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1.
A growing body of data suggests that therapies based on Toll-like receptors (TLR) targeting, in particular TLR4, holds promise in curing autoimmune and inflammatory pathologies still lacking specific treatment, included several rare diseases. While TLR4 activators (agonists) have already found successful clinical application as vaccine adjuvants, the use of TLR4 blockers (antagonists) as antisepsis agents or as agents against inflammatory diseases (including arthritis, multiple sclerosis, neuroinflammations) and cancer is still at a preclinical phase of development. This minireview focuses on recent achievements on the development of TLR4 modulators based on lipid A structure simplification, in particular on compounds having disaccharide or monosaccharide structures. As the TLR4 activity of natural TLR4 ligands (lipopolysaccharide, LPS and its biologically active part, the lipid A) depends on both the structure of endotoxin aggregates in solution and on single-molecule interaction with MD-2 and CD14 receptors, the rational design of TLR4 modulators should in principle take into account both these factors. In the light of the most recent advances in the field, in this minireview we discuss the structure–activity relationship in simplified lipid A analogs, with cationic or anionic amphiphilic structures. 相似文献
2.
A Y Shalev S P Orr T Peri S Schreiber R K Pitman 《Archives of general psychiatry》1992,49(11):870-875
Orbicularis oculi (eye blink) electromyogram, skin conductance, and heart rate responses to 15 consecutive 95-dB, 500-millisecond, 1000-Hz tones with 0-millisecond rise and fall times were measured in 14 patients with posttraumatic stress disorder, 14 patients with other anxiety disorders, 15 mentally healthy subjects with past traumatic experiences, and 19 mentally healthy subjects with no trauma history. The patients with posttraumatic stress disorder showed significantly larger skin conductance and heart rate responses and a trend toward larger electromyogram responses to the tones than every other group. These effects were not explained by subjective anxiety, resting physiologic arousal, physiologic arousal preceding the tone trials, or initial physiologic responsivity. The group with posttraumatic stress disorder was the only one that failed to show habituation of skin conductance responses. 相似文献
3.
In the period 1970-1984 alcoholic hepatitis was diagnosed by liver biopsy in 52 females. Thirty-six patients with cirrhosis were generally in a worse clinical and biochemical state than those without cirrhosis. Biochemical tests for liver function showed significant improvement from admission to the time of liver biopsy. At follow-up liver function tests were generally better in patients who had stopped drinking alcohol compared to those who continued to do so. The 5-year survival rate was 82% for females without cirrhosis, and 45% for those with cirrhosis (p less than 0.03). Considering the sex-related differences in alcohol abuse in the general population we found no evidence of increased susceptibility to the hepatotoxic effect of alcohol in females. 相似文献
4.
In order to investigate the DA activity in polycystic ovary syndrome (PCOS) we studied the response of LH, FSH and PRL to a dopamine receptor antagonist metoclopramide (MCP-10 mg iv) in 12 PCO subjects (7 with normal and 5 with elevated levels of prolactin). The prolactin and LH responses to metoclopramide were compared to those obtained in 6 normal cycling women. Although a significant increase in PRL levels was documented after MCP administration in all PCO patients and normal cycling women (p less than 0.01), the highest increment in PRL levels was observed in normoprolactinemic PCO subjects. In contrast a blunted PRL response was observed in hyperprolactinemic PCO patients. There was a negative correlation between basal PRL levels and the maximum net increase in PRL after MCP. In both groups of PCO subjects MCP administration caused initial decrease in LH levels followed by an increase after 4 h. In hyperprolactinemic PCO patients this observed MCP effect on LH was more pronounced and significantly different in comparison with normoprolactinemic PCO patients (p less than 0.01). MCP administration did not cause significant acute alterations in LH levels in normal cycling women and no significant FSH changes in either PCO or control subjects. A relative dopamine deficiency might cause hypersecretion of PRL and LH in patients with PCOS and hyperprolactinemia. 相似文献
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7.
Pericić D Bujas M Mirković K Jazvinsćak M 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1999,129(3):451-456
The effects of adrenalectomy, gonadectomy and combined adrenalectomy plus gonadectomy on the previously described sex-dependent
anticonvulsive effect of swim stress were studied in rats. The convulsive signs (myoclonic twitch, generalized convulsions,
tonic hindlimb extension) were produced by constant i.v. infusion of γ-aminobutyric acidA (GABAA) antagonist bicuculline, which started 15 min after termination of swim stress (10-min swim at 18–19°C). Adrenalectomy decreased
the threshold doses of bicuculline producing the first myoclonic twitch and the onset of generalized convulsions only in females.
In adrenalectomized females, but not in males, swim stress enhanced the threshold dose of bicuculline producing generalized
convulsions, but, unlike in adrenal-intact animals, it failed to enhance the dose of bicuculline producing tonic hindlimb
extension. In gonadectomized stressed and unstressed animals all sex differences disappeared, and swim stress enhanced in
both sexes only the threshold doses of bicuculline producing tonic hindlimb extension. Adrenalectomized plus gonadectomized
animals displayed clear sex differences in doses of bicuculline necessary to produce all the convulsive signs. In the same
animals swim stress postponed, especially in females, the onset of the first myoclonic twitch and generalized convulsions,
but not the onset of tonic hindlimb extension. In summary, our results suggest that hormones of the adrenal and gonadal glands
are only partly responsible for decreased susceptibility, especially of female rats, to the GABAA antagonist bicuculline. Moreover, they have demonstrated that stress produces a gender-specific anticonvulsive effect even
in the animals completely deprived of steroid hormones of peripheral origin.
Received: 4 June 1998 / Accepted: 11 June 1999 相似文献
8.
HLA-A and -B alleles in 74 Danish patients and 21 homozygous relatives with idiopathic haemochromatosis (IH) were compared with those in a sample of 1719 chromosomes from healthy Danish control subjects. The following alleles occurred with higher frequencies in IH compared to controls: A3: 53.6% vs. 15.1% (Pc less than 0.001); B7: 33.1% vs. 15.6% (Pc less than 0.001); B14: 6.9% vs. 3.0% (Pc greater than 0.05); B38: 5% vs. 0.9% (Pc greater than 0.05); B47: 4.0% vs. 0.4% (Pc greater than 0.05). Pedigree analyses disclosed 19 different haplotypes in IH subjects, compared to 286 haplotypes in controls. The following haplotypes occurred with higher frequency in IH compared to controls: A3,B5: 10.3% vs. 0.3% (Pc less than 0.001); A3,B7: 25.6% vs. 6.6% (Pc = 0.001); A3,B14: 3.4% vs. 0.6% (Pc greater than 0.05); A3,B47: 6.9% vs. 0.2% (Pc greater than 0.05). The major IH marker HLA-A3 was found in 56% of the haplotypes. The patterns of HLA-alleles associated with IH in Denmark show similarities to those in Central Europe, Australia, USA and Canada, being A3,B7 dominated and those in Central Sweden, England and Ireland, being A3,B14 dominated. 相似文献
9.
Estimation of genetic risk for type 1 diabetes 总被引:8,自引:0,他引:8
Ilonen J Sjöroos M Knip M Veijola R Simell O Akerblom HK Paschou P Bozas E Havarani B Malamitsi-Puchner A Thymelli J Vazeou A Bartsocas CS 《American journal of medical genetics》2002,115(1):30-36
The most important gene loci defining risk of type 1 diabetes mellitus (T1DM) are located within the HLA gene region. HLA-DQ molecules are of primary importance but HLA-DR gene products modify the risk conferred by HLA-DQ. The risk associated with an HLA genotype is defined by the particular combination of susceptible and protective alleles. The highest risk is associated with a combination of two different risk haplotypes (7% risk to develop T1DM in Finland) whereas protective genotypes covering 69% of population have a risk of less than 0.2%). The complicated analysis of HLA genotypes is simplified by strong linkage disequilibrium between HLA-DRB1, -DQA1 and -DQB1 loci. In many cases one can deduce the alleles of other loci based on determination of the alleles in one locus. Differences between various populations in the frequency of marker alleles and in the linkages between them has to be taken into account. We have developed PCR based typing methods that utilize blood spot samples, microtiter plate format and lanthanide labeled oligonucleotide probes to define HLA-DQ and -DR alleles relevant for T1DM risk. Typing is run stepwise so that after initial HLA-DQB1 typing only those samples will be further analyzed in which -DQA1 or -DRB1 typing is informative and expected to contribute to the risk estimation. This method has been used to screen more than 50,000 newborn infants in Finland over a time period of 6 years, and it has been able to identify most children who have developed T1D during the follow-up period. The efficiency of the procedure has also been tested in Finnish and Greek populations. 相似文献
10.
The long pentraxin PTX3 up-regulates tissue factor in activated monocytes: another link between inflammation and clotting activation 总被引:4,自引:0,他引:4
Napoleone E di Santo A Peri G Mantovani A de Gaetano G Donati MB Lorenzet R 《Journal of leukocyte biology》2004,76(1):203-209
Pentraxin-3 (PTX3), an acute-phase protein that belongs to the family of the PTXs, is found elevated in septic shock and increased in patients with acute myocardial infarction. As tissue factor (TF) plays a key role in thrombosis and inflammation associated with atherosclerosis and as we have recently reported that PTX3 increases TF synthesis in endothelial cells, we tested whether PTX3 could modulate TF expression in monocytes. Monocytes from peripheral blood of healthy donors were incubated with highly purified PTX3 with or without lipopolysaccharide (LPS). Cells were then disrupted, and procoagulant activity was assessed by a one-stage clotting time. PTX3 enhanced TF activity and antigen from LPS-stimulated monocytes in a dose-dependent way. The effect was specific, as other PTXs, such as C-reactive protein and serum amyloid P component, were ineffective. Moreover, the increase in activity was specific for LPS, as in the presence of other TF-inducing agents such as interleukin-1beta and tumor necrosis factor alpha, PTX3 was not effective. The increase in TF activity requires mRNA synthesis, as assessed by polymerase chain reaction. The mechanism by which PTX3 modulates TF synthesis resides in an enhanced IkappaB, alpha phosphorylation and degradation and increased migration of the transacting factor c-Rel/p65 into the nucleus, as determined by Western blot and electro-mobility shift assay. These results show that PTX3 is an enhancer of the expression of TF by mononuclear cells. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. PTX3 increases TF expression, thus potentially playing a role in thrombogenesis and wound healing. 相似文献