Demasi M.,Butantan Institute |
Laurindo F.R.M.,University of Sao Paulo
Cardiovascular Research | Year: 2012
Vascular smooth muscle cell (VSMC) plasticity implies a capacity for rapid change and adaptability through processes requiring protein turnover. The ubiquitinproteasome system (UPS) is at the core of protein turnover as the main pathway for the degradation of proteins related to cell-cycle regulation, signalling, apoptosis, and differentiation. This review briefly addresses some structural UPS aspects under the perspective of VSMC (patho)biology. The UPS loss-of-function promotes direct cell effects and many indirect effects related to the adaptation to apoptosis/survival signalling, oxidative stress, and endoplasmic reticulum stress. The UPS regulates redox homeostasis and is redox-regulated. Also, the UPS closely interacts with endoplasmic reticulum (ER) homeostasis as the effector of un/misfolded protein degradation, and ER stress is strongly involved in atherosclerosis. Inhibition of cell cycle-controlling ubiquitin ligases or the proteasome reduces VSMC proliferation and prevents modulation of their synthetic phenotype. Proteasome inhibition also strongly promotes VSMC apoptosis and reduces neointima. In atherosclerosis models, proteasome inhibitors display vasculoprotective effects and reduce inflammation. However, worsening of atherosclerosis or vascular dysfunction has also been reported. Proteasome inhibitors sensitize VSMC to increased ER stress-mediated cell death and suppress unfolded protein response signalling. Taken together, these observations show that the UPS has powerful effects in the control of VSMC phenotype and survival signalling. However, more profound knowledge of mechanisms is needed in order to render the UPS an operational therapeutic target. © 2012 The Author.
Kretzer I.F.,University of Sao Paulo |
Maria D.A.,Butantan Institute |
Maranhao R.C.,University of Sao Paulo
Cellular Oncology | Year: 2012
Background Lipid nanoemulsions (LDE) may be used as carriers of paclitaxel (PTX) and etoposide (ETP) to decrease toxicity and increase the therapeutic action of those drugs. The current study investigates the combined chemotherapy with PTX and ETP associated with LDE. Methods Four groups of 10-20 B16F10 melanoma-bearing mice were treated with LDE-PTX and LDE-ETP in combination (LDE-PTX+ETP), commercial PTX and ETP in combination (PTX+ETP), single LDE-PTX, and single LDE-ETP. PTX and ETX doses were 9 μmol/kg administered in three intraperitoneal injections on three alternate days. In two control groups mice were treated with saline solution or LDE alone. Tumor growth, metastasis presence, cell-cycle distribution, blood cell counts and histological data were analyzed. Toxicity of all treatments was evaluated in mice without tumors. Results Tumor growth inhibition was similarly strong in all treatment groups. However, there was a greater reduction in the number of animals bearing metastases in the LDE-PTX+ ETP group (30 %) in comparison to the PTX+ETP group (82 %, p>0.05). Reduction of cellular density, blood vessels and increase of collagen fibers in tumor tissues were observed in the LDE-PTX+ETP group but not in the PTX+ETP group, and in both groups reduced melanoma-related anemia and thrombocytosis were observed. Flow cytometric analysis suggested that LDE-PTX+ETP exhibited greater selectivity to neoplastic cells than PTX-ETP, showing arrest (65 %) in the G2/M phase of the cell cycle (p>0.001). Toxicity manifested by weight loss and myelosuppression was markedly milder in the LDE-PTX+ETP than in the PTX+ETP group. Conclusion LDE-PTX+ETP combined drug-targeting therapy showed markedly superior anti-cancer properties and reduced toxicity compared to PTX+ETP.© International Society for Cellular Oncology 2012.
Alvarez Flores M.P.,Butantan Institute
Pathophysiology of Haemostasis and Thrombosis | Year: 2010
Despite the nearly worldwide distribution of Lepidoptera, there are few species with clear documentation of adverse reactions in humans. Most syndromes caused by Lepidoptera are consequences of direct contact with the hairs or setae of caterpillars. In most instances, the adverse effects caused by moth and caterpillars are self-limited and the treatment is based on the removal of hairs, application of topical antipruritics and, in some cases, the use of oral antihistamines. However, in the case of envenoming by South American Lonomiaobliqua caterpillars, the antilonomic serum produced at Instituto Butantan in Brazil is the only effective treatment to re-establish the physiological coagulation parameters in poisoned patients and to abolish the complications seen in severe cases (e.g. consumptive coagulopathy, intracerebral hemorrhage, and acute renal failure). Many studies have been carried out to understand the pathophysiological mechanism of envenoming by L. obliqua. Several toxic principles were found in bristle extract and the hemolymph, probably related to the envenoming. An interesting fact is that some toxins from the venom usually have more than one function. With the advent of molecular biology techniques it has become possible to analyze these processes at a molecular level, thus giving rise to hypotheses on the molecular basis of envenomation. This review contributes to enhance our understanding of the dramatic alterations that hemorrhagic syndrome causes in patients, current treatment, and the diversity of the molecules involved in this pathology. Copyright © 2010 S. Karger AG, Basel.
News Article | March 4, 2016
Coral snake venom carries significant neurotoxicity and human injuries can be severe or even lethal. Despite this, antivenom treatments are scarce due to challenges collecting adequate amounts of venom needed to produce anti-elapidic serum. PLOS Neglected Tropical Diseases highlights exciting new research from the Butantan Institute in Brazil using synthetically designed DNA to produce coral-snake antivenom.
Forget mosquito bites. Volunteers let researchers inject them with the dengue virus in the name of science - and an experimental vaccine protected them. Next up, scientists plan to use this same strategy against dengue's cousin, the Zika virus. It's called a human challenge, a little-known but increasing type of research where healthy people agree to be deliberately infected in the quest for new or improved vaccines against a variety of health threats, from flu to malaria. Wednesday's dengue study offered more evidence that what sounds bizarre not only can be done safely, it can offer important clues for how well a shot might work. "What we're trying to do is accelerate vaccine research," said senior author Dr. Anna Durbin of Johns Hopkins University's school of public health. It may be the best way "to know if you have a stinker before you try to test it in thousands or tens of thousands of people." The dengue candidate proved highly promising, researchers reported in the journal Science Translational Medicine. Dengue fever may have slipped from the headlines as the related Zika virus sweeps through Latin America, but every year mosquito-borne dengue causes devastating outbreaks throughout the tropics and subtropics. While most people survive dengue with few or even no symptoms, more than 2 million a year suffer serious illness and about 25,000 die. Creating a vaccine has been tough. It must work against four separate strains of dengue, and a shot that's only partially protective might backfire. That's because people who survive one type of dengue can suffer worse symptoms if they're later infected with another strain. Enter an experimental vaccine created at the National Institutes of Health, made from four live but weakened dengue strains. Initial studies had suggested the shots were safe and promising. But, "we really wanted to have an early clue that it was go to work," especially against the hard-to-prevent dengue serotype 2, said Dr. Stephen Whitehead of NIH's National Institute of Allergy and Infectious Diseases, who led the vaccine development. Researchers at Hopkins and the University of Vermont gave 41 healthy people who'd never been exposed to dengue either a single dose of the vaccine or a dummy shot. Six months later, those volunteers were challenged - injected with a weakened version of that dengue-2 strain. The results were striking: All 21 people who'd gotten the real vaccine were completely protected - while all 20 who'd gotten a placebo had dengue virus in their bloodstream and either a mild rash or a temporary drop in white blood cell count, researchers reported Wednesday. This kind of study mimics "the closest that it can be to what may happen in natural infection," said Dr. Nikos Vasilakis, a virologist at the University of Texas Medical Branch in Galveston, who wasn't involved in the new work but calls the NIH shot "one of the better vaccine candidates." Based in part on the findings, the Butantan Institute in Brazil last month began recruiting 17,000 people, ages 2 to 59, for the final testing needed to prove how well the NIH vaccine works against dengue in real-world conditions, when it is spread by mosquitoes. A competing vaccine, made by Sanofi Pasteur, recently was approved by Brazilian regulators for ages 9 to 45. What about Zika, the dengue relative that's been linked to babies born with unusually small heads? Already, researchers are planning similar challenge studies that could start even before there's a vaccine candidate, Durbin said. "We see a Zika challenge model as really beneficial for not only vaccine development but also to learn more about Zika itself," she explained. "We know very little about Zika right now," including how long it stays in blood and other parts of the body. Key to these challenge studies: Scientists must modify a virus strain in the laboratory so that it doesn't make volunteers openly ill but still is strong enough to spark a mild infection, what Whitehead called "that perfect in-between." Plus, that mimics what happens with both dengue and Zika, where most people who become infected never report symptoms. Before deliberately infecting someone, "you have to know that it's a completely controllable situation, that it's a mild and controlled infection," said Dr. Beth Kirkpatrick, who directs the University of Vermont Vaccine Testing Center that tested the dengue model.