We determined previously that lipoproteins of

We have recently demonstrated that interleukin-10 (IL-10), produced by THP-1 monocytes in response to Borrelia burgdorferi lipoproteins, dampens the production of concomitantly elicited inflammatory cytokines. Thus, IL-10 could potentially down-regulate inflammatory and microbicidal effector mechanisms of the innate immune response to a B. burgdorferi infection, facilitating the establishment of the spirochete. To understand the mechanism(s) implicated in the regulation of the synthesis and release of IL-10 during early infection, we investigated the autocrine effects of IL-6, IL-12, tumor necrosis factor alpha (TNF-␣), and IL-10 itself, as well as the exocrine effect of IFN-␥ on the production of macrophage-derived IL-10 with lipoprotein as a stimulant. In addition, in view of the differences in the receptor and signal transduction pathways of lipopolysaccharide (LPS) and bacterial lipoproteins, we also investigated the effects described above with LPS as a stimulant. Borrelia burgdorferi, the spirochete that causes Lyme disease, is spread to humans and other mammals through the bite of infected Ixodes ticks (7). Infection may involve multiple organs (3, 42) and may persist in certain tissues for prolonged periods of time (35,48). Spirochetal persistence in the tissues has been associated with severe pathology (9, 16, 48) and both acute and chronic inflammatory conditions (37, 42). B. burgdorferi lacks lipopolysaccharide (LPS) (43), but its genome contains no fewer than 150 genes coding for putative lipoproteins (18); this amounts roughly to 11% of its genome coding capacity. Lipoproteins can directly elicit inflammatory responses both in vitro and in vivo (20,36,38,39,47). Recent findings that lipoproteins can elicit not only inflammatory but also antiinflammatory mediators (e.g., interleukin-10 [IL-10]) from mononuclear cells present in peripheral blood (21, 22) and synovial fluid (49) have added support to the contention that lipoproteins play a crucial role in Lyme disease pathogenesis.One of the hallmarks of Lyme disease is arthritis. This form of the disease has been studied extensively in the mouse model, with an emphasis on the role of cytokines in its etiology. Infection of different inbred mouse strains with B. burgdorferi results in distinct disease outcomes (2,32,48). B. burgdorferi infection elicits severe arthritis in C3H/HeN mice, but mild arthritis in C57BL/6N mice, although both strains harbor similar numbers of spirochetes in their ankles (32). These findings indicate that C57BL/6N mice either produce less proinflammatory cytokines or are better able to regulate inflammation in response to B. burgdorferi lipoproteins than C3H/HeN mice, resulting in a less intense inflammatory response and decreased arthritis severity. Recently, Brown and colleagues (6) corroborated this hypothesis by showing that macrophages from C57BL/6N mice, when stimulated with the lipoprotein outer surface protein A (OspA) or LPS, secreted significantly less proinflammatory cytokines (IL-6 and tumor necrosis factor alpha ...

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New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.

Macrofilaricidal activity of the stembark of Sfreblus asper and its major active constituents.Drug Dev. Res. 26:67-78, 1992.The crude extract of the stembark of Sfreblus asper, a traditionally used medicinal plant of India, revealed significant macrofilaricidal activity against tifomosoides carinii and Brugia malayi in rodents. The study revealed two cardiac glycosides, KO29 (asperoside) and KO30 (strebloside) of the extract to be responsible for antifilarial activity. Of the two glycosides, the more effective macrofilaricide was KO29 which was active at 50 mgikg orally against L.carinii (>go%), B. malayi (>70%), and Acanfhocheilonema vifeae (>70%) in their respective hosts. The glycosides were also active in vitro against all the three filarial species. Significantly weak activity was detected in glycon and aglycon portions of the parent glycosides (KO29 and K030). Several cardiac glycosides of other origins did not show any comparable antifilarial efficacy. The aglycosidic portion of the extract, however, showed poor adulticidal activity (44.5% activity at 1 gikg against L. carinio. The present finding, thus, opens up the possibility of generating new leads in the development of novel macrofilaricides. o 1992 Wiley-Liss, Inc.

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Lymphatic filariasis, onchocerciasis, loaisis, and other helminth infections cause serious health problems especially in resource-limited tropical and subtropical developing countries of the world, and more than 2 billion people are infected with at least one helminth species. From times immemorial, man looked up to the plant kingdom in search of anthelmintics, antifilarials, and remedies for parasite-induced health problems. Although more than 50 % of drugs in modern medicine are derived from plants or leads from plants, a success story of plant-based anthelminthics or antifilarials is yet to be told. In the last 5 decades, more than 100 plant products were reported to be beneficial in the treatment or control of these parasitic infections but they could not be developed into viable drugs for a variety of reasons. This review focuses on the plant products reported to be useful in the control and treatment of human helminth infections with the main emphasis on filariasis and the in vitro and in vivo systems available for assaying anthelmintic activity.

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