α-Tocopherol Polyethylene Glycol 1000 Succinate-Based Cationic Liposome for the Intracellular Delivery of Doxorubicin in MDA-MB-231 Triple-Negative Breast Cancer Cell Line.

Present research work reports the development of doxorubicin (DOX) loaded α-tocopherol polyethylene glycol 1000 succinate (TPGS)-coated cationic liposomes. The developed formulation was evaluated for its anticancer potential and intracellular uptake against the MDA-MB-231 breast cancer cell line. Moreover, hemocompatibility studies were also done on human blood red blood cells for the determination of blood compatibility. The prepared doxorubicin-loaded TPGS liposomes (DOX-LIPO-TPGS) and doxorubicin-loaded cationic liposomes (DOX-LIPO+-TPGS) reveal vesicle size (177.5 ± 2.5 and 201.7 ± 2.3 nm), polydispersity index (0.189 ± 0.01 and 0.218 ± 0.02), zeta potential (-36.9 ± 0.7 and 42 ± 0.9 mv), and % entrapment efficiency (65.88% ± 3.7% and 74.5% ± 3.9%). Furthermore, in vitro, drug release kinetics of the drug alone and drug from formulation shows sustained release behavior of developed formulation with 99.98% in 12 h and 80.98% release of the drug in 72 h, respectively. In addition, cytotoxicity studies and cellular DOX uptake on the MDA-MB-231 breast cancer cell line depict higher cytotoxic and drug uptake potential with better hemocompatibility of DOX-LIPO+-TPGS with respect to DOX. The data from the study revealed that TPGS plays an important role in enhancing the formulation's quality attributes like stability, drug release, cytotoxicity, and hemocompatibility behavior. This may serve that TPGS-coated cationic liposome as a vital candidate for the treatment of cancer and drug delivery in case of breast cancer.

Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats.

This study aimed to analyze the effects of the quercetin (100 mg/kg), 1% glutamine and 1% α-tocopherol antioxidants in the myocardium of rats with streptozotocin-induced diabetes mellitus. Twenty male rats were subdivided into four groups (n = 5): N (normoglycemic); D (diabetic); NT (normoglycemic treated with antioxidants); and DT (diabetic treated with antioxidants) treated for 60 days. Clinical parameters, oxidative stress markers, inflammatory cytokines, myocardial collagen fibers and immunoexpression of superoxide dismutase 1 (SOD-1), glutathione peroxidase-1 (GPx-1), interleukin-1ß (IL-1-ß), transforming growth factor-beta (TGF-ß), and fibroblast growth factor-2 (FGF-2) were evaluated. Results showed reduced body weight, hyperphagia, polydipsia and hyperglycemic state in groups D and DT. The levels of glutathione (GSH) were higher in NT and DT compared to N (p < 0.01) and D (p < 0.001) groups, respectively. Greater GSH levels were found in DT when compared to N animals (p < 0.001). In DT, there was an increase in IL-10 in relation to N, D and NT (p < 0.05), while GPx-1 expression was similar to N and lower compared to D (p < 0.001). TGF-ß expression in DT was greater than N (p < 0.001) group, whereas FGF-2 in DT was higher than in the other groups (p < 0.001). A significant reduction in collagen fibers (type I) was found in DT compared to D (p < 0.05). The associated administration of quercetin, glutamine and α-tocopherol increased the levels of circulating interleukin-10 (IL-10) and GSH, and reduced the number of type I collagen fibers. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats.

Effect of pentoxifylline and α-tocopherol on medication-related osteonecrosis of the jaw in rats: Before and after dental extraction.

OBJECTIVE: Evaluate the effect of pentoxifylline and α-tocopherol administration in the prevention or treatment of medication-related jaw osteonecrosis (MRONJ). METHODOLOGY: Sixty Wistar rats were divided into three prevention (C-prev, BP-prev and BP/PT-prev) and three treatment groups (C-treat, BP-treat and BP/PT-treat), n = 10. The animals in the BP-prev, BP/PT-prev, BP-treat and BP/PT-treat groups received zoledronic acid (0.1 mg/kg) for 12 weeks, while the animals in the C-prev and C-treat groups received saline solution. At week 6, all animals underwent tooth extraction. Between week 5 and week 12, the BP/PT-prev group was treated with pentoxifylline (50 mg/kg/day) and α-tocopherol (80 mg/kg/day), with euthanasia at the end of week 12. The BP/PT-treat group received the same drug protocol, but it was performed between week 12 and week 16, with euthanasia at the end of week 16. Afterwards, the presence of osteonecrosis was evaluated by clinical analysis, radiographic and histological. RESULTS: BP/PT-treat group showed a reduction in the histological incidence of osteonecrosis by 50%, decrease the percentage of empty osteocyte gaps and the necrotic area, decrease the presence of bone sequestration and increase the number of osteocytes and alveolar blood flow (p < 0.05). However, BP/PT-prev group showed only a reduction in the necrotic area percentage when compared to BP-prev (p < 0.05). CONCLUSIONS: Pentoxifylline and α-tocopherol administration before tooth extraction was not effective in preventing MRONJ. However, this drug protocol was able to reduce MRONJ manifestation when administrate after discontinuation of bisphosphonate, thus it can be considered as a viable strategy for the treatment of this pathological condition.

Poly(2-ethyl-2-oxazoline)-IR780 conjugate nanoparticles for breast cancer phototherapy.

Aims: To address the limitations of IR780 by preparing hydrophilic polymer-IR780 conjugates and to employ these conjugates in the assembly of nanoparticles (NPs) intended for cancer photothermal therapy. Materials & methods: The cyclohexenyl ring of IR780 was conjugated for the first time with thiol-terminated poly(2-ethyl-2-oxazoline) (PEtOx). This novel poly(2-ethyl-2-oxazoline)-IR780 (PEtOx-IR) conjugate was combined with D-α-tocopheryl succinate (TOS), leading to the assembly of mixed NPs (PEtOx-IR/TOS NPs). Results: PEtOx-IR/TOS NPs displayed optimal colloidal stability as well as cytocompatibility in healthy cells at doses within the therapeutic range. In turn, the combination of PEtOx-IR/TOS NPs and near-infrared light reduced heterotypic breast cancer spheroid viability to just 15%. Conclusion: PEtOx-IR/TOS NPs are promising agents for breast cancer photothermal therapy.

Conventional anticancer approaches are often associated with severe side effects. Herein, the authors assembled a novel nanoparticle whose therapeutic effect is triggered by laser light. In in vitro assays, the produced nanomaterial was able to, after interacting with laser light, reduce the viability of classic and advanced cancer models. In these conditions, but in the absence of laser light, no cytotoxicity was observed. In this way, the on-demand effect (triggered by laser light) may contribute to reduced side effects. Moreover, the produced nanoparticle revealed good stability, which is important for its future translation.

The Vitamin E Isoform α-Tocopherol is Not Effective as a Complementary Treatment in Cancer Treatment: A Systematic Review.

The term vitamin E describes tocopherols and tocotrienols, whose chemical variations result in different biological activities including antioxidants. Neuroprotective effects of alpha-tocopherol against different toxins are assumed, therefore, it is discussed as a possible protective factor for adverse effects in cancer treatment. In July 2020, a systematic search was conducted searching five databases (Embase, Cochrane, PsychInfo, Cinahl, Medline) to find studies concerning the impact of α-tocopherol application and its potential harm on cancer patients. From 7546 search results, 22 publications referring to 20 studies with 1941 patients were included. Included patients were diagnosed with various cancer types and stages. Outcome variables were overall survival of cancer, symptom management of mucositis and chemotherapy-induced peripheral neuropathy (CIPN). The studies had different methodological qualities (mainly acceptable) and reported heterogeneous results: some reported significant improvement of mucositis and CIPN while others did not find changes concerning these endpoints. Due to heterogeneous results and methodical limitations of the included studies, a clear statement regarding the effectiveness of α-tocopherol as complementary treatment for cancer patients is not possible. Despite findings regarding reduction of oral side effects, usage of α-tocopherol during therapy must be discouraged because of potential negative influence on survival rates.

Selenite Downregulates STAT3 Expression and Provokes Lymphocytosis in the Liver of Chronically Exposed Syrian Golden Hamsters.

Arsenic is considered a worldwide pollutant that can be present in drinking water. Arsenic exposure is associated with various diseases, including cancer. Antioxidants as selenite and α-tocopherol-succinate have been shown to modulate arsenic toxic effects. Since changes in STAT3 and PSMD10 gene expression have been associated with carcinogenesis, the aim of this study was to evaluate the effect of arsenic exposure and co-treatments with selenite or α-tocopherol-succinate on the expression of these genes, in the livers of chronically exposed Syrian golden hamsters. Animals were divided into six groups: (i) control, (ii) chronically treated with 100 ppm arsenic, (iii) treated with 6 ppm α-tocopherol-succinate (α-TOS), (iv) treated with 8.5 ppm selenite, (v) treated with arsenic + α-TOS, and (vi) treated with arsenic + selenite. Urine samples and livers were collected after 20 weeks of continuous exposure. The urine samples were analyzed for arsenic species by atomic absorption spectrophotometry, and real-time RT-qPCR analysis was performed for gene expression evaluation. A reduction in STAT3 expression was observed in the selenite-treated group. No differences in PSMD10 expression were found among groups. Histopathological analysis revealed hepatic lymphocytosis in selenite-treated animals. As a conclusion, long-term exposure to arsenic does not significantly alter the expression of STAT3 and PSMD10 oncogenes in the livers of hamsters; however, selenite down-regulates STAT3 expression and provokes lymphocytosis.

Effect of δ-Tocopherol on Mice Adipose Tissues and Mice Adipocytes Induced Inflammation.

The study aim was to evaluate the potential anti-inflammatory effects of vitamin E analogs, especially α-tocopherol and δ-tocopherol. We used male C57BL/6JJcl mice, which were divided into four groups: the control (C), high-fat and high-sucrose diet (H), high-fat and high-sucrose diet+α-tocopherol (Ha) and high-fat and high-sucrose diet+δ-tocopherol (Hd) groups. The mice were fed for 16 weeks. To the high-fat and high-sucrose diet, 800 mg/kg of α-tocopherol or δ-tocopherol was added more. The final body weight was significantly higher in the H group than in the C group. On the other hand, the final body weight was drastically lower in the Ha group and Hd group than in the H group. However, the energy intake was not significantly different among all groups. Therefore, we assumed that α-tocopherol and δ-tocopherol have potential anti-obesity effect. Besides, inflammatory cytokine gene expression was significantly higher in the epididymal fat of the H group than in the C group. These results showed that inflammation was induced by epididymal fat of mice fed a high-fat and high-sucrose diet for 16 weeks. Unfortunately, addition of α-tocopherol or δ-tocopherol to the diet did not restrain inflammation of epididymal fat. Investigation of the anti-inflammatory effects of α-tocopherol or δ-tocopherol in co-cultured 3T3-L1 cells and RAW264.7 cells showed that δ-tocopherol inhibited increased gene expression of the inflammatory cytokines, IL-1ß, IL-6, and iNOS. These results suggest that an anti-inflammatory effect in the δ-tocopherol is stronger than that in the α-tocopherol in vitro. We intend to perform an experiment by in vivo sequentially in the future.

Multi-functional carboxymethyl chitin-based nanoparticles for modulation of tumor-associated macrophage polarity.

Current challenge of using cytokines is its poor distribution and systemic side effects. To avoid this issue, we prepared the tumor-targeted and microenvironment-responsive nanocarriers (TRN), which were consisted of α-tocopheryl succinate (α-TOS) loaded mesoporous silica nanoparticles as cores, and surface-modified by thioketal-linkage, electrostatically coated with carboxymethyl chitin, and further anchored glucose-regulated protein 78-binding peptide as shells for encapsulating IL-12. TRN showed a size of 260 nm after encapsulated IL-12 and α-TOS with loading content of 0.0206% and 7.21%, respectively, and exhibited good biocompatibility to 4 T1 cells and macrophages. Moreover, IL-12/α-TOS loaded TRN displayed obvious anti-tumor efficacy on BALB/c nude mice bearing 4 T1 tumors, which was derived from promoted targeting to tumor tissue, endocytosed by macrophages and locally release IL-12 to subsequently repolarize tumor-associated macrophages into tumoricidal M1 phenotype with reduced side effects. The nanosystem exhibited as a promising strategy with functional conversion of macrophages in tumor microenvironment for anti-tumor therapy.

Açaí (Euterpe oleracea Mart.) reduces the inflammatory response triggered in vitro by the antipsychotic drug olanzapine in RAW 264.7 macrophage cells.

BACKGROUND: Açaí (Euterpe oleracea Mart), a Brazilian fruit, is considered a "superfruit" due its energetic properties and bioactive compounds. The açai's anti-inflammatory effects could attenuate the undesirable metabolic and pro-inflammatory side effects triggered by some antipsychotic drugs, such as Olanzapine (OLZ). It is possible to infer that açai supplement could potentially minimize the adverse effects of OLZ. Aim. This study tested the potential in vitro effects of açai hydroalcoholic extract on the inflammatory activation of the RAW 264.7 macrophage line triggered by OLZ antipsychotic drugs. METHODS: An in vitro protocol was performed using commercial RAW 264.7 macrophages, cultured under sterile conditions at 37°C with 5% CO2 saturation. Initially, a pharmacological curve was defined to determine the concentration of Olanzapine to be used. After this, the cells were supplemented with different concentrations of hydroalcoholic extract of açaí, which had been previously chemically characterized. After 24 and 72 hours of treatment, oxidative and inflammatory tests were performed. Therefore, the aim of this study was to verify whether the hydroalcoholic extract of açaí can modulate the oxy-inflammatory response of olanzapine in vitro. RESULTS: From a preliminary analysis, the açai extract at 5 mg/mL presented higher activity against inflammation triggered by OLZ (0.03 µg/mL). At this concentration, açai was able to reduce several oxidative and inflammatory markers triggered by OLZ (0.03 µg/mL) exposure, such as nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokine levels (IL-1b, IL-6, TNF-a, IFN-g) caused by OLZ (0.03 µg/mL). Moreover, açaí reverted the levels of anti-inflammatory cytokine IL-10 that had been dropped by OLZ exposure to their pre-exposure treatments. CONCLUSIONS: The results suggest that açai extract could be useful in attenuating the peripheral inflammatory states triggered by OLZ. Additional pre-clinical and clinical investigations could be useful in testing therapeutic açai extract supplements.

t(1;22)(p13;q13) Acute Megakaryoblastic Leukemia Complicated by Hepatic Fibrosis: Antifibrosis Therapy?

BACKGROUND: There is no established effective treatment for patients with t(1;22)(p13;q13) acute megakaryoblastic leukemia (AMKL) and hepatic fibrosis. OBSERVATION: Here we report the outcomes of 2 t(1;22)(p13;q13) AMKL patients with hepatic fibrosis. One patient died from liver failure despite the control of leukemia. The other patient was successfully treated with reduced-intensity chemotherapy and antifibrosis therapy with tretinoin and α-tocopheryl acetate, the hepatic fibrosis resolved and leukemia was in remission for 3 years. CONCLUSIONS: Reduced-intensity chemotherapy plus antifibrosis therapy with tretinoin and α-tocopheryl acetate could be a treatment option for these patients with t(1;22)(p13;q13) AMKL and hepatic fibrosis.

Corneal UV Protective Effects of a Topical Antioxidant Formulation: A Pilot Study on In Vivo Rabbits.

This study aimed to evaluate the protective effect of a topical antioxidant and ultraviolet (UV) shielding action formulation containing riboflavin and D-α-tocopherol polyethylene glycol succinate (TPGS) vitamin E against corneal UV-induced damage in vivo rabbit eyes. In vivo experiments were performed using male albino rabbits, which were divided into four groups. The control group (CG) did not receive any UV irradiation; the first group (IG) was irradiated with a UV-B-UV-A lamp for 30 min; the second (G30) and third (G60) groups received UV irradiation for 30 and 60 min, respectively, and were topically treated with one drop of the antioxidant and shielding formulation every 15 min, starting one hour before irradiation, until the end of UV exposure. The cornea of the IG group showed irregular thickening, detachment of residual fragments of the Descemet membrane, stromal fluid swelling with consequent collagen fiber disorganization and disruption, and inflammation. The cornea of the G30 group showed edema, a mild thickening of the Descemet membrane without fibrillar collagen disruption and focal discoloration, or inflammation. In the G60 group, the cornea showed a more severe thickening, a more abundant fluid accumulation underneath the Descemet membrane with focal detachment, and no signs of severe tissue alterations, as were recorded in the IG group. Our results demonstrate that topical application of eye drops containing riboflavin and TPGS vitamin E counteracts UV corneal injury in exposed rabbits.

Drugs for preventing lung cancer in healthy people.

BACKGROUND: This is the second update of this Cochrane Review. Some studies have suggested a protective effect of antioxidant nutrients and higher dietary levels of fruits and vegetables on lung cancer. OBJECTIVES: To determine whether vitamins and minerals and other potential agents, alone or in combination, reduce lung cancer incidence and lung cancer mortality in healthy populations. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase from 1974 to May 2019 and screened references included in published studies and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing vitamins or mineral supplements with placebo, administered to healthy people with the aim of preventing lung cancer. DATA COLLECTION AND ANALYSIS: Four review authors independently selected the trials to be included in the review, assessed their methodological quality and extracted data. For dichotomous outcomes we calculated risk ratios (RRs) and 95% confidence intervals (CIs) and pooled results using the random-effects model. We assessed the risk of bias using Cochrane's 'Risk of bias' assessment tool and certainty of evidence using the GRADE approach. MAIN RESULTS: In this update, we identified three new trials for a total of 12 studies. Six analysed vitamin A, three vitamin C, three combined vitamin D3 + calcium, four vitamin E combined with other products, one selenium supplements and nine studied combinations of two or more products. Four studies included only men and five only women. Vitamin A results in little to no difference in lung cancer incidence (RR 1.09, 95% CI 1.00 to 1.19; 5 RCTs, 212314 participants; high-certainty evidence) and lung cancer mortality (RR 1.06, 95% CI 0.81 to 1.38; 3 RCTs, 190118 participants; high-certainty evidence). But in smokers or asbestos workers vitamin A increases the risk of lung cancer incidence (RR 1.10, 95% CI 1.01 to 1.20; 3 RCTs, 43995 participants; high-certainty evidence), lung cancer mortality (RR 1.18, 95% CI 1.01 to 1.38; 2 RCTs, 29426 participants; high-certainty evidence) and all-cause mortality (RR 1.09, 95% CI 1.05 to 1.13; 2 RCTs, 32883 participants; high-certainty evidence). Vitamin A increases the risk of minor side effects, such as yellowing of the skin and minor gastrointestinal symptoms (high-certainty evidence). Vitamin C likely results in little to no difference in lung cancer incidence (RR 1.29, 95% CI 0.67 to 2.49; 2 RCTs, 14953 participants; moderate-certainty evidence). In women, vitamin C increases the risk of lung cancer incidence (RR 1.84, 95% CI 1.14 to 2.95; 1 RCT, 7627 participants; high-certainty evidence). In men, vitamin C results in little to no difference in mortality for lung cancer (RR 0.81, 95% CI 0.53 to 1.23; 1 RCT, 7326 participants; high-certainty evidence). Vitamin D + calcium may result in little to no difference in lung cancer incidence in postmenopausal women (RR 0.90, 95% CI 0.39 to 2.08; 3 RCTs, 37601 women; low-certainty evidence). Vitamin E results in little to no difference in lung cancer incidence (RR 1.01, 95% CI 0.90 to 1.14; 3 RCTs, 36841 participants; high-certainty evidence) or to lung cancer mortality (RR 0.96, 95% CI 0.77 to 1.18; 2 RCTs, 29214 participants; high-certainty evidence), but increases the risk of haemorrhagic strokes (hazard ratio (HR), 1.74, 95% CI 1.04 to 2.91; 1 RCT, 14641 participants; high-certainty evidence). Calcium results in little to no difference in lung cancer incidence in postmenopausal women (RR 0.65, 95% CI 0.13 to 3.18; 1 RCT, 733 participants) or in risk of renal calculi (RR 1.94, 95% CI 0.20 to 18.57; 1 RCT, 733 participants; low-certainty evidence). Selenium in men results in little to no difference in lung cancer incidence (RR 1.11, 95% CI 0.80 to 1.54; 1 RCT, 17448 participants; high-certainty evidence) and lung cancer mortality (RR 1.09, 95% CI 0.72 to 1.66; 1 RCT, 17448 participants; high-certainty evidence) and increases the risk for grade 1 to 2 dermatitis (RR 1.16, 95% CI 1.04 to 1.31; 1 RCT, 17448 participants; high-certainty evidence) and for alopecia (RR 1.28, 95% CI 1.07 to 1.53; 1 RCT, 17448 participants; high-certainty evidence). The combination of vitamins A, C, E + selenium + zinc results in little to no difference in lung cancer incidence (RR 0.64, 95% CI 0.28 to 1.48; 1 RCT, 12741 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: Well-designed RCTs have shown no beneficial effect of supplements for the prevention of lung cancer and lung cancer mortality in healthy people. Vitamin A supplements increase lung cancer incidence and mortality in smokers or persons exposed to asbestos. Vitamin C increases lung cancer incidence in women. Vitamin E increases the risk of haemorrhagic strokes.

Poly(ester-thioether) microspheres co-loaded with erlotinib and α-tocopheryl succinate for combinational therapy of non-small cell lung cancer.

Polymer microspheres are attracting wide attention in localized cancer therapy owing to the excellent biocompatibility and drug loading capacity, controllable biodegradation speeds, and minimized systemic toxicity. Herein, we presented poly(ester-thioether) microspheres, porous and nonporous, as drug depots for localized therapy of non-small cell lung cancer (NSCLC). Specifically, erlotinib and α-tocopheryl succinate (α-TOS), which are respectively an epidermal growth factor receptor (EGFR) inhibitor and mitochondria destabilizer, were efficiently loaded into porous and nonporous poly(ester-thioether) microspheres for the treatment of EGFR-overexpressing NSCLC (A549 cells). The poly(ester-thioether) microspheres significantly improved the bioavailability of both erlotinib and α-TOS in comparison to the free drug combination, realizing synergistic inhibition of A549 cells both in vitro and in vivo. The porous microspheres displayed faster degradation and drug release than the nonporous counterpart, thereby showing better anticancer efficacy. Overall, our study reported a new anticancer strategy of erlotinib and α-TOS combination for therapy of NSCLC, and established that poly(ester-thioether) microspheres could be a robust and biodegradable reservoir for drug delivery and localized cancer therapy.

Self-Delivery Micellar Nanoparticles Prevent Premetastatic Niche Formation by Interfering with the Early Recruitment and Vascular Destruction of Granulocytic Myeloid-Derived Suppressor Cells.

Distal metastases of tumors result from the interaction between "seeds" (circulating tumor cells, CTCs) and "soil" (premetastatic niche, PMN). Various strategies focus on CTC inhibition, but only a few strategies inhibit PMN formation. The main predisposition of PMN formation in melanoma lies in the pulmonary recruitment of granulocytic myeloid-derived suppressor cells (G-MDSCs, CD11b+Ly6G+ cells) induced by tumors, which increase vascular permeability by secreting matrix metalloproteinase-9 (MMP-9) and result in immunosuppression by secreting interleukin-10 (IL-10) in premetastatic lungs. Here, a micellar hypotoxic low molecular weight heparin-tocopherol succinate nanoparticle (LMWH-TOS nanoparticle, LT NP) was established and investigated for its influence on PMN formation in this study. We first demonstrated that the hydrophilic segment LMWH in LT NPs can inhibit early pulmonary recruitment of G-MDSCs through interrupting their extravasation by inhibiting P-selectin/PSGL-1-mediated adhesion between vascular endothelial cells and G-MDSCs. In addition, the hydrophobic segment (TOS) in LT NPs significantly inhibited the expression of MMP-9 in G-MDSCs. As a result, the drug-free nanoparticles could maintain the normal microenvironment of lungs, thus effectively inhibiting implantation and colonization of CTCs. Further, phenylboronic acid (PBA)-modified and doxorubicin/immunopotentiator α-galactosylceramide (αGC)-coloaded nanoparticles (PLT/DOX/αGC NPs) were exploited. PBA modification achieved targeted chemotherapy by binding to overexpressed sialic acid residues on the tumor cell surface. This nanosystem effectively inhibited the postoperative metastasis and tumor recurrence simultaneously. Our work provides a proof of concept that the prevention of PMN formation through interfering G-MDSCs with self-delivery nanosystems is a safe and effective antimetastasis strategy.

Treatment of Metastatic or High-Risk Solid Cancer Patients by Targeting the Immune System and/or Tumor Burden: Six Cases Reports.

This article summarizes the histories of six patients with different solid tumors treated with a new strategy based on tumor burden reduction and immune evasion as potential targets. All six patients were at a high risk of relapse and were likely to have a minimal residual disease following conventional therapy: biochemical recurrence (BCR) following radical prostatectomy (RP) (two prostate cancers patients), removal of distant metastases (one colorectal and one breast cancer), and complete response (CR) of distant metastases to conventional therapy (one breast cancer and one esophageal-gastric junction cancer). Four of the patients, two after RP and BCR, one after removal of a single pulmonary metastasis from breast cancer, and one after CR to chemotherapy of peritoneal metastases and ascites from an esophageal-gastric junction primary cancer, regularly received cycles of a new drug schedule with the aim of inhibiting immune suppression (IT). In these four patients, preliminary laboratory tests of peripheral blood suggested an interleukin (IL)-2/IL-12 mediated stimulation of cellular immune response with a concomitant decrease in vascular endothelial growth factor (VEGF) immune suppression. The fifth case was a breast cancer patient with distant metastases in CR, while receiving beta-interferon and interleukin-2 in addition to conventional hormone therapy. To date, all five patients are alive and doing well and they have been unexpectedly disease-free for 201 and 78 months following BCR, 28 months following the removal of a single pulmonary metastases, 32 months following CR to chemotherapy of peritoneal metastases and ascites, and 140 months following diagnosis of multiple bone metastases, respectively. The sixth patient, who had colorectal cancer and multiple synchronous liver metastases and underwent nine surgical interventions for metastatic disease, although not disease-free, is doing well 98 months after primary surgery. Our six cases reports can be interpreted with the hypothesis that immune manipulation and/or a concomitant low tumor burden favored their clinical outcome.

TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model.

Genetic mutations in TBC1D24 have been associated with multiple phenotypes, with epilepsy being the main clinical manifestation. The TBC1D24 protein consists of the unique association of a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin motif domain/catalytic (TLDc) domain. More than 50 missense and loss-of-function mutations have been described and are spread over the entire protein. Through whole genome/exome sequencing we identified compound heterozygous mutations, R360H and G501R, within the TLDc domain, in an index family with a Rolandic epilepsy exercise-induced dystonia phenotype (http://omim.org/entry/608105). A 20-year long clinical follow-up revealed that epilepsy was self-limited in all three affected patients, but exercise-induced dystonia persisted into adulthood in two. Furthermore, we identified three additional sporadic paediatric patients with a remarkably similar phenotype, two of whom had compound heterozygous mutations consisting of an in-frame deletion I81_K84 and an A500V mutation, and the third carried T182M and G511R missense mutations, overall revealing that all six patients harbour a missense mutation in the subdomain of TLDc between residues 500 and 511. We solved the crystal structure of the conserved Drosophila TLDc domain. This allowed us to predict destabilizing effects of the G501R and G511R mutations and, to a lesser degree, of R360H and potentially A500V. Next, we characterized the functional consequences of a strong and a weak TLDc mutation (TBC1D24G501R and TBC1D24R360H) using Drosophila, where TBC1D24/Skywalker regulates synaptic vesicle trafficking. In a Drosophila model neuronally expressing human TBC1D24, we demonstrated that the TBC1D24G501R TLDc mutation causes activity-induced locomotion and synaptic vesicle trafficking defects, while TBC1D24R360H is benign. The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity, which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or α-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity. Our data thus show that mutations in the TLDc domain of TBC1D24 cause Rolandic-type focal motor epilepsy and exercise-induced dystonia. The humanized TBC1D24G501R fly model exhibits sustained activity and vesicle transport defects. We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies. The TLDc and TBC domain mutations' response to antioxidant treatment we observed in the animal model suggests a potential for combining antioxidant-based therapeutic approaches to TBC1D24-associated disorders with previously described lipid-altering strategies for TBC domain mutations.

Promising role of filgrastim and α-tocopherol succinate in amelioration of gastrointestinal acute radiation syndrome (GI-ARS) in mice.

The protective role of α-tocopherol succinate (α-TCS) and the therapeutic efficacy of filgrastim were investigated in gastrointestinal acute radiation syndrome (GI-ARS) induced following 10 Gy whole-body γ-irradiation. Mice were randomly allocated into 5 groups: [1] normal-control, [2] irradiated-control, [3] subcutaneous (s.c.) injection of filgrastim (5 µg/kg/day) for 4 consecutive days given 1 h post-irradiation, [4] s.c. injection with α-TCS (400 mg/kg) 1 day prior to irradiation, [5] s.c. injection with α-TCS (400 mg/kg) 1 day prior to irradiation and filgrastim (5 µg/kg/day) for 4 consecutive days 1 h post-irradiation. Histopathological analysis, serum citrulline level, intestinal interleukin-1ß (IL-1ß), reduced glutathione (GSH), and malondialdehyde (MDA) contents as well as myeloperoxidase (MPO) activity were measured. Intestinal caspase-3, p53, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) immunopositivity were examined. In irradiated-control, MDA increased (249%) and GSH decreased (25%) compared to normal and were unaffected by filgrastim. α-TCS alone significantly reduced MDA (84.5%) and normalized GSH. The combination significantly reduced MDA (59%) and dramatically increased GSH (1573%), pointing to a possible synergistic action. In irradiated-control, MPO and IL-1ß significantly increased (111% and 613%, respectively) compared to normal-control and both were significantly decreased in all treated groups. Compared to normal-control, citrulline significantly declined (68%) in irradiated-control; a significant elevation was achieved by treatments with α-TCS alone or combined with filgrastim (88% and 94%, respectively). The combination therapy significantly decreased the degree of irradiation-induced injury of the epithelium and cellular infiltration and showed the lowest histopathological scoring compared to the other groups (p ≤ 0.05). In irradiated-control, immune-reactive expressions of iNOS, COX-2, caspase-3, and p53 were remarkable (18.62%, 34.27%, 31.19%, and 27.44%, respectively) and after combination therapy were reduced (1.04%, 22.39%, 8.76%, and 4.91%, respectively). The current findings represent a first-hand strategy in dealing with GI-ARS with a potential preference to using a combined therapy of filgrastim and α-TCS.

Insulin-like growth factor I, binding proteins -1 and -3, risk of type 2 diabetes and macronutrient intakes in men.

The insulin-like growth factor (IGF) axis may be involved in the development of type 2 diabetes. We examined the associations of IGF-I and IGF binding proteins (IGFBP)-1 and -3 with diabetes risk and evaluated macronutrient intakes related to the observed associations. In a nested case-control study of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers aged 50-69 years, the IGF variables were measured from baseline serum samples for a random sample of 310 men with diabetes diagnosed during a 12-year follow-up and for 310 controls matched by age, recruitment day and intervention group. Diet at baseline was assessed using a validated FFQ. The associations of IGF proteins with diabetes risk were estimated using conditional logistic regression and the associations with macronutrient intakes using linear regression. IGF-I and IGFBP-3 were not associated with the incidence of diabetes. Higher IGFBP-1 was associated with lower diabetes risk in an unadjusted crude model (OR 0·25; 95 % CI 0·15, 0·42 in the highest quartile compared with the lowest), but not after adjustment for BMI (corresponding OR 0·76; 95 % CI 0·41, 1·40). Intakes of carbohydrates, plant protein and milk protein associated positively and intake of meat protein and fat negatively with IGFBP-1 (P<0·005). IGFBP-1 was inversely associated with diabetes risk, but the association was substantially dependent on BMI. The associations between macronutrient intakes and IGFBP-1 may reflect influences of nutrients or foods on insulin concentrations.

Effects of alpha-tocopherol on acute pancreatitis in rat.

BACKGROUND: Acute pancreatitis is a disease with high morbidity and mortality, despite all the advances in technology. The overall mortality rate of acute pancreatitis is 10%, whereas the mortality rate in infected necrotizing pancreatitis is approximately 35%. In this study, we aimed to establish acute pancreatitis in rats in order to try out the alpha-tocopherol treatment protocol and to reveal the results biochemically and histopathologically. METHODS: Twenty-four male male Sprague-Dawley rats weighing between 300 and 350 g were used in the study. In Group 1, 80 µg/kg of normal saline was subcutaneously injected into eight rats; in Group 2, 80 µg/kg of cerulein was subcutaneously injected into eight rats; and in Group 3, 80 µg/kg of cerulein was subcutaneously injected into eight rats. In addition, 30 mg/kg of alpha-tocopherol was intraperitoneally injected into eight rats. RESULTS: The mean Schoenberg score, serum amylase, and lipase and Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels were statistically significantly higher in Group 2 than in Group 1. The mean Schoenberg score and serum amylase and lipase levels were statistically significantly lower in Group 3 than in Group 2. CONCLUSION: In this experimental study rat model of cerulein-induced acute pancreatitis, 30 mg/kg of alpha-tocopherol was injected intraperitoneally to examine its effect on pancreatitis. The improvement was observed in the histopathological examination of pancreatic tissues. We think that alpha-tocopherol may have a therapeutic effect on pancreatic tissue.

Anticancer effects of methotrexate in combination with α­tocopherol and α­tocopherol succinate on triple­negative breast cancer.

Triple­negative breast cancers (TNBCs) lack the estrogen receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Therefore, hormone or targeted therapies are not effective in the treatment of TNBC and thus the development of novel therapeutic strategies is crucial. Methotrexate (MTX), a folate antagonist, has been used in the treatment of various types of cancer; however, the anticancer effects of MTX treatment on breast cancer have thus far been ineffective. Vitamin E variants and derivatives have been applied for cancer therapy. Previous studies have indicated that vitamin E variants and derivatives exert distinct anticancer effects on different types of cancer. However, whether MTX plus vitamin E variants or its derivatives can inhibit TNBC remains unclear. The aim of the present study was to examine the anticancer effects and mechanisms of action of MTX in combination with vitamin E variants (α­tocopherol) and derivatives (α­tocopherol succinate) on TNBC. In the present study, MTT assay and western blot analysis were used to determine the cell survival rates and protein levels. The results demonstrated that combination treatment with MTX and α­tocopherol suppressed TNBC cell proliferation. In addition, various concentrations of MTX exerted distinct cytotoxic effects on α­tocopherol succinate­treated cells. Furthermore, high­dose MTX enhanced α­tocopherol succinate­induced anticancer activity; however, low­dose MTX inhibited α­tocopherol succinate­induced anticancer activity. The present study also demonstrated that caspase­3 activation and poly(adenosine diphosphate­ribose) polymerase cleavage were observed in the α­tocopherol succinate/MTX­treated cells. In conclusion, the findings of the present study demonstrated that high­dose MTX enhanced anticancer activity in α­TOS­treated TNBC, while low­dose MTX reduced anticancer activity in α­TOS­treated TNBC.