Display omitted
Sophorolipids (SLs) are biosurfactants synthesized as secondary metabolites by non-pathogenic yeasts and other microorganisms. They are members of glycolipid microbial surfactant ...family that consists of a sophorose polar head group and, most often, an ω-1 hydroxylated fatty acid glycosidically linked to the sophorose moiety. Since the fermentative production of SLs is high (>200 g/L), SLs have the potential to provide low-cost therapeutics. Natural and modified SLs possess anti-cancer activity against a wide range of cancer cell lines such as those derived from breast, cervical, colon, liver, brain, and the pancreas. Corresponding data on their cytotoxicity against noncancerous cell lines including human embryo kidney, umbilical vein, and mouse fibroblasts is also discussed. These results are compiled to elucidate trends in SL-structures that lead to higher efficacy against cancer cell lines and lower cytotoxicity for normal cell lines. While extrapolation of these results provides some insights into the design of SLs with optimal therapeutic indices, we also provide a critical assessment of gaps and inconsistencies in the literature as well as the lack of data connecting structure-to-anticancer and cytotoxicity on normal cells. Furthermore, SL-mechanism of action against cancer cell lines, that includes proliferation inhibition, induction of apoptosis, membrane disruption and mitochondria mediated pathways are discussed. Perspectives on future research to develop SL anticancer therapeutics is discussed.
Developing new antimicrobials as alternatives to conventional antibiotics has become an urgent race to eradicate drug-resistant bacteria and to save human lives. Conventionally, antimicrobial ...molecules are studied independently even though they can be cosecreted in vivo. In this research, we investigate two classes of naturally derived antimicrobials: sophorolipid (SL) esters as modified yeast-derived glycolipid biosurfactants that feature high biocompatibility and low production cost; piscidins, which are host defense peptides (HDPs) from fish. While HDPs such as piscidins target the membrane of pathogens, and thus result in low incidence of resistance, SLs are not well understood on a mechanistic level. Here, we demonstrate that combining SL–hexyl ester (SL-HE) with subinhibitory concentration of piscidins 1 (P1) and 3 (P3) stimulates strong antimicrobial synergy, potentiating a promising therapeutic window. Permeabilization assays and biophysical studies employing circular dichroism, NMR, mass spectrometry, and X-ray diffraction are performed to investigate the mechanism underlying this powerful synergy. We reveal four key mechanistic features underlying the synergistic action: (1) P1/3 binds to SL-HE aggregates, becoming α-helical; (2) piscidin–glycolipid assemblies synergistically accumulate on membranes; (3) SL-HE used alone or bound to P1/3 associates with phospholipid bilayers where it induces defects; (4) piscidin–glycolipid complexes disrupt the bilayer structure more dramatically and differently than either compound alone, with phase separation occurring when both agents are present. Overall, dramatic enhancement in antimicrobial activity is associated with the use of two membrane-active agents, with the glycolipid playing the roles of prefolding the peptide, coordinating the delivery of both agents to bacterial surfaces, recruiting the peptide to the pathogenic membranes, and supporting membrane disruption by the peptide. Given that SLs are ubiquitously and safely used in consumer products, the SL/peptide formulation engineered and mechanistically characterized in this study could represent fertile ground to develop novel synergistic agents against drug-resistant bacteria.
Initial therapy of multiple myeloma with lenalidomide-based regimens can compromise stem cell collection, which can be overcome with the addition of plerixafor. Plerixafor is typically given ...subcutaneously (SQ), with collection ∼11 h later for maximum yield. Intravenous administration may allow more rapid and predictable mobilization. This trial was designed to assess the efficacy and feasibility of IV plerixafor in patients receiving initial therapy with a lenalidomide-based regimen. Patients received G-CSF at 10 μg/kg/day for 4 days followed by IV plerixafor at 0.24 mg/kg/dose starting on day 5; plerixafor was administered early in the morning with apheresis 4-5 h later. Thirty-eight (97%) patients collected at least 3 × 10(6) CD34+ cells/kg within 2 days of apheresis. The median CD34+ cells/kg after 1 day of collection was 3.9 × 10(6) (range: 0.7-9.2) and after 2 days of collection was 6.99 × 10(6) (range: 1.1-16.5). There were no grade 3 or 4 non-hematological adverse events, and one patient experienced grade 4 thrombocytopenia. The most common adverse events were nausea, diarrhea and abdominal bloating. IV plerixafor is an effective strategy for mobilization with low failure rate and is well tolerated. It offers flexibility with a schedule of early-morning infusion followed by apheresis later in the day.
Sophorolipids are biosurfactants derived from the nonpathogenic yeasts such as Starmerella bombicola with potential efficacy in anticancer applications. Simple and cost-effective synthesis of these ...drugs makes them a promising alternative to traditional chemotherapeutics, pending their success in preliminary drug-screening. Drug-screening typically utilizes 2D cell monolayers due to their simplicity and ease of high-throughput assessment. However, 2D assays fail to capture the complexity and 3D context of the tumor microenvironment and have consequently been implicated in the high percentage of drugs investigated in vitro that later fail in clinical trials. Herein, we screened two sophorolipid candidates and a clinically-used chemotherapeutic, doxorubicin, on in vitro breast cancer models ranging from 2D monolayers to 3D spheroids, employing optical coherence tomography to confirm these morphologies. We calculated corresponding IC50 values for these drugs and found one of the sophorolipids to have comparable toxicities to the chemotherapeutic control. Our findings show increased drug resistance associated with model dimensionality, such that all drugs tested showed that 3D spheroids exhibited higher IC50 values than their 2D counterparts. These findings demonstrate promising preliminary data to support the use of sophorolipids as a more affordable alternative to traditional clinical interventions and demonstrate the importance of 3D tumor models in assessing drug response.
There has been growing interest in the use of voluntary agreements (VAs) as an environmental policy tool. This article uses a simple model to determine whether VAs are likely to lead to efficient ...environmental protection. We consider cases where polluters are induced to participate either by a background threat of mandatory controls (the “stick” approach) or by cost-sharing subsidies (the “carrot” approach). The results suggest that the overall impact on environmental quality could be positive or negative, depending on a number of factors, including the allocation of bargaining power, the magnitude of the background threat, and the social cost of funds.
Surfactin, a negatively charged amphiphilic lipopeptide biosurfactant, is synthesized by the bacterium Bacillus subtilis. It consists of a cyclic heptapeptide and an 11–15C β-hydroxy fatty acid. To ...probe how the modification of the molecular skeleton of surfactin influences its selectivity and activity against breast cancer, six synthetic surfactins were generated. Modifications were accomplished by conjugating amine-functionalized molecules to the Glu and Asp carboxyl moieties of the heptapeptide. The resulting synthetic surfactins provided a diverse series of molecules with differences in charge, size, and hydrophilicity. After purification and structural analysis, insights into biological activity and specificity were generated for each compound. Dose-dependent growth inhibition was determined for four tumorigenic breast cancer cell lines in monolayer and spheroid morphologies, as well as nontumorigenic fibroblasts and sheep erythrocytes, which were utilized to determine selectivity indices. Results indicated that two compounds, which have amplified anionic charge, had increased activity on breast cancer, with reduced activity on nontumorigenic fibroblasts and erythrocytes. Cationic derivative surf-ethylenediamine has increased activity on all cell lines tested. Novel correlations between dose–response activities and physicochemical properties of all compounds determined that there is a significant correlation between the critical micelle concentration and activity against multiple cell lines.
This paper develops a general theory of land inheritance rules that distinguishes between two classes of rules: those allowing a testator discretion in disposing of his land (e.g., a best-qualified ...rule) and those constraining his choice (e.g., primogeniture). The primary benefit of the latter is to prevent rent seeking by heirs, but the cost is that the testator cannot use information about the relative abilities of his heirs to manage the land. We also account for the impact of scale economies in land use, and discuss the impact of the presence of a land market on the form of the inheritance rule. We conclude by offering some empirical tests of the model using a cross-cultural sample of societies.
► Ottomans heavily regulated printing for centuries; printing quickly spread in Europe. ► Different reaction to technology explained by economic incentives of rulers and agents. ► Cultural arguments ...do not suffice; Ottomans quickly adopted military technology. ► Printing regulations prevented undermining legitimacy given by religious authorities. ► Ottomans allowed printing in 18th century after other sources of legitimacy emerged.
New technologies have not always been greeted with full enthusiasm. Although the Ottomans were quick to adopt advancements in military technology, they waited almost three centuries to sanction printing in Ottoman Turkish (in Arabic characters). Printing spread relatively rapidly throughout Europe following the invention of the printing press in 1450 despite resistance by interest groups and temporary restrictions in some countries. We explain differential reaction to technology through a political economy approach centered on the legitimizing relationships between rulers and their agents (e.g., military, religious, or secular authorities). The Ottomans regulated the printing press heavily to prevent the loss it would have caused to the ruler’s net revenue by undermining the legitimacy provided by religious authorities. On the other hand, the legitimizing relationship between European religious and political authorities was undermined over a century prior to the invention of the press. European rulers thus had little reason to stop the spread of printing as public policy, nor could the Church have stopped it had it wanted to. The Ottomans eventually sanctioned printing in Arabic script in the 18th century after alternative sources of legitimacy emerged.
Conventional tort law does not allow exposure victims to seek compensation until they develop symptoms of illness. Because this may bar recovery if the injurer is judgment proof some have advocated ...allowing victims to sue at exposure. However, critics charge that such a tort for risk would create a "race to file" We show that a race may or may not occur in equilibrium, and that when it does occur, not all victims choose to file even if bankruptcy is an inevitable result. We examine the consequences of the possible equilibria on compensation of victims, litigation costs, and injurer care.
PDF
