identify this same benefit in patients who received high-precision imaging and conformal RT. HBO2 therapy is under challenge as preferred treatment for early stage ORN. A recently introduced "fibroatrophic" mechanism contrasts with the hypovascular-hypocellular-hypoxic injury pattern that formed the basis for HBO2's therapeutic use. This alternative pathophysiologic state appears to benefit from an oral antioxidant medication regimen. The continuing necessity of HBO2 in support of mandibular reconstruction for advanced ORN is in question. Microsurgery-based vascularized bone flaps increasingly represent standard care, invariably in the absence of perioperative HBO2. Renewed interest in hyperbaric oxygen as a radiation sensitizer offers some promise. Hypoxia remains a critical radio-resistant factor in many solid tumors. Malignant gliomas have been a primary focus of several small studies, with resulting improvements in local control and median survival. Hyperbaric radiation sensitization has recently addressed oropharyngeal cancer. Preliminary data indicates that addition of HBO2 to chemo-radiation standard of care is technically feasible, well tolerated and safe. A Phase II efficacy trial will investigate the potential for of HBO2 to improve progression-free and relapse-free survival in newly diagnosed locally advanced head and neck cancers. What follows is a review and summary of relevant peer-reviewed literature.

Protocol for prospective randomised assessor-blinded pilot study comparing hyperbaric oxygen therapy with PENtoxifylline+TOcopherol± CLOdronate for the management of early osteoradionecrosis of the mandible.

INTRODUCTION: Osteoradionecrosis (ORN) of the mandible is a painful and debilitating condition occurring after radiotherapy to the head and neck to treat cancer. For decades, hyperbaric oxygen (HBO) has formed the mainstay of the early management of ORN. Literature about the efficacy of HBO is contentious. Recently, Oral and Maxillofacial surgical units in France and UK have trialled a combination of medications to treat ORN, also known as PENTOCLO (PENtoxifylline+TOcopherol±CLOdronate). This regime has shown promising results to date however randomised controlled trials in the area comparing HBO against PENTOCLO are lacking and there are no current trials registered in Europe, UK, Australia and the USA. The purpose of this pilot study is to generate a hypothesis that can be tested in large multi-centre controlled trials. METHODS AND ANALYSIS: For this pilot study we will recruit 16 patients who will be randomly allocated to one of either HBO or PENTOCLO. After a 4 week period of uniform 'pre-treatment' medication patients will be commenced on their allocated treatment. Standard follow-up examination, imaging and photographs will be taken and de-identified and then presented to two Oral and Maxillofacial surgeons for allocation of a Notani & Lyons classification score. Data for each patient will be tracked over the 18 months of treatment and follow-up. The results will then be analysed using descriptive statistics and all patients included in an intention to treat analysis. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the South Metropolitan Health Service HREC (PRN RGS0000001193). Data generated by conducting this study will be uploaded to an open access repository in a de-identified form. Results from this study will be disseminated at national and international conferences as well as peer reviewed medical publications. TRIAL REGISTRATION NUMBER: ACTRN12618001099213; Pre-results.

Redox-regulation of haemostasis in hypoxic exercising humans: a randomised double-blind placebo-controlled antioxidant study.

KEY POINTS: In vitro evidence has identified that coagulation is activated by increased oxidative stress, though the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial in healthy participants to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise given their synergistic capacity to promote free radical formation. Systemic free radical formation was shown to increase during hypoxia and was further compounded by exercise, responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation at rest in normoxia, and this was normalised only in the face of prevailing oxidation. Collectively, these findings suggest that human free radical formation is an adaptive phenomenon that serves to maintain vascular haemostasis. ABSTRACT: In vitro evidence suggests that blood coagulation is activated by increased oxidative stress although the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise. Healthy males were randomly assigned double-blind to either an antioxidant (n = 20) or placebo group (n = 16). The antioxidant group ingested two capsules/day that each contained 500 mg of l-ascorbic acid and 450 international units (IU) of dl-α-tocopherol acetate for 8 weeks. The placebo group ingested capsules of identical external appearance, taste and smell (cellulose). Both groups were subsequently exposed to acute hypoxia and maximal physical exercise with venous blood sampled pre-supplementation (normoxia), post-supplementation at rest (normoxia and hypoxia) and following maximal exercise (hypoxia). Systemic free radical formation (electron paramagnetic resonance spectroscopic detection of the ascorbate radical (A•- )) increased during hypoxia (15,152 ± 1193 AU vs. 14,076 ± 810 AU at rest, P < 0.05) and was further compounded by exercise (16,569 ± 1616 AU vs. rest, P < 0.05), responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation as measured by thrombin-antithrombin complex, at rest in normoxia (28.7 ± 6.4 vs. 4.3 ± 0.2 µg mL-1 pre-intervention, P < 0.05) and was restored but only in the face of prevailing oxidation. Collectively, these findings are the first to suggest that human free radical formation likely reflects an adaptive response that serves to maintain vascular haemostasis.

Antioxidants from diet or supplements do not alter inflammatory markers in adults with cardiovascular disease risk. A pilot randomized controlled trial.

Antioxidants have been reported to have anti-inflammatory effects, but there is a lack of research comparing food to supplement antioxidant sources. The aim of this study was to determine if increases in intake of foods naturally rich in antioxidants would lower blood levels of inflammatory markers more than consuming antioxidant supplements among adults with cardiovascular disease risk factors. Eighty-eight generally healthy adults with ≥1 elevated risk factor for cardiovascular disease were randomized in a single-blind (diets)/double-blind (supplements), parallel-group study for 8 weeks. Participants consumed (1) usual diet and placebo pills (n = 29), (2) usual diet and antioxidant supplements (n = 29), or (3) antioxidant-rich foods closely matched to antioxidant content of supplements and placebo (n = 30). Usual diet combined with antioxidant supplements or increased antioxidant-rich food intake was designed to approximately double daily habitual antioxidant intake. Antioxidant pills included carotenoids, mixed tocopherols, vitamin C, and selenium. Fasting blood samples were analyzed for inflammatory marker concentrations of interleukin-6, monocyte chemotactic protein-1, and soluble intercellular adhesion molecule-1. Participants in the intervention groups successfully doubled most antioxidants as verified by diet records and elevated blood concentrations in treatment groups. Baseline levels of inflammatory markers for the entire study group were 110 ± 65 pg/mL for monocyte chemotactic protein-1, 0.9 ± 0.7 pg/mL for interleukin-6, and 217 ± 56 ng/mL for soluble intercellular adhesion molecule-1 (means ± standard deviation) and did not differ by treatment arm. After 8 weeks, there were no significant within-group changes or between-group 8-week change differences in inflammatory marker concentrations. In conclusion, no beneficial effects were detected on the inflammatory markers investigated in response to antioxidants from foods or supplements.

Tocopherol and Tocotrienol: Therapeutic Potential in Animal Models of Stress.

BACKGROUND: Scientific reports had shown that stress is related to numerous pathological changes in the body. These pathological changes can bring about numerous diseases and can significantly cause negative effects in an individual. These include gastric ulcer, liver pathology and neurobehavioral changes. A common pathogenesis in many diseases related to stress involves oxidative damage. Therefore, the administration of antioxidants such as vitamin E is a reasonable therapeutic approach. However, there is conflicting evidence about antioxidant supplementation. OBJECTIVE: The aim of this work was to summarize documented reports on the effects of tocopherol and tocotrienol on various pathological changes induced by stress. RESULTS AND CONCLUSION: This review will reveal the scientific evidence of enteral supplementation of vitamin E in the forms of tocotrienol and tocopherol in animal models of stress. These models mimic the stress endured by critically ill patients in a clinical setting and psychological stress in individuals. Positive outcomes from enteral feeding of vitamin E in reducing the occurrence of stress-induced pathological changes are discussed in this review. These positive findings include their ability to reduced stress-induced gastric ulcers, elevated liver enzymes and improved locomotors activity. Evidences showing tocotrienol and tocopherol effects are not just related to its ability to reduce oxidative stress but also acting on other mechanism, are discussed.

Effects of d-alpha-tocopherol on skeletal muscle regeneration in crushed injury of diabetic rats

Muscular atrophy in diabetes is believed to be due to uncontrolled hyperglycemia and oxidative stress. Vitamin E, a natural antioxidant, is considered important to maintain skeletal muscle structures and functions. The current study is designed to explore the regenerative potential of d-α-tocopherol after crushed injury of skeletal muscle in healthy and diabetic rats. Diabetes was induced through single subcutaneous injection of alloxan at the dose of 100 mg/kg at hip region. Twenty four albino rats were divided into four groups; healthy control, diabetic control, healthy treated and diabetic treated. Treated groups were administered d-α-tocopherol orally and daily at the dose of 200 mg/kg for three weeks. A horizontal skin incision was made on the shaved right mid-thigh region and after splitting of the fascia between gluteus maximus and tensor fascia lata the gluteus maximus was crushed with Kocher's forceps. Skin wound was closed with an absorbable suture. The crushed muscle changes were studied by assessing the histopathological features, histomorphological measurements and biochemical analyses at the end of 3rd week. One way 'ANOVA' followed by Tukeys test and Student t test were used for statistical analysis. Results obtained through various methods indicate that the d-α-tocopherol helps in skeletal muscle regeneration by improving antioxidant status, myoblast proliferation, revascularization, reinnervation and connective tissue remodeling. Hence it is concluded that d-α-tocopherol is a useful therapeutic dietary supplement in the management of skeletal muscle crushed injuries in both healthy and diabetics

No disponible

δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages.

Tocopherols, the major forms of vitamin E, are a family of fat-soluble compounds that exist in alpha (α-T), beta (ß-T), gamma (γ-T), and delta (δ-T) variants. A cancer preventive effect of vitamin E is suggested by epidemiological studies. However, past animal studies and human intervention trials with α-T, the most active vitamin E form, have yielded disappointing results. A possible explanation is that the cancer preventive activity of α-T is weak compared to other tocopherol forms. In the present study, we investigated the effects of δ-T, γ-T, and α-T (0.2% in diet) in a novel colon cancer model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS)-induced colitis in CYP1A-humanized (hCYP1A) mice. PhIP/DSS treatments induced multiple polypoid tumors, mainly tubular adenocarcinomas, in the middle to distal colon of the hCYP1A mice after 10 wk. Dietary supplementation with δ-T and γ-T significantly reduced colon tumor formation and suppressed markers of oxidative and nitrosative stress (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory mediators (i.e., NF-κB p65 and p-STAT3) in tumors and adjacent tissues. By administering δ-T at different time periods, we obtained results suggesting that the inhibitory effect of δ-T against colon carcinogenesis is mainly due to protection against early cellular and DNA damages caused by PhIP. α-T was found to be ineffective in inhibiting colon tumors and less effective in attenuating the molecular changes. Altogether, we demonstrated strong cancer preventive effects of δ-T and γ-T in a physiologically relevant model of human colon cancer. © 2016 Wiley Periodicals, Inc.

New perspectives on the conservative management of osteoradionecrosis of the mandible: A literature review.

Over the last decades, several therapeutic options were considered in the treatment of the osteoradionecrosis (ORN) of the mandible, including supportive measures, ultrasound therapy, corticosteroids, hyperbaric oxygen, surgical resection with reconstruction, and, more recently, drugs capable of reversing the fibroatrophic process. Once established, the ORN does not spontaneously disappear and a standard treatment has not yet been defined. The clear clinical effectiveness of hyperbaric oxygen therapy (HBOT) varies according to the literature and there are some economic/logistic issues to be considered; the triplet tocopherol/pentoxifylline/clodronate demands greater evidence from randomized clinical trials and also resilience from the patient, given the long treatment duration and its possible side effects. Controversy around the ideal treatment of the initial stage ORN of the mandible persists. More rigorous randomized prospective trials are essential. The purpose of this article was to review the relevant literature on the physiopathology of ORN of the mandible and discuss the new perspectives of its conservative treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

Use of pentoxifylline and tocopherol in the management of osteoradionecrosis.

Osteoradionecrosis (ORN) is a complication of radiotherapy, and is difficult to manage once established. However, its pathogenesis has been reinvestigated, and it is now thought to be potentially amenable to treatment with pentoxifylline and tocopherol (vitamin E). We made a retrospective analysis of 62 patients with established ORN who were treated in this way. When only pentoxifylline and vitamin E was used ORN resolved in 14/25 (56%) but paradoxically, when it was combined with antibiotics, only 6/22 resolved (27%). The next stage would ideally be to incorporate the treatment in a randomised clinical trial against both standard antibiotic treatment and hyperbaric oxygen.

Tissue repair in osteoradionecrosis using pentoxifylline and tocopherol--report of three cases.

PURPOSE: Osteoradionecrosis is a complication of head and neck radiotherapy, with a difficult resolution and no well-established treatment. The disease progression can cause important loss on patient's quality of life after cancer treatment. The options for treatment are limited and include clinical monitoring, prescription, or surgical procedures. As an alternative for bone necrosis treatment, a combination of drugs, pentoxifylline and tocopherol, can be used. Studies have shown that this combination significantly reduces chronic radiotherapy damage. The article reports successful treatment with this prescription protocol. METHODS: We report three cases of patients referred to the Service of Oral and Maxillofacial Surgery at Erasto Gaertner Hospital, in Curitiba, Brazil. They were submitted to radiotherapy for the treatment of malignant head and neck tumors and later developed osteoradionecrosis. They were treated with the combination pentoxifylline and tocopherol. RESULTS: All patients achieved complete remission in less than 1 year, with complete healing of bone exposure and without clinical symptoms. CONCLUSIONS: This results show that this combination of drugs is beneficial in cases of bone necrosis induced by radiation, avoiding more aggressive treatments and reducing morbidity.

Focus on Pivotal Role of Dietary Intake (Diet and Supplement) and Blood Levels of Tocopherols and Tocotrienols in Obtaining Successful Aging.

Numerous specific age-related morbidities have been correlated with low intake and serum levels of tocopherols and tocotrienols. We performed a review in order to evaluate the extant evidence regarding: (1) the association between intake and serum levels of tocopherols and tocotrienols and age-related pathologies (osteoporosis, sarcopenia and cognitive impairment); and (2) the optimum diet therapy or supplementation with tocopherols and tocotrienols for the treatment of these abnormalities. This review included 51 eligible studies. The recent literature underlines that, given the detrimental effect of low intake and serum levels of tocopherols and tocotrienols on bone, muscle mass, and cognitive function, a change in the lifestyle must be the cornerstone in the prevention of these specific age-related pathologies related to vitamin E-deficient status. The optimum diet therapy in the elderly for avoiding vitamin E deficiency and its negative correlates, such as high inflammation and oxidation, must aim at achieving specific nutritional goals. These goals must be reached through: accession of the elderly subjects to specific personalized dietary programs aimed at achieving and/or maintaining body weight (avoid malnutrition); increase their intake of food rich in vitamin E, such as derivatives of oily seeds (in particular wheat germ oil), olive oil, hazelnuts, walnuts, almonds, and cereals rich in vitamin E (such as specific rice cultivar rich in tocotrienols) or take vitamin E supplements. In this case, vitamin E can be correctly used in a personalized way either for the outcome from the pathology or to achieve healthy aging and longevity without any adverse effects.

Tocopherols in the Prevention and Treatment of Atherosclerosis and Related Cardiovascular Disease.

Oxidants/antioxidants play an important role in cellular homeostasis. The human body has endogenous molecules that work as antioxidants, such as glutathione, superoxide dismutase, peroxidases, and catalase. Exogenous substances in the diet, such as ß-carotene, ascorbate, and vitamin E, are vital antioxidants. Of these, vitamin E is likely the most important antioxidant in the human diet, and many studies have been performed to elucidate its role in health and disease. Vitamin E is a family of several compounds, of which α-tocopherol is the most widely known analog. α-Tocopherol exhibits antioxidative property in vitro and inhibits oxidation of low-density lipoprotein cholesterol. In addition, α-tocopherol shows anti-inflammatory activity and modulates expression of proteins involved in the uptake, transport, and degradation of atherogenic lipids. Though α-tocopherol exhibits important antioxidant, anti-inflammatory, and antiatherogenic features in vitro, α-tocopherol supplements have failed to consistently reduce atherosclerosis-related events in human trials. The conflicting results have led to reconsideration of the importance previously given to α-tocopherol and led to interest in other members of vitamin E family, especially γ-tocopherol, which exerts a much more potent antioxidant, anti-inflammatory, and cardioprotective effect than α-tocopherol. This reconsideration has been backed by solid laboratory and clinical research. We suggest that the absence of γ-tocopherol in traditional preparations may be one reason for the lack of consistent salutary effects of vitamin E preparations in clinical trials. This review summarizes our current understanding of tocopherols as antioxidant molecules and emerging evidence of an important role of γ-tocopherol in the pathophysiology of atherosclerosis-related cardiovascular disease.

The management of osteoradionecrosis of the jaws--a review.

PURPOSE: To review the conservative and surgical management options of osteoradionecrosis, in particular, highlighting the recent the use of anti-radiation fibrosis drugs (pentoxifylline, tocopherol and clodronate). MATERIAL AND METHODS: We performed a literature review. The management options were divided into two groups, conservative and surgical management. RESULTS: Over the years several treatment options have been proposed including; conservative management (antibiotics, analgesics, oral hygiene), ultrasound therapy, hyperbaric oxygen therapy, surgical resection with reconstruction and more recently the use of anti-radiation fibrosis drugs (pentoxifylline, tocopherol and clodronate). Early or low grade ORN can be managed conservatively using a combination of treatment options. In advanced or refractory cases of ORN (pathological fracture, orocutaneous fistula) surgical treatment, at present, remains the only treatment option available. A new understanding of the pathophysiology of ORN (radiation induced fibroatrophic process) has lead to the development of new therapeutic management regimes. CONCLUSION: In advanced or refractory cases of ORN surgical treatment, including microvascular reconstructive techniques for bone and soft tissue, remains the only option available.

Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats.

Oxidative stress is known to play a key role in estrogen-induced breast cancer. This study assessed the chemopreventive activity of the naturally occurring γ-tocopherol-rich mixture of tocopherols (γ-TmT) in early stages of estrogen-induced mammary hyperplasia in ACI rats. ACI rats provide an established model of rodent mammary carcinogenesis due to their high sensitivity to estrogen. Female rats were implanted with 9 mg of 17ß-estradiol (E2) in silastic tubings and fed with control or 0.3% γ-TmT diet for 1, 3, 7, and 14 d. γ-TmT increased the levels of tocopherols and their metabolites in the serum and mammary glands of the rats. Histological analysis revealed mammary hyperplasia in the E2 treated rats fed with control or γ-TmT diet. γ-TmT decreased the levels of E2-induced nitrosative and oxidative stress markers, nitrotyrosine, and 8-oxo-dG, respectively, in the hyperplastic mammary tissues. 8-Isoprostane, a marker of oxidative stress in the serum, was also reduced by γ-TmT. Noticeably, γ-TmT stimulated Nrf2-dependent antioxidant response in the mammary glands of E2 treated rats, evident from the induced mRNA levels of Nrf2 and its downstream antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. Therefore, inhibition of nitrosative/oxidative stress through induction of antioxidant response is the primary effect of γ-TmT in early stages of E2-induced mammary hyperplasia. Due to its cytoprotective activity, γ-TmT could be a potential natural agent for the chemoprevention of estrogen-induced breast cancer.