Metabolomic fingerprint of breast cancer cells treated with the antidiabetic drug metformin revealed a significant accumulation of 5-formimino-tetrahydrofolate, one of the tetrahydrofolate forms carrying activated one-carbon units that are essential for the de novo synthesis of purines and pyrimidines. De novo synthesis of glutathione, a folate-dependent pathway interconnected with one-carbon metabolism was concomitantly depleted in response to metformin. End-product reversal studies demonstrated that thymidine alone leads to a significant but incomplete protection from metformin's cytostatic effects. The addition of the substrate hypoxanthine for the purine salvage pathway produces major rightward shifts in metformin's growth inhibition curves. Metformin treatment failed to activate the DNA repair protein ATM kinase and the metabolic tumor suppressor AMPK when thymidine and hypoxanthine were present in the extracellular milieu. Our current findings suggest for the first time that metformin can function as an antifolate chemotherapeutic agent that induces the ATM/AMPK tumor suppressor axis secondarily following the alteration of the carbon flow through the folate-related one-carbon metabolic pathways. 相似文献
Spinal cord injury (SCI) is a disease that affects millions of people worldwide, causing a temporary or permanent impairment of neuromotor functions. Mostly associated to traumatic lesions, but also to other forms of disease, the appropriate treatment is still unsure. In this review, several ongoing studies are presented that aim to provide methods of prevention that ensure quality of life, and rehabilitation trends to patients who suffer from this injury. Stem cell research, highlighted in this review, seeks to reduce damage caused to the tissue, as also provide spinal cord regeneration through the application of several types of stem cells. On the other hand, research using brain–computer interface (BCI) technology proposes the development of interfaces based on the interaction of neural networks with artificial tools to restore motor control and full mobility of the injured area. PubMed, MEDLINE and SciELO data basis analyses were performed to identify studies published from 2000 to date, which describe the link between SCI with stem cells and BCI technology. 相似文献
Myeloid-derived suppressor cells contribute to the immunosuppressive microenvironment during tumor development and limit the efficacy of cancer immunotherapy. Identifying myeloid-derived suppressor cells and associated factors is the first step in creating strategies to reverse the suppressive effects of these cells on the immune system.
METHODS:
To induce lung cancer, we administered 2 doses of urethane to BALB/c mice and observed these animals for 120 days. After this period, we evaluated the percentage of myeloid-derived suppressor cells in the blood, lung and bone marrow. The expression of alpha-smooth muscle actin, transforming growth factor-β, Toll-like receptor 2, Toll-like receptor 4, and interleukin-6 was also determined in the lung tissue.
RESULTS:
Myeloid-derived suppressor cells were increased in all evaluated tissues after lung cancer development in association with increased Toll-like receptor 4 expression and decreased interleukin-6 expression in the lung. We observed alpha-smooth muscle actin and transforming growth factor-β expression in lung nodules.
CONCLUSIONS:
We believe that the early diagnosis of cancer through determining the blood levels of myeloid-derived suppressor cells followed by the depletion of these cells should be further investigated as a possible approach for cancer treatment. 相似文献
This study aimed to evaluate adherence to antiretroviral treatment (ART) among HIV + adults, assess its association with HIV viral load (VL) and identify factors associated to adherence. A survey involving a random sample of adults followed at a HIV/AIDS reference center in S?o Paulo city, Brazil, from 2007 to 2009 was done. A questionnaire was applied and data were retrieved from the pharmacy and medical records. The study involved 292 subjects: 70.2% men; median age: 43 years; median duration of ART: 8 years. 89.3% self-reported taken all prescribed pills in the last 3 days but only 39.3% picked up ≥95% of the prescribed ART from the pharmacy in the last 12 months. At the multivariate analysis having symptoms prior to ART, taking fewer ART pills, and not missing medical appointments were independently associated to higher adherence. Adherence was strongly associated with undetectable HIV VL. Rates of undetectable HIV VL did not differ from 80 to ≥95% of adherence. 相似文献
This study evaluated if Carbon dioxide (CO2) (λ 10.6 μm) laser irradiation combined with acidulated phosphate fluoride gel application (APF gel) enhances “CaF2” uptake by demineralized enamel specimens (DES) and inhibits enamel lesion progression. Thus, two studies were conducted and DES were subjected to APF gel combined or not with CO2 laser irradiation (11.3 or 20.0 J/cm2, 0.4 or 0.7 W) performed before, during, or after APF gel application. In study 1, 165 DES were allocated to 11 groups. Fluoride as “CaF2 like material” formed on enamel was determined in 100 DES (n?=?10/group), and the surface morphologies of 50 specimens were evaluated by scanning electron microscopy (SEM) before and after “CaF2” extraction. In study 2, 165 DES (11 groups, n?=?15), subjected to the same treatments as in study 1, were further subjected to a pH-cycling model to simulate a high cariogenic challenge. The progression of demineralization in DES was evaluated by cross-sectional microhardness and polarized light microscopy analyses. Laser at 11.3 J/cm2 applied during APF gel application increased “CaF2” uptake on enamel surface. Laser irradiation and APF gel alone arrested the lesion progression compared with the control (p?<?0.05). Areas of melting, fusion, and cracks were observed. CO2 laser irradiation, combined with a single APF application enhanced “CaF2” uptake on enamel surface and a synergistic effect was found. However, regarding the inhibition of caries lesion progression, no synergistic effect could be demonstrated. In conclusion, the results have shown that irradiation with specific laser parameters significantly enhanced CaF2 uptake by demineralized enamel and inhibited lesion progression. 相似文献
Objectives: The aim of this study was to compare the clinical performance of depot medroxyprogesterone acetate (DMPA) in women who received injections every 3 months at the Family Planning Clinic, and those who received every other injection at a health care facility near their place of residence, only returning to the clinic every 6 months.
Materials and methods: The medical charts of DMPA users from 2 January 1980 through 31 December 2012 were evaluated for this study. Two cohorts of women were created and compared: those who regularly received DMPA injections every 3 months (3-month group) at the clinic and those who received alternating 3-month injections at a health care facility near their residence house, returning to the clinic every 6 months for an injection (6-month group). In addition, effectiveness rates, reasons for discontinuation, and continuation rates were evaluated.
Results: Overall, 2637 women received all injections at 3-month intervals at the clinic, and 1190 women received every other injection at a health care facility near their residence. The women in the 3-month group had higher pregnancy rates and higher discontinuation rates (with the exception of discontinuation due to the loss of libido).
Conclusion: The women who received alternating injections near their homes were more likely to continue using DMPA as a contraception method and presented lower pregnancy and discontinuation rates (for the majority of reasons), when compared to those women who returned to the clinic every 3 months. 相似文献
Etidocaine (EDC) is a long lasting local anesthetic, which alleged toxicity has restricted its clinical use. Liposomes can prolong the analgesia time and reduce the toxicity of local anesthetics. Ionic gradient liposomes (IGL) have been proposed to increase the upload and prolong the drug release, from liposomes.
Methods
First, a HPLC method for EDC quantification was validated. Then, large unilamellar vesicles composed of hydrogenated soy phosphatidylcholine:cholesterol with 250 mM (NH4)2SO4 - inside gradient - were prepared for the encapsulation of 0.5% EDC. Dynamic light scattering, nanotracking analysis, transmission electron microscopy and electron paramagnetic resonance were used to characterize: nanoparticles size, polydispersity, zeta potential, concentration, morphology and membrane fluidity. Release kinetics and in vitro cytotoxicity tests were also performed.
Results
IGLEDC showed average diameters of 172.3?±?2.6 nm, low PDI (0.12?±?0.01), mean particle concentration of 6.3?±?0.5?×?1012/mL and negative zeta values (?10.2?±?0.4 mV); parameters that remain stable during storage at 4°C. The formulation, with 40% encapsulation efficiency, induced the sustained release of EDC (ca. 24 h), while reducing its toxicity to human fibroblasts.
Conclusion
A novel formulation is proposed for etidocaine that promotes sustained release and reduces its cytotoxicity. IGLEDC can come to be a tool to reintroduce etidocaine in clinical use.