Can the dopaminergic-related effects of general anesthetics be linked to mechanisms involved in drug abuse and addiction?

BACKGROUND: General anesthetics (GA) are well known for the ability to induce a state of reversible loss of consciousness and unresponsiveness to painful stimuli. However, evidence from animal models and clinical studies show that GA exposure may induce behavioral changes beyond acute effects. Most research and concerns are focused on changes in cognition and memory. METHODS: We will look at effects of GA on behavior that is mediated by the dopaminergic system. RESULTS: Pharmacological resemblance of GA with drugs of abuse, and the complexity and importance of dopaminergic systems in both reward seeking and addictive illnesses make us believe that it deserves an overview about what is already known and what matters to us as healthcare workers and specifically as anesthesiologists. CONCLUSION: A review of available evidence strongly suggests that there may be a link between the effects of GA on the brain and substance abuse, partly explained by their influence on the dopaminergic system.

In vitro chondrogenic commitment of human Wharton's jelly stem cells by co-culture with human articular chondrocytes.

Wharton's jelly stem cells (WJSCs) are a potential source of transplantable stem cells in cartilage-regenerative strategies, due to their highly proliferative and multilineage differentiation capacity. We hypothesized that a non-direct co-culture system with human articular chondrocytes (hACs) could enhance the potential chondrogenic phenotype of hWJSCs during the expansion phase compared to those expanded in monoculture conditions. Primary hWJSCs were cultured in the bottom of a multiwell plate separated by a porous transwell membrane insert seeded with hACs. No statistically significant differences in hWJSCs duplication number were observed under either of the culture conditions during the expansion phase. hWJSCs under co-culture conditions show upregulations of collagen type I and II, COMP, TGFβ1 and aggrecan, as well as of the main cartilage transcription factor, SOX9, when compared to those cultured in the absence of chondrocytes. Chondrogenic differentiation of hWJSCs, previously expanded in co-culture and monoculture conditions, was evaluated for each cellular passage using the micromass culture model. Cells expanded in co-culture showed higher accumulation of glycosaminoglycans (GAGs) compared to cells in monoculture, and immunohistochemistry for localization of collagen type I revealed a strong detection signal when hWJSCs were expanded under monoculture conditions. In contrast, type II collagen was detected when cells were expanded under co-culture conditions, where numerous round-shaped cell clusters were observed. Using a micromass differentiation model, hWJSCs, previously exposed to soluble factors secreted by hACs, were able to express higher levels of chondrogenic genes with deposition of cartilage extracellular matrix components, suggesting their use as an alternative cell source for treating degenerated cartilage.

The synthesis of novel 5-aminoimidazoles derivatives with anticancer activity

[Excerpt] The imidazole nucleus is present in a significant number of biomolecules and the inclusion of this moiety in organic scaffolds is considered an important synthetic strategy in drug discovery.[1] 5-Aminoimidazoles are interesting building blocks in medicinal chemistry since they are key components in many bioactive molecules and their derivatives showed a wide pharmacological potential as anticancer drugs.[1] The hydrazones constitute an important class of biological active drug molecules due to their wide range of pharmacological properties that include antitumoral activities.[2] Amidrazone derivatives could be considered very promising in the perspective of new drug discovery, because they are very effective as building blocks to obtain various heterocycles.[2,3] The α-hydrazononitriles are a special case of compounds belonging to the family of hydrazones that is less common in the literature, but has a great interest due to their pharmacological applications.[4] (...)

A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B

Amanita phalloides is responsible for more than 90 % of mushroom-related fatalities, and no effective antidote is available. a-Amanitin, the main toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and kidney failure. In silico studies included docking and molecular dynamics simulation coupled to molecular mechanics with generalized Born and surface area method energy decomposition on RNAP II. They were performed with a clinical drug that shares chemical similarities to a-amanitin, polymyxin B. The results show that polymyxin B potentially binds to RNAP II in the same interface of a-amanitin, preventing the toxin from binding to RNAP II. In vivo, the inhibition of the mRNA transcripts elicited by a-amanitin was efficiently reverted by polymyxin B in the kidneys. Moreover, polymyxin B significantly decreased the hepatic and renal a-amanitin-induced injury as seen by the histology and hepatic aminotransferases plasma data. In the survival assay, all animals exposed to a-amanitin died within 5 days, whereas 50 % survived up to 30 days when polymyxin B was administered 4, 8, and 12 h post-a-amanitin. Moreover, a single dose of polymyxin B administered concomitantly with a-amanitin was able to guarantee 100 % survival. Polymyxin B protects RNAP II from inactivation leading to an effective prevention of organ damage and increasing survival in a-amanitin-treated animals. The present use of clinically relevant concentrations of an already human-use-approved drug prompts the use of polymyxin B as an antidote for A. phalloides poisoning in humans.

Magnetoliposomes based on manganese ferrite nanoparticles as nanocarriers for antitumor drugs

Manganese ferrite nanoparticles with a size distribution of 26 ± 7 nm (from TEM measurements) were synthesized by the coprecipitation method. The obtained nanoparticles exhibit a superparamagnetic behaviour at room temperature with a magnetic squareness of 0.016 and a coercivity field of 6.3 Oe. These nanoparticles were either entrapped in liposomes (aqueous magnetoliposomes, AMLs) or covered with a lipid bilayer, forming solid magnetoliposomes (SMLs). Both types of magnetoliposomes, exhibiting sizes below or around 150 nm, were found to be suitable for biomedical applications. Membrane fusion between magnetoliposomes (both AMLS and SMLs) and GUVs (giant unilamellar vesicles), the latter used as models of cell membranes, was confirmed by F¨orster Resonance Energy Transfer (FRET) assays, using a NBD labeled lipid as the energy donor and Nile Red or rhodamine B-DOPE as the energy acceptor. A potential antitumor thienopyridine derivative was successfully incorporated into both aqueous and solid magnetoliposomes, pointing to a promising application of these systems in oncological therapy, simultaneously as hyperthermia agents and nanocarriers for antitumor drugs.

Biosurfactants produced by marine microorganisms with therapeutic applications

Marine microorganisms possess unique metabolic and physiological features and are an important source of new biomolecules, such as biosurfactants. Some of these surface-active compounds synthesized by marine microorganisms exhibit antimicrobial, anti-adhesive and anti-biofilm activity against a broad spectrum of human pathogens (including multi-drug resistant pathogens), and could be used instead of the existing drugs to treat infections caused by them. In other cases, these biosurfactants show anti-cancer activity, which could be envisaged as an alternative to conventional therapies. However, marine biosurfactants have not been widely explored, mainly due to the difficulties associated with the isolation and growth of their producing microorganisms. Culture-independent techniques (metagenomics) constitute a promising approach to study the genetic resources of otherwise inaccessible marine microorganisms without the requirement of culturing them, and can contribute to discover novel biosurfactants with significant biological activities. This paper reviews the most relevant biosurfactants produced by marine microorganisms with potential therapeutic applications and discusses future perspectives and opportunities to discover novel molecules from marine environments.

Treating the entire person

[Excerpt] A critical case from a Portuguese hospital reveals how the ultimate healthcare customer, the patient, is a complete system, not a jumble of parts. (...) The lean production philosophy has made inroads into service sectors, including medical care in the United Kingdom and the United States. Unfortunately, numerous medical organizations in those two countries and the rest of the world treat patients like they are made up of parts, not as a whole system. This leads to disjointed handoffs, bottlenecks in information flow that delay treatment, and sending the patient back and forth from department to department. The following case in Portugal shows how most of the world’s health systems still suffer from functional silos and how waste is all over the place. In this case, the missing links in communication between doctors, nurses, auxiliary staff, the patient and her family led to the patient’s death. Adopting lean healthcare with its proven tools would be a solution to many of the problems described. When a patient dies in a hospital, the family often is told that the doctors did everything they could. Normally, that is the case, as healthcare providers – doctors, nurses, auxiliary staff, therapists – do their best with the system they have.

Propolis: A complex natural product with a plethora of biological activities that can be explored for drug development

The health industry has always used natural products as a rich, promising, and alternative source of drugs that are used in the health system. Propolis, a natural resinous product known for centuries, is a complex product obtained by honey bees from substances collected from parts of different plants, buds, and exudates in different geographic areas. Propolis has been attracting scientific attention since it has many biological and pharmacological properties, which are related to its chemical composition. Several in vitro and in vivo studies have been performed to characterize and understand the diverse bioactivities of propolis and its isolated compounds, as well as to evaluate and validate its potential. Yet, there is a lack of information concerning clinical effectiveness. The goal of this review is to discuss the potential of propolis for the development of new drugs by presenting published data concerning the chemical composition and the biological properties of this natural compound from different geographic origins.

Magnetoliposomes based on manganese ferrite nanoparticles as nanocarriers for antitumor drugs

Publicado em "NanoPT2016 book of abstracts"