Novel derivatives of ISO-1 as potent inhibitors of MIF biological function

A series of novel 1,2,4-oxadiazole, phthalimide, amide and other derivatives of ISO-1 were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds inhibited MIF enzymatic activity at levels better than ISO-1. Of note, compounds 7, 22, 23, 24, 25 and 27 inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells and, more importantly, inhibited the MIF-induced production of interleukin-6 (IL-6) and/or interleukin-1β (IL-1β) significantly better than ISO-1.     

Mycobacterium leprae induces insulin-like growth factor and promotes survival of Schwann cells upon serum withdrawal

Peripheral nerve lesions are considered the most relevant symptoms of leprosy, a chronic infectious disease caused by Mycobacterium leprae . The strategies employed by M. leprae to infect and multiply inside Schwann cells (SCs), however, remain poorly understood. In this study, it is shown that treatment of SCs with M. leprae significantly decreased cell death induced by serum deprivation. Not displayed by Mycobacterium smegmatis or Mycobacterium bovis BCG , the M. leprae survival effect was both dose dependent and specific . The conditioned medium (CM) of M. leprae -treated cultures was seen to mimic the protective effect of the bacteria, suggesting that soluble factors secreted by SCs in response to M. leprae were involved in cell survival. Indeed, by quantitative RT-PCR and dot blot/ELISA, it was demonstrated that M. leprae induced the expression and secretion of the SC survival factor insulin-like growth factor-I. Finally, the involvement of this hormone in M. leprae -induced SC survival was confirmed in experiments with neutralizing antibodies. Taken together, the results of this study delineate an important strategy for the successful colonization of M. leprae in the nerve based on the survival maintenance of the host cell through induction of IGF-I production.     

The effect of establishing native woodland on habitat selection and ranging of moorland mountain hares (Lepus timidus), a flexible forager

Mountain hares Lepus timidus L. typify species that occupy a broad geographic range and have flexible foraging and nutritional strategies. Such species may show a range of responses to habitat modification. This study aimed to provide a basis for prediction of the impact of mountain hares on woodland establishment, and of woodland establishment on mountain hare distribution. The selection of and the extent of incorporation of new woodland into the home range of mountain hares was investigated in an area where Scots pine Pinus sylvestris L. woodland was establishing within their usual habitat in Britain, upland heather moorland. Seasonal home, day and night-range sizes of radio-tracked mountain hares were determined using the multinuclear probability polygon technique and analysed using residual maximum likelihood (REML). Habitat selection was analysed using compositional analysis. Three main habitat types were available to hares: heather moorland with trees, heather moorland and grassland-mire. Mean home-range size of mountain hares in summer was 10.3 ha and in winter 9.6 ha. There were no significant seasonal or sex differences in home-range size. Females selected grassland-mire habitat in summer and showed no strong selection for any habitat in winter. Males selected heather moorland in both summer and winter. Heather moorland with trees was not selected preferentially by mountain hares of either sex in summer or winter. The absence of selection for areas of newly establishing-Scots pine woodland suggests that any browsing damage to trees by hares is most likely to be a function of the local abundance of mountain hares, rather than a result of active preference of hares for the modified habitat.     

Activated mouse T-cells synthesize MHC class II, process, and present morbillivirus nucleocapsid protein to primed T-cells

A pivotal step in the initiation of T-cell immunity is the presentation of antigenic peptides by major histocompatibility complex (MHC) expressed on antigen presenting cells. The expression of MHC class II molecules by mouse T-cells has not been shown unequivocally. In the present work, we demonstrate that activated mouse T-cells synthesize MHC class II molecules de novo and express them on their surface. Further, we have demonstrated that in vitro activated T-cells take up extra-cellular soluble nucleocapsid protein of a morbillivirus. The internalized antigen goes to antigen processing compartment as shown by co-localization of antigen and LAMP-1 using confocal microscopy. We show that activated T-cells express H2M, a chaperone molecule known to have a role in antigen presentation. Further, we demonstrate that activated T-cells process and present internalized extra-cellular antigen to primed T-cells as shown by IL-2 secretion and in vitro proliferation. The presentation of antigen by T-cells may have implications in immuno-regulation, control of infection by lymphotropic viruses and maintenance of immunological memory.     

Perpetuation of immunological memory: role of serum antibodies and accessory cells

A self-sustaining mechanism for perpetuation of immunological memory is proposed which requires the involvement of idiotypic-anti-idiotypic antibody immune-complexes, antigen-presenting cells and follicular dendritic cells, but not long-lived memory cells or persisting antigens.     

Disruption of male sexual behavior in rats by tetrahydrofurandiols (THF-diols)

The mitogenic agent that disrupts male and female sexual behavior has been isolated from corncob bedding. The disrupting activity resides in an isomeric mixture of linoleic acid derivatives with a tetrahydrofuran ring and two hydroxyl groups (THF-diols) that include 9, (12)-oxy-10, 13-dihydroxtstearic acid and 10, (13)-oxy-9, 12-dihydroxystearic acid. We examined the effects of exposure of male rats to THF-diols in drinking water on several parameters of male sexual behavior. THF-diols disrupt sexual behavior in male rats by reducing mounting and intromission frequencies. The mount, intromission and ejaculatory latencies are enhanced while the ejaculatory responses are diminished. These findings suggest that the THF-diols modulate hypothalamo-pituitary axis to regulate steroid hormone-dependent male sexual behavior.     

In Vitro Catabolism of Histidine by Mixed Rumen Bacteriaand Protozoa

An in vitro study was conducted to examine the metabolism of histidine (His) by mixed rumen bacteria (B), mixed rumen protozoa (P), and a combination of the two (BP). Rumen microorganisms were collected from fistulated goats fed with lucerne cubes (Medicago sativa) and a concentrate mixture twice a day. Microbial suspensions were anaerobically incubated with or without 2 mm each of His, or histamine (HTM), or 1 mm urocanic acid (URA) at 39°C for 12 h. His and other related compounds in both supernatant and microbial hydrolysates were analyzed by HPLC. After 6- and 12-h incubations, the net degradation of His was 26.1% and 51.7% in B, 13.5% and 20.9% in P, and 21.7% and 46.0% in BP, respectively. The rate of the net degradation of His in B (98.0 μmol/g microbial nitrogen/h) was about 2.6 times higher than that of P during a 12-h incubation period. His was found to be degraded into urocanic acid (URA), imidazolelactic acid (ImLA), imidazoleacetic acid (ImAA), and histamine (HTM). Of these degraded His was mainly converted into URA in all microbial suspensions. The production of ImLA and ImAA was higher in B than in P suspensions, whereas the production of HTM was higher in P than in B suspensions. From these results, the existence of diverse catabolic routes of His in rumen microorganisms was indicated. Received: 23 May 2000 / Accepted: 31 July 2000