New drugs from traditional medicines: pharmacological evaluation of plant extracts from Chapada Diamantina (Brazil)

Plants are rich sources of medicines and Brazil is among the most biodiverse nations in the world.info:eu-repo/semantics/publishedVersio

Biocompatibility of a self-assembled glycol chitosan nanogel

The research of chitosan-based nanogel for biomedical applications has grown exponentially in the last years; however, its biocompatibility is still insufficiently reported. Hence, the present work provides a thorough study of the biocompatibility of a glycol chitosan (GC) nanogel. The obtained results showed that GC nanogel induced slight decrease on metabolic activity of RAW, 3T3 and HMEC cell cultures, although no effect on cell membrane integrity was verified. The nanogel does not promote cell death by apoptosis and/or necrosis, exception made for the HMEC cell line challenged with the higher GC nanogel concentration. Cell cycle arrest on G1 phase was observed only in the case of RAW cells. Remarkably, the nanogel is poorly internalized by bone marrow derived macrophages and does not trigger the activation of the complement system. GC nanogel blood compatibility was confirmed through haemolysis and whole blood clotting time assays. Overall, the results demonstrated the safety of the use of the GC nanogel as drug delivery system.Paula Pereira thanks FCT, the Ph.D. grant ref SFRH/BD/64977/2009. This work was also supported by a grant from the Spanish Ministry of Economy and Competitivity (SAF2011-30337-C02-02). We also acknowledge the European Union Seventh Framework Programme [FP7/REGPOT-2012-2013.1] under grant agreement BIOCAPS-316265. MP acknowledges fellowship from Spanish Ministry of Education (FPU predoctoral grant program)

Quercetin enhances 5-fluorouracil-induced apoptosis in MSI colorectal cancer cells through p53 modulation

Purpose: Colorectal tumors (CRC) with microsatellite instability (MSI) show resistance to chemotherapy with 5-fluorouracil (5-FU), the most widely used pharmacological drug for CRC treatment. The aims of this study were to test the ability of quercetin (Q) and luteolin (L) to increase sensitivity of MSI CRC cells to 5-FU and characterize the dependence of the effects on cells´ p53 status. Methods: Two MSI human CRC derived cell lines were used, CO115 wild-type (wt) for p53 and HCT15 that harbors a p53 mutation. Apoptosis induction in these cells by 5-FU, Q and L alone and in combinations were evaluated by TUNEL and western. The dependence on p53 of the effects was confirmed by small interference RNA (siRNA) in CO115 cells and in MSI HCT116 wt and p53 knockout cells. Results: CO115 p53-wt cells are more sensitive to 5-FU than the p53 mutated HCT15. The combination treatment of 5-FU with L and Q increased apoptosis with a significant effect for Q in CO115. Both flavonoids increased p53 expression in both cell lines, an effect particularly remarkable for Q. The significant apoptotic enhancement in CO115 incubated with Q plus 5-FU involved the activation of the apoptotic mitochondrial pathway. Importantly, knockdown of p53 by siRNA in CO115 cells and p53 knockout in HCT116 cells totally abrogated apoptosis induction, demonstrating the dependence of the effect on p53 modulation by Q. Conclusion: This study suggests the potential applicability of these phytochemicals for enhancement 5-FU efficiency in MSI CRC therapy, especially Q in p53 wt tumors.CPRX was supported by the Foundation for Science and Technology (FCT), Portugal, through the grant SFRH/BD/27524/2006 and the work was supported by the FCT research grant PTDC/AGR-AAM/70418/2006

Anticancer effects of lactoferrin: underlying mechanisms and future trends in cancer therapy

Lactoferrin has been widely studied over the last 70 years, and its role in diverse biological functions is now well known and generally accepted by the scientific community. Usually, alterations of the lactoferrin gene in cells are associated with an increased incidence of cancer. Several studies suggest that exogenous treatment with lactoferrin and its derivatives can efficiently inhibit the growth of tumors and reduce susceptibility to cancer. None of these studies, however, reported a consistent outcome with regard to the mechanisms underlying the anticancer effects of lactoferrin. In this review, the association of lactoferrin with cancer is thoroughly discussed, from lactoferrin gene expression to the potential use of lactoferrin in cancer therapy. Lactoferrin cytotoxicity against several cancers is reported to occur in distinct ways under different conditions, namely by cell membrane disruption, apoptosis induction, cell cycle arrest, and cell immunoreaction. Based on these mechanisms, new strategies to improve the anticancer effects of the lactoferrin protein and/or its derivatives are proposed. The potential for lactoferrin in the field of cancer research (including as a chemotherapeutic agent in cancer therapy) is also discussed.Funding. Financial support was received from the Erasmus Mundus External Cooperation Window (Y), the Strategic Project PEst-OE/EQB/LA0023/2013, and the Fundacao para a Ciencia e a Tecnologia (project reference RECI/BBB-EBI/0179/2012; project no. FCOMP-01-0124-FEDER-027462)

Heat Stress and Hormetin-Induced Hormesis in Human Cells: Effects on Aging, Wound Healing, Angiogenesis, and Differentiation

Accumulation of molecular damage and increased molecular heterogeneity are hallmarks of cellular aging. Mild stress-induced hormesis can be an effective way for reducing the accumulation of molecular damage, and thus slowing down aging from within. We have shown that repeated mild heat stress (RMHS) has anti-aging effects on growth and various other cellular and biochemical characteristics of normal human skin fibroblasts and keratinocytes undergoing aging in vitro. RMHS given to human cells increased the basal levels of various chaperones, reduced the accumulation of damaged proteins, stimulated proteasomal activities, increased the cellular resistance to other stresses, enhanced the levels of various antioxidant enzymes, enhanced the activity and amounts of sodium-potassium pump, and increased the phosphorylation-mediated activities of various stress kinases. We have now observed novel hormetic effects of mild heat stress on improving the wound healing capacity of skin fibroblasts and on enhancing the angiogenic ability of endothelial cells. We have also tested potential hormetins, such as curcumin and rosmarinic acid in bringing about their beneficial effects in human cells by inducing stress response pathways involving heat shock proteins and hemeoxygenase HO-1. These data further support the view that mild stress-induced hormesis can be applied for the modulation, intervention and prevention of aging and age-related impairments

Metformin-like effect of salvia officinalis (common sage) : is it useful in diabetes prevention?

Common sage (Salvia officinalis L) is among the plants that are claimed to be beneficial to diabetic patients, and previous studies have suggested that some of its extracts have hypoglycaemic effects in normal and diabetic animals. In this study we purposed to verify the antidiabetic effects of the most common form of consumption of this plant as an infusion (tea). Replacing water with sage tea for 14 days lowered fasting plasma glucose in normal mice but had no effect on glucose clearance in response to an intraperitoneal glucose tolerance test. This indicated effects at level of the liver on gluconeogenesis. Hepatocyte primary cultures of healthy sage tea drinking rats showed, after stimulation, high glucose uptake capacity and a decreased gluconeogenesis in response to glucagon. Sage essential oil further increased hepatocyte sensitivity to insulin and inhibited gluconeogenesis. Overall these effects resemble those of the pharmaceutical drug metformin, a known inhibitor of gluconeogenesis used in the treatment and prevention of type 2 diabetes mellitus. In primary cultures of rat hepatocytes isolated from streptozotocin-induced diabetic rats none of these activities were observed. These results seem to indicate that sage tea does not possess antidiabetic effects at this level. However, its effects on fasting glucose levels in normal animals and the metformin-like effects on rat hepatocytes suggest that sage may be useful as food supplement in the prevention of type 2 diabetes mellitus by lowering plasma glucose of individuals at risk.Fundação para a Ciência e Tecnologia - FCT SFRH/BD/6942/2001; SFRH/BD/12527/2003; POCTI/AGR/62040/2004

Bovine lactoferrin induces cell cycle arrest and inhibits mTOR signaling in breast cancer cells

Lactoferrin (LF) is predominantly found in mammalian secretions with recognized anticancer potential, although the mechanisms involved in such activity are still unclear. Here, the stability, internalization, and cytotoxicity of bovine LF (bLF) and its variants were tested against a panel of breast cancer cells. bLF was found to be very stable under incubation with cells and also able to internalize them, although most of the protein remained in the culture medium. Furthermore, bLF (up to 30 μM) inhibited the growth of breast cancer cells (T-47D, MDA-MB-231, Hs578T, and MCF-7) in a higher extent than in the normal counterpart cell line (MCF-10-2A), thus suggesting its selectivity. Regarding its variants, only the iron-saturated protein showed a higher activity compared with the commercial bLF. bLF growth inhibitory activity was associated with the induction of cell cycle arrest, but not with apoptosis. Moreover, exposure to bLF increased the cells phospho-AMPKα levels and decreased both phospho threonine mammalian target of rapamycin (mTOR) and total mTOR levels, indicating a novel mechanism of action through its ability to induce nutrient/energy-related stress. This study disclosed important findings to better understand the mechanisms underlying the bLF effects on breast cancer cell lines, which could be valuable for novel advances in the cancer research field.We acknowledge the financial support from Erasmus Mundus External Cooperation window (Bridging the Gap), the Strategic Projects PEst-OE/EQB/LA0023/2013 and PEst-OE/AGR/UI4033/2014, as well as the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462), all funded by Fundacao para a Ciencia e a Tecnologia

Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography Main Results From the Randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT)

Background-It remains uncertain whether acetylcysteine prevents contrast-induced acute kidney injury. Methods and Results-We randomly assigned 2308 patients undergoing an intravascular angiographic procedure with at least 1 risk factor for contrast-induced acute kidney injury (age >70 years, renal failure, diabetes mellitus, heart failure, or hypotension) to acetylcysteine 1200 mg or placebo. The study drugs were administered orally twice daily for 2 doses before and 2 doses after the procedure. The allocation was concealed (central Web-based randomization). All analysis followed the intention-to-treat principle. The incidence of contrast-induced acute kidney injury (primary end point) was 12.7% in the acetylcysteine group and 12.7% in the control group (relative risk, 1.00; 95% confidence interval, 0.81 to 1.25; P = 0.97). A combined end point of mortality or need for dialysis at 30 days was also similar in both groups (2.2% and 2.3%, respectively; hazard ratio, 0.97; 95% confidence interval, 0.56 to 1.69; P = 0.92). Consistent effects were observed in all subgroups analyzed, including those with renal impairment. Conclusions-In this large randomized trial, we found that acetylcysteine does not reduce the risk of contrast-induced acute kidney injury or other clinically relevant outcomes in at-risk patients undergoing coronary and peripheral vascular angiography.Ministério da Saúde do BrasilBrazilian Ministry of Healt