Doxil®--the first FDA-approved nano-drug: lessons learned.

Solubilization of membranes by detergents

Photodynamic therapy (PDT) employs a non-toxic dye, termed a photosensitizer (PS), and low intensity visible light which, in the presence of oxygen, combine to produce cytotoxic species. PDT has the advantage of dual selectivity, in that the PS can be targeted to its destination cell or tissue and, in addition, the illumination can be spatially directed to the lesion. PDT has previously been used to kill pathogenic microorganisms in vitro, but its use to treat infections in animal models or patients has not, as yet, been much developed. It is known that Gram-(−) bacteria are resistant to PDT with many commonly used PS that will readily lead to phototoxicity in Gram-(+) species, and that PS bearing a cationic charge or the use of agents that increase the permeability of the outer membrane will increase the efficacy of killing Gram-(−) organisms. All the available evidence suggests that multi-antibiotic resistant strains are as easily killed by PDT as naive strains, and that bacteria will not readily develop resistance to PDT. Treatment of localized infections with PDT requires selectivity of the PS for microbes over host cells, delivery of the PS into the infected area and the ability to effectively illuminate the lesion. Recently, there have been reports of PDT used to treat infections in selected animal models and some clinical trials: mainly for viral lesions, but also for acne, gastric infection by Helicobacter pylori and brain abcesses. Possible future clinical applications include infections in wounds and burns, rapidly spreading and intractable soft-tissue infections and abscesses, infections in body cavities such as the mouth, ear, nasal sinus, bladder and stomach, and surface infections of the cornea and skin.

Photodynamic therapy: a new antimicrobial approach to infectious disease?

The idea that glycosphingolipids (or, briefly, glycolipids) are ubiquitous components of plasma membrane and display cell type-specific patterns perhaps stemmed from the classical studies on glycolipids of erythrocyte membranes.(1,2) Subsequently, plasma membranes of various animal cells were successfully isolated and analyzed; all were characterized by their much higher content of glycolipid than was found in intracellular membranes.(3–8) It is generally assumed that glycolipids are present at the outer leaflet of the plasma membrane bilayer, although this assumption is based only on experiments with surface-labeling by galactose oxidase-NaB[3H]4 of intact and lysed erythrocyte membranes and inside-out vesicles.(9,10) Obviously, further extensive studies of the organization of glycolipid in other eukaryotic cell membranes are necessary. Interestingly, the majority of neutral glycolipids present in plasma membranes are cryptic (see Section 4.2.1).

Glycosphingolipids in Cellular Interaction, Differentiation, and Oncogenesis

Over the last 25 years a considerable research effort has concentrated on the eicosanoids, and great progress has been made in the elucidation of the chemical structure of these compounds, of their physiological roles, and of the ways in which their synthesis is controlled. It is on the last of these that this Review will concentrate, for it is now established that in most tissues the synthesis of eicosanoids is limited by the availability of their common precursor, free arachidonic acid, which must be liberated from esterified stores in complex lipids (van Dorp et al., 1964; Bergstrom et al., 1964; Vogt et al., 1966; Lands & Samuelsson, 1968; Vonkeman & van Dorp, 1968). Control of the subsequent metabolism of the free acid will not be discussed here, nor will the original derivation of arachidonate from dietary sources (reviewed by Willis, 1981). The purposes of this Review are twofold: firstly, it is useful to summarize briefly the present state of knowledge in order to help newcomers in the field; secondly, and more importantly, in order to move forward both conceptually and experimentally it is necessary to take a critical look at the complexities and problems associated with studying arachidonate liberation. Liberation of arachidonate, as defined here, must involve hydrolysis of an ester bond i.e. lipase activity. The three essential questions concerning the control of arachidonate availability are therefore: (1) Which lipases are involved? (2) How are they controlled? (3) Which substrates are hydrolysed?

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How is the level of free arachidonic acid controlled in mammalian cells

Enzymatic Hydrolysis of Sphingolipids I. HYDROLYSIS AND SYNTHESIS OF CERAMIDES BY AN ENZYME FROM RAT BRAIN

Enzymic hydrolysis and synthesis of ceramides.

The reverse activity of human acid ceramidase.

An inherited deficiency of acid sphingomyelinase (ASM) activity results in the Type A and B forms of Niemann-Pick disease (NPD). Using the ASM-deficient mouse model (ASMKO) of NPD, we evaluated the...

/pdf/infusion-of-recombinant-human-acid-sphingomyelinase-into-4qrjcb8oj4.pdf

Infusion of recombinant human acid sphingomyelinase into Niemann-Pick disease mice leads to visceral, but not neurological, correction of the pathophysiology

Shimon Gatt

Papers

Enzymatic Hydrolysis of Sphingolipids I. HYDROLYSIS AND SYNTHESIS OF CERAMIDES BY AN ENZYME FROM RAT BRAIN

Enzymic hydrolysis and synthesis of ceramides.

The reverse activity of human acid ceramidase.

Infusion of recombinant human acid sphingomyelinase into Niemann-Pick disease mice leads to visceral, but not neurological, correction of the pathophysiology

Enzymatic Hydrolysis of Sphingolipids: II. HYDROLYSIS OF SPHINGOMYELIN BY AN ENZYME FROM RAT BRAIN