Miguel A. Pineda

Performance of zinc oxide based sorbents for hot coal gas desulfurization in multicycle tests in a fixed-bed reactor

Zinc oxide based sorbents doped with CuO or TiO2 have been studied in 5-cycles tests in a fixed-bed reactor, as regenerable sorbents for desulfurization of coal gas at high temperature (600°C). TiO2 increases the stability of ZnO and zinc ferrite, under the reducing power of coal gas, and the sorbent porosity. However, it also increases the H2S concentration in the outlet gas before breakthrough, and the sorbent reactivity is not substantially modified. In addition, the presence of TiO2 makes more difficult the formation of mixed oxides and the behaviour of the fresh sorbents is usually different than that of the first regenerated samples. The presence of CuO increases sorbent reactivity and the efficiency for the first 1–3 cycles is excellent. Unfortunately, neither CuO nor TiO2 can prevent the excessive decay in performance of the studied sorbents as the number of cycles increases. This feature appears correlated, not with structural changes as shown by XRD, but with a decrease of the sorbent porosity due to progressive thermal sintering. The presence of iron oxides in the sorbent composition causes different behaviour with the appearance, after breakthrough, of COS in sulfidation and H2S and elemental sulphur in regeneration.

The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17-producing cellular network at multiple sites.

OBJECTIVE Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62. METHODS DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA. RESULTS ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17-producing network, involving signaling between dendritic cells and γ/δ or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL-1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of γ/δ T cells and this was reflected by direct suppression of CD44 up-regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. CONCLUSION Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA.

Characterization of zinc oxide and zinc ferrite doped with Ti or Cu as sorbents for hot gas desulphurization

Three series of samples based on zinc oxide and zinc ferrite doped with copper or titanium oxides have been prepared in order to improve their performance as regenerable sorbents for hot gas desulphurization. In each series the oxide concentration was varied over a broad range to enhance the formation of different chemical species. The stability against reducing agents and the performance of these sorbents were studied elsewhere. The characterization of fresh, sulphided and regenerated samples was undertaken using XRD, FT-Raman and XPS techniques. The addition of Ti increased the stability of ZnO against reducing agents such as H2, up to an atomic ratio Ti/Zn= 0.5 through the formation of Zn2TiO4. Furthermore, the Ti excess is segregated as TiO2. The addition of Cu to zinc ferrite did not affect the stability but improved the sorbent performance enhancing the ferrite formation and migrating to the sorbent surface during the calcination and regeneration steps. The addition of Ti to zinc ferrite prevented its decomposition into the two component oxides below 600°C stabilizing the structure through the inclusion of Ti in the ferrite lattice. In the sulphiding process Fe, Zn and Cu oxides were converted into the lowest oxidation state sulphides that facilitated the sorbent regeneration during the regeneration process.

Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis.

In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.

Inducible Nitric Oxide Synthase and Arginase Expression in Heart Tissue during Acute Trypanosoma cruzi Infection in Mice: Arginase I Is Expressed in Infiltrating CD68+ Macrophages

In Chagas disease, which is caused by Trypanosoma cruzi, macrophages and cardiomyocytes are the main targets of infection. Classical activation of macrophages during infection is protective, whereas alternative activation of macrophages is involved in the survival of host cells and parasites. We studied the expression of inducible nitric oxide synthase (iNOS) and arginase as markers of classical and alternative activation, respectively, in heart tissue during in vivo infection of BALB/c and C57BL/6 mice. We found that expression of arginase I and II, as well as that of ornithine decarboxylase, was much higher in BALB/c mice than in C57BL/6 mice and that it was associated with the parasite burden in heart tissue. iNOS and arginase II were expressed by cardiomyocytes. Interestingly, heart-infiltrated CD68+ macrophages were the major cell type expressing arginase I. T helper (Th) 1 and Th2 cytokines were expressed in heart tissue in both infected mouse strains; however, at the peak of parasite infection, the balance between Th1 and Th2 predominantly favored Th1 in C57BL/6 mice and Th2 in BALB/c mice. The results of the present study suggest that Th2 cytokines induce arginase expression, which may influence host and parasite cell survival but which might also down-regulate the counterproductive effects triggered by iNOS in the heart during infection.

ES-62, a therapeutic anti-inflammatory agent evolved by the filarial nematode Acanthocheilonema viteae.

Filarial nematodes cause long-term infections in hundreds of millions of people. A significant proportion of those affected develop a number of debilitating health problems but, remarkably, such infections are often unnoticed for many years. It is well known that parasitic worms modulate, yet do not completely inhibit, host immunological pathways, promoting their survival by limiting effective immune mechanisms. Such immunoregulation largely depends on molecules released by the worms, termed excretory-secretory products (ES). One of these products is the molecule ES-62, which is actively secreted by the rodent filarial nematode Acanthocheilonema viteae. ES-62 has been shown to exert anti-inflammatory actions thorough its phosphorylcholine (PC)-containing moiety on a variety of cells of the immune system, affecting intracellular signalling pathways associated with antigen receptor- and TLR-dependent responses. We summarise here how ES-62 modulates key signal transduction elements and how such immunomodulation confers protection to mice subjected to certain experimental models of inflammatory disease. Finally, we discuss recent results showing that it is possible to synthetise small molecule analogues (SMAs) that mimic the anti-inflammatory properties of ES-62, opening an exciting new drug development field in translational medicine.

ES‐62 Protects Against Collagen‐Induced Arthritis by Resetting Interleukin‐22 Toward Resolution of Inflammation in the Joints

The parasitic worm–derived immunomodulator ES‐62 protects against disease in the mouse collagen‐induced arthritis (CIA) model of rheumatoid arthritis (RA) by suppressing pathogenic interleukin‐17 (IL‐17) responses. The Th17‐associated cytokine IL‐22 also appears to have a pathogenic role in autoimmune arthritis, particularly in promoting proinflammatory responses by synovial fibroblasts and osteoclastogenesis. The present study was undertaken to investigate whether the protection against joint damage afforded by ES‐62 also reflects suppression of IL‐22.

Protection against collagen-induced arthritis in mice afforded by the parasitic worm product, ES-62, is associated with restoration of the levels of interleukin-10-producing B cells and reduced plasma cell infiltration of the joints

We have previously reported that ES‐62, a molecule secreted by the parasitic filarial nematode Acanthocheilonema viteae, protects mice from developing collagen‐induced arthritis (CIA). Together with increasing evidence that worm infection may protect against autoimmune conditions, this raises the possibility that ES‐62 may have therapeutic potential in rheumatoid arthritis and hence, it is important to fully understand its mechanism of action. To this end, we have established to date that ES‐62 protection in CIA is associated with suppressed T helper type 1 (Th1)/Th17 responses, reduced collagen‐specific IgG2a antibodies and increased interleukin‐10 (IL‐10) production by splenocytes. IL‐10‐producing regulatory B cells have been proposed to suppress pathogenic Th1/Th17 responses in CIA: interestingly therefore, although the levels of IL‐10‐producing B cells were decreased in the spleens of mice with CIA, ES‐62 was found to restore these to the levels found in naive mice. In addition, exposure to ES‐62 decreased effector B‐cell, particularly plasma cell, infiltration of the joints, and such infiltrating B cells showed dramatically reduced levels of Toll‐like receptor 4 and the activation markers, CD80 and CD86. Collectively, this induction of hyporesponsiveness of effector B‐cell responses, in the context of the resetting of the levels of IL‐10‐producing B cells, is suggestive of a modulation of the balance between effector and regulatory B‐cell responses that may contribute to ES‐62‐mediated suppression of CIA‐associated inflammation and inhibition of production of pathogenic collagen‐specific IgG2a antibodies.

Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2−/− mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA.

The parasitic worm product, ES-62 targets MyD88-dependent effector mechanisms to suppress ANA production and proteinuria in MRL/Lpr mice

The hygiene hypothesis suggests that parasitic helminths (worms) protect against the development of autoimmune disease via a serendipitous side effect of worm‐derived immunomodulators that concomitantly promote parasite survival and limit host pathology. The aim of this study was to investigate whether ES‐62, a phosphorylcholine‐containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage in an MRL/lpr mouse model of systemic lupus erythematosus (SLE).