Methodological challenges involved in compiling the Nahua pharmacopeia.

Recent work in the history of science has questioned the Eurocentric nature of the field and sought to include a more global approach that would serve to displace center-periphery models in favor of approaches that take seriously local knowledge production. Historians of Iberian colonial science have taken up this approach, which involves reliance on indigenous knowledge traditions of the Americas. These traditions present a number of challenges to modern researchers, including availability and reliability of source material, issues of translation and identification, and lack of systematization. This essay explores the challenges that emerged in the author's attempt to compile a pre-contact Nahua pharmacopeia, the reasons for these challenges, and the ways they may - or may not - be overcome.

The "Prince of Medicine": Yuhanna ibn Masawayh and the foundations of the western pharmaceutical tradition.

This essay examines three medieval pharmaceutical treatises purportedly authored by Yuhanna ibn Masawayh (anglicized to John Mesue) and traces their immense influence on the development of pharmacy in early modem Europe and the Hispanic world. Despite the importance of these works throughout the early modern period, Mesue is relatively unknown in the history of pharmacy and medicine, and his exact identity remains unclear. This essay argues that "Mesue" was most likely a pseudonym used by an unknown author of the Latin West and that the three works were crafted to meet the demands of the developing "medical marketplace" of late thirteenth-century Europe, where the manuscripts first appeared. At the same time, however, as the Arabic reference of the pseudonym suggests, these treatises were clearly products of the medieval Islamic world, including many innovations that would provide the basis for the theory and practice of pharmacy for centuries and arguably formed part of the artisanal epistemological influence on the Scientific Revolution.

IL-15 aggravates atherosclerotic lesion development in LDL receptor deficient mice.

BACKGROUND: Interleukin 15 (IL-15) is a pro-inflammatory cytokine involved in inflammatory diseases and IL-15 is expressed in atherosclerotic plaques. METHODS: To establish the role of IL-15 in atherosclerosis we studied the effect of IL-15 on atherosclerosis associated cells in vitro and in vivo by neutralizing IL-15 using a DNA vaccination strategy. RESULTS: Upon feeding a Western type diet LDLr(-/-) mice do express higher levels of IL-15 within the spleen and the number of IL-15 expressing cells among blood leukocytes and spleen cells is increased. Addition of IL-15 to macrophages induces the expression TNF-α and CCL-2. After the mice were vaccinated against IL-15, we observe a reduction in plaque size of 75% plaque. Unexpectedly, the relative number of macrophages within the plaque was 2-fold higher in IL-15 vaccinated mice than in control mice. Vaccination against IL-15 leads to an increased cytotoxicity against IL-15 overexpressing target cells, resulting in a reduction in IL-15 expressing cells and macrophages in blood and spleen and a decreased CD4/CD8 ratio. CONCLUSION: Hypercholesterolemia leads to upregulation of IL-15 within spleen and blood. DNA vaccination against IL-15 does markedly reduces atherosclerotic lesion size, but does not promote lesion stability.

European materia medica in historical texts: longevity of a tradition and implications for future use.

AIM OF THE STUDY: This study uses historical texts in order to obtain information on the natural products used in traditional medicines in European/Mediterranean therapeutics over the last two millennia. The information obtained may lead to new directions in the area of drug discovery, as recent research has demonstrated the continued promise of looking to natural products for bioactive compounds. Researchers have increasingly turned to traditional medicines to provide clues as to which natural products to investigate, but the oral traditions on which much of this medical knowledge rests are often unstable. Thus researchers have been prompted to use historical medical texts, as this study does, to find potential sources of new drugs. MATERIALS AND METHODS: This study uses twelve Mediterranean/European medical texts from the 5th century BC to the 19th century AD to compile a list of the most commonly used "simples"--or single action drugs substances--used in therapeutics in traditional European medicine. This list was then compared to present-day herbal pharmacopoeia as represented by the National Institutes of Health (NIH). RESULTS: This study finds that traditional European materia medica was based on a Dioscoridean tradition that lasted through the 19th century with remarkably little variation, but is significantly different from the present-day herbal pharmacopoeia according to the NIH. CONCLUSIONS: The most prominent simples in the European/Mediterranean medical tradition can provide clues to further bioactive compounds that have not as of yet been fully exploited for their potential, but were clearly of great use in the past.

Vaccination using oxidized low-density lipoprotein-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice.

AIMS: Modification of lipoproteins plays an important role in the development of atherosclerosis. Oxidatively modified low-density lipoprotein (oxLDL) has a number of pro-inflammatory effects, whereas immunization with various forms of oxLDL is able to reduce atherosclerosis. The uptake of modified LDL by dendritic cells (DCs) and the presentation of epitopes thereof may form an important step in the immunomodulatory effects of LDL. In this study, we transferred oxLDL-pulsed mature DCs (mDCs) to LDL receptor-null (LDLr(-/-)) mice and examined the effects on atherosclerosis. METHODS AND RESULTS: Bone marrow-derived DCs were cultured for 10 days in the presence of granulocyte-macrophage colony-stimulating factor. Immature DCs were matured by lipopolysaccharide and pulsed with copper-oxidized LDL. These mDCs were transferred three times to LDLr(-/-) mice before the induction of atherosclerosis by Western-type diet feeding. The transfer of oxLDL-pulsed mDCs resulted in an 87% reduction in carotid artery lesion size (P < 0.001) with a concurrent increase in plaque stability, whereas treatment using mDCs pulsed with the atherosclerosis-irrelevant antigen, ovalbumin, did not influence lesion size or stability. Furthermore, the vaccination procedure resulted in the induction of oxLDL-specific T cells with a reduced Th1 profile and an increase in oxLDL-specific IgG levels, which contributed to a reduction in foam cell formation. CONCLUSION: These data indicate that vaccination with oxLDL-pulsed mDCs provides a novel and powerful strategy for the immunomodulation of atherosclerosis.

Effect of natural killer T cell activation on the initiation of atherosclerosis.

It has been shown that natural killer T (NKT) cell activation accelerates atherosclerosis in apoE(-/-) mice. ApoE is, however, an important mediator in the presentation of lipids which may complicate conclusions on the role of NKT cells in atherosclerosis. Treatment of LDLr(-/-) mice with alpha-GalCer during Western-type diet feeding is therefore of interest. Atherosclerosis was induced by Western-type diet feeding and collar placement around the carotid arteries in both LDLr(-/-) and apoE(-/-) mice. Subsequently, the mice were treated twice a week with alpha-GalCer. This resulted in an 84% reduction in plaque size in LDLr(-/-) mice (P < 0.05), while no effect was observed in apoE(-/-) mice. In-vitro incubation of splenocytes with alpha-GalCer showed that LDLr(-/-) splenocytes proliferated stronger than apoE(-/-) splenocytes. This is reflected in a larger increase in production of cytokines and especially IL-10 after in-vitro stimulation with alpha-GalCer in LDLr(-/-) mice compared with apoE(-/-) splenocytes. Additionally, feeding a Western-type diet for 1.5 weeks induced a strong increase in the number of NKT cells in LDLr(-/-) mice and this increase was slower and less prominent in apoE(-/-) mice. Administration of alpha-GalCer to LDLr(-/-) mice in combination with Western-type diet feeding reduced plaque formation, but this effect was not seen in apoE(-/-) mice. This may be explained by the decreased presentation of lipids on CD1d molecules due to the lack of apoE. In this study we proved for the first time that NKT cells may also act in an atheroprotective manner.

Vaccination against TIE2 reduces atherosclerosis.

BACKGROUND: TIE2(+) cells play a crucial role in processes that are involved in atherosclerosis, such as angiogenesis. Therefore, the specific deletion of TIE2(+) cells by means of DNA vaccination may affect atherosclerosis. METHODS: Cellular immunity against cells that overexpress TIE2 was established in LDLr(-/-) mice by a novel oral DNA vaccination technique, in which an attenuated Salmonella typhimurium strain was used as a carrier for plasmid pcDNA3.1 encoding TIE2. After three oral vaccinations with 2-week time intervals LDLr(-/-) mice were put on a Western type diet and atherosclerosis was induced. RESULTS: Eight weeks after vaccination FACS analysis of circulating peripheral blood mononuclear cells (PBMCs) revealed a significant decrease (33%, p<0.05) in TIE2(+) cells upon vaccination against TIE2, indicating the successful induction of cellular immunity following vaccination against TIE2. Six weeks after collar placement vaccination against TIE2 resulted in significantly decreased carotid atherosclerosis, as indicated by 30% (p<0.05) reduced intima area and 27% (p<0.05) reduced intima/lumen ratios. Furthermore, atherosclerosis was attenuated in the aortic root by 42% (p<0.05), further underlining the anti-atherosclerotic effect of vaccination against TIE2. Adventitial angiogenesis was reduced by 61% (p<0.05) upon vaccination against TIE2 providing a mechanism via which vaccination against TIE2 inhibits lesion formation. Histochemical analysis of the atherosclerotic lesion composition revealed a 1.6-fold (carotid artery, p<0.05) and 1.9-fold (aortic root, p<0.05) increase in collagen content upon vaccination against TIE2, indicating a more stable plaque phenotype. CONCLUSIONS: We demonstrate that vaccination against TIE2 induces cellular immunity against cells that overexpress TIE2 and results in smaller atherosclerotic lesions with a more stable phenotype. Therefore, vaccination strategies that target cells that contribute to atherosclerosis, may be of potential use in the development of novel treatments of atherosclerosis.

Vaccination against CD99 inhibits atherogenesis in low-density lipoprotein receptor-deficient mice.

AIMS: Murine CD99 was recently found to be expressed on leukocytes and endothelial cells, where it is concentrated at inter-endothelial contacts. Blockade of CD99 by specific antibodies inhibits leukocyte extravasation to inflamed sites in vivo. The aim of the present study is to show the role of CD99 in atherosclerosis using a CD99 vaccination protocol to block the function of CD99 during atherosclerosis. METHODS AND RESULTS: We constructed a DNA vaccine against CD99 by cloning the extracellular domain of murine CD99 into pcDNA3. Vaccination was performed by oral administration of attenuated Salmonella typhimurium transformed with pcDNA3-CD99. This vaccination results in a CD99-specific, CD8-mediated cytotoxic response and subsequent reduction of CD99-expressing cells. We showed that CD99 is expressed on vascular endothelium overlying atherosclerotic plaques and found that CD99 expression is upregulated during western-type diet feeding. CD99 vaccination induced the formation of CD8-positive T cells that were cytotoxic against cells transfected with pcDNA3-CD99. Activation of CD8(+) T cells was demonstrated by a 30% increase in CD8(+)CD69(+) double-positive T cells in spleen and mediastinal lymph nodes. Furthermore, lymphocytes isolated from CD99-vaccinated mice specifically lysed CD99-expressing cells. More importantly, vaccination against CD99 attenuated atherosclerotic lesion formation in the aortic valve leaflets by 38% and in the carotid artery by 69% compared with mice that were vaccinated with a control vector. Furthermore, a lower number of cells were found in atherosclerotic lesions, implying that fewer leukocytes were recruited to these sites. These observations were accompanied by a decrease in CD99 expression on leukocytes. CONCLUSION: We conclude that vaccination against CD99 decreases atherogenesis by the selective removal of CD99-expressing cells, which could reduce leukocyte recruitment into atherosclerotic lesions and attenuate atherogenesis.

CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice.

OBJECTIVE: The chemokine receptor CXCR3 is implicated in migration of leukocytes to sites of inflammation. Antagonizing CXCR3 may be a strategy to inhibit inflammation-induced leukocyte migration and subsequently reduce atherosclerosis. We used the CXCR3 specific antagonist NBI-74330 to block CXCR3-mediated signaling in peritonitis and diet-induced atherosclerosis. METHODS AND RESULTS: Antagonizing CXCR3 with NBI-74330 resulted in a significant reduction in CD4+ T cell and macrophage migration to the peritoneal cavity, which was as shown in ex vivo migration studies totally CXCR3 dependent. Atherosclerotic lesion formation in the aortic valve leaflet area and the entire aorta was significantly inhibited in NBI-74330 treated mice. Lymph nodes draining from the aortic arch were significantly smaller in treated mice and were enriched in regulatory T cells and contained fewer activated T cells, whereas the markers for regulatory T cells within the lesion were enhanced after NBI-74330 treatment. CONCLUSIONS: This study shows for the first time that treatment with a CXCR3 antagonist results in attenuating atherosclerotic lesion formation by blocking direct migration of CXCR3+ effector cells from the circulation into the atherosclerotic plaque and by beneficially modulating the inflammatory response in the lesion and the lymph nodes draining from the atherosclerotic lesion.

Vaccination against VEGFR2 attenuates initiation and progression of atherosclerosis.

OBJECTIVE: Vascular endothelial growth factor receptor 2 (VEGFR2)-overexpressing cells may form an interesting target for the treatment of atherosclerosis because of their involvement in processes that contribute to this disease, such as angiogenesis. METHODS AND RESULTS: We vaccinated mice against VEGFR2 by an orally administered DNA vaccine, comprising a plasmid, encoding murine VEGFR2, carried by live attenuated Salmonella typhimurium. This vaccine induces cellular immunity against cells that overexpress VEGFR2. Vaccination of hypercholesterolemic mice against VEGFR2 resulted in a marked induction of CD8+ cytotoxic T cells specific for VEGFR2 and led to an inhibition of angiogenesis in a hindlimb ischemia model. Interestingly, VEGFR2 vaccination attenuated the progression of preexisting advanced atherosclerotic lesions in the brachiocephalic artery of apoE-/- mice. Furthermore, VEGFR2 vaccination strongly reduced the initiation of collar-induced atherosclerosis in the carotid arteries of LDLr-/- mice. In addition, denudation of the carotid artery, as a model for postinterventional lesion formation, resulted in delayed endothelial replacement and significantly increased neointima formation on VEGFR2 vaccination. CONCLUSIONS: These data indicate the prominent role of VEGFR2+ cells in cardiovascular diseases and show that induction of cellular immunity against atherosclerosis-associated cells by means of DNA vaccination may contribute to the development of novel therapies against atherosclerosis.

Total body ABCG1 expression protects against early atherosclerotic lesion development in mice.

OBJECTIVE: ABCG1 has recently been identified as a facilitator of cholesterol and phospholipid efflux from macrophages to HDL. In bone marrow transplantation studies, we and others have now shown that the absence of macrophage ABCG1 may differentially influence atherosclerotic lesions dependent on the experimental setting and/or the stage of atherosclerotic lesion development. To further define the role of ABCG1 in atherogenesis, we investigated in the current study the effect of total body deficiency of ABCG1 on atherosclerotic lesion development. METHODS AND RESULTS: ABCG1-/- mice and wild-type littermates were fed an atherogenic diet for 12 weeks to induce atherosclerotic lesion formation. Both before and after the start of the atherogenic diet, serum lipid levels and lipoprotein profiles did not differ significantly between the two groups. In addition no significant difference in serum apoE levels was found after diet feeding. In wild-type mice the atherogenic diet induced the formation of macrophage-rich early lesions (size: 24+/-7x10(3) microm2 [n=6]). Feeding ABCG1-/- mice the atherogenic diet led to a significant 1.9-fold stimulation of atherosclerotic lesion size (46+/-6x10(3) microm2 [n=7]; Student t test P=0.034 and Mann-Whitney test P=0.050) compared with controls, suggesting a clear antiatherogenic role for ABCG1. At the same time, excessive lipid accumulation was observed in macrophage-rich areas of the lungs and spleens of ABCG1-/- mice as compared with wild-type mice. CONCLUSIONS: Total body ABCG1 expression protects against early atherosclerotic lesion development.

Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) pathway attenuates atherogenesis in low-density lipoprotein receptor-deficient mice.

OBJECTIVE: Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development. METHODS AND RESULTS: We treated low-density lipoprotein receptor-deficient (LDLr-/-) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control. CONCLUSIONS: We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.

HIV entry inhibitor TAK-779 attenuates atherogenesis in low-density lipoprotein receptor-deficient mice.

OBJECTIVE: HIV combination therapy using protease inhibitors is associated with elevated plasma levels of atherogenic lipoproteins and increased risk for atherosclerosis. We investigated whether the HIV entry inhibitor TAK-779 affects lipoprotein levels and atherogenesis in low-density lipoprotein receptor-deficient mice. TAK-779 is an antagonist for the chemokine receptors CCR5 and CXCR3, which are expressed on leukocytes, especially T-helper 1 cells, and these receptors may be involved in recruitment of these cells to atherosclerotic plaques. METHODS AND RESULTS: TAK-779 treatment of low-density lipoprotein receptor-deficient mice did not elevate the levels of atherogenic lipoproteins, whereas it dramatically reduced atherosclerosis in the aortic root and in the carotid arteries. The number of T cells in the plaque was reduced by 95%, concurrently with a 98% reduction in the relative IFN-gamma area. TAK-779-treated animals showed a decreased percentage of CD4+ and CD8+ T cells in peripheral blood and in mediastinal lymph nodes compared with control-treated animals. CONCLUSIONS: TAK-779 not only suppresses HIV entry via blockade of CCR5 but also attenuates atherosclerotic lesion formation by blocking the influx of T-helper 1 cells into the plaque. TAK-779 treatment may be especially beneficial for young HIV patients as they face lifelong treatment, and this drug impairs atherogenesis.

Adenovirus-mediated hepatic overexpression of scavenger receptor class B type I accelerates chylomicron metabolism in C57BL/6J mice.

The function of scavenger receptor class B type I (SR-BI) in mediating the selective uptake of HDL cholesteryl esters is well established. In SR-BI-deficient mice, we recently observed a delayed postprandial triglyceride (TG) response, suggesting an additional role for SR-BI in facilitating chylomicron (CM) metabolism. Here, we assessed the effect of adenovirus-mediated hepatic overexpression of SR-BI (Ad.SR-BI) in C57BL/6J mice on serum lipids and CM metabolism. Infection of 5 x 10(8) plaque-forming units per mouse of Ad.SR-BI significantly decreases serum cholesterol (>90%), phospholipids (>90%), and TG levels (50%), accompanied by a 41.4% reduction (P < 0.01) in apolipoprotein B-100 levels. The postprandial TG response is 2-fold lower in mice treated with Ad.SR-BI compared with control mice (area under the curve = 31.4 +/- 2.4 versus 17.7 +/- 3.2; P < 0.05). Hepatic mRNA expression levels of genes known to be involved in serum cholesterol and TG clearance are unchanged and thus could not account for the decreased plasma TG levels and the change in postprandial response. We conclude that overexpression of SR-BI accelerates CM metabolism, possibly by mediating the initial capture of CM remnants by the liver, whereby the subsequent internalization can be exerted by additional receptor systems such as the LDL receptor (LDLr) and LDLr-related protein 1.

Scavenger receptor BI plays a role in facilitating chylomicron metabolism.

The function of scavenger receptor class B type I (SR-BI) in mediating the selective uptake of high density lipoprotein (HDL) cholesterol esters is well established. However, the potential role of SR-BI in chylomicron and chylomicron remnant metabolism is largely unknown. In the present investigation, we report that the cell association of 160 nm-sized triglyceride-rich chylomicron-like emulsion particles to freshly isolated hepatocytes from SR-BI-deficient mice is greatly reduced (>70%), as compared with wild-type littermate mice. Competition experiments show that the association of emulsion particles with isolated hepatocytes is efficiently competed for (>70%) by the well established SR-BI ligands, HDL and oxidized low density lipoprotein (LDL), whereas LDL is ineffective. Upon injection into SR-BI-deficient mice the hepatic association of emulsion particles is markedly decreased ( approximately 80%) as compared with wild-type mice. The relevance of these findings for in vivo chylomicron (remnant) metabolism was further evaluated by studying the effect of SR-BI deficiency on the intragastric fat load-induced postprandial triglyceride response. The postprandial triglyceride response is 2-fold higher in SR-BI-deficient mice as compared with wild-type littermates (area-under-the-curve 39.6 +/- 1.2 versus 21.1 +/- 3.6; p < 0.005), with a 4-fold increased accumulation of chylomicron (remnant)-associated triglycerides in plasma at 6 h after intragastric fat load. We conclude that SR-BI is important in facilitating chylomicron (remnant) metabolism and might function as an initial recognition site for chylomicron remnants whereby the subsequent internalization can be exerted by additional receptor systems like the LDL receptor and LDL receptor-related protein.

An herbal El Dorado: the quest for botanical wealth in the Spanish Empire.

Few historians of science would associate the Spanish Empire with scientific innovation. However, recent research is increasingly demonstrating the Crown's strong commitment to scientific research, particularly in the areas of botany, natural history and medicine. Although this commitment began in the 16th century, it reached full development in the 18th, when Enlightenment ideals led to growing interest in exploiting natural resources in the New World. Interest in new resources, which offered alternatives to silver and traditional cash crops, focused largely on medicinal herbs indigenous to the Americas. Herbs that provided 'miracle cures' for age-old diseases would bring both material and moral wealth to the Crown, and were thus pursued vigorously throughout Spanish America. The result was a search for an 'herbal' El Dorado, reminiscent of 16th-century expeditions in search of a mythical land of gold--only in this case, medicine, not metal, was the goal.