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PubMed2026

Preliminary mapping of wheat (Triticum aestivum L.) tolerance genes to the English grain aphid (Sitobion avenae Fabricius) by genome-wide association study.

Six Sitobion avenae-tolerant wheat accessions, mapped 110 associated SNPs and six candidate genes were identified, providing valuable genetic resources for breeding wheat with tolerance to S. avenae. Wheat tolerance to the English grain aphid (Sitobion avenae) is rarely incorporated into integrated pest management strategies for wheat fields. The scarcity of tolerant accession and insufficient mapping of tolerance-related gene are key limiting factors. To address these gaps, 640 wheat accessions were evaluated for S. avenae tolerance, combined with genome-wide association study (GWAS) and qPCR validation. Six wheat accessions with stable tolerance were identified: Lerma Rojo 64, AC Vista, Hanxuan 10, Zimai, Ningnuomai 1, Louguding. A total of 110 single nucleotide polymorphism (SNP) loci associated with tolerance to S. avenae were mapped, and six candidate genes (TraesCS2D03G0041800, TraesCS2Dnew048215, TraesCS2D03G0046300, TraesCS6B03G0655800, TraesCS2Dnew048223, TraesCS2D03G0040800) were examined for transcriptional responses following aphid infestation via qRT-PCR. These genes are involved in cellular redox homeostasis, ADP-binding-mediated defense, and photosystem II (PSII) functionality. This study provides valuable genetic resources for breeding wheat with tolerance to S. avenae and lays a foundation for subsequent functional validation of these tolerance genes and its molecular mechanism exploration.

Animals↗
PubMed2006

Low-temperature tolerance and genetic potential in wheat (Triticum aestivum L.): response to photoperiod, vernalization, and plant development.

It is frequently observed that winter habit types are more low-temperature (LT) tolerant than spring habit types. This raises the question of whether this is due to pleiotropic effects of the vernalization loci or to the linkage of LT-tolerance genes to these vernalization loci. Reciprocal near-isogenic lines (NILs) for alleles at the Vrn-A1 locus, Vrn-A1 and vrn-A1, determining spring and winter habit respectively, in two diverse genetic backgrounds of wheat (Triticum aestivum L.) were used to separate the effects of vernalization, photoperiod, and development on identical, or near identical, genetic backgrounds. The vrn-A1 allele in the winter lines allowed full expression of genotype dependent LT tolerance potential. The winter allele (vrn-A1) in a very cold tolerant genetic background resulted in 11 degrees C, or a 2.4-fold, greater LT tolerance compared to the spring allele. Similarly, the delay in development caused by short-day (SD) versus long-day (LD) photoperiod in the identical spring habit NIL resulted in an 8.5 degrees C or 2.1-fold, increase in LT tolerance. The duration of time in early developmental stages was shown to underlie full expression of genetic LT-tolerance potential. Therefore, pleiotropic effects of the vernalization loci can explain the association of LT tolerance and winter habit irrespective of either the proposed closely linked Fr-A1 or the more distant Fr-A2 LT-tolerance QTLs. Plant development progressively reduced LT-acclimation ability, particularly after the main shoot meristem had advanced to the double ridge reproductive growth stage. The Vrn-1 genes, or other members of the flowering induction pathway, are discussed as possible candidates for involvement in LT-tolerance repression.

Acclimatization↗
PubMed2004

Cold and heat tolerance of drosophilid flies with reference to their latitudinal distributions.

The relation between thermal tolerance and latitudinal distribution was studied with 30 drosophilid species collected from the cool-temperate region (Sapporo), the warm-temperate region (Tokyo and Kyoto) and the subtropical region (Iriomote island) in Japan. In addition, intraspecific variation was examined for five species collected from two localities. The subtropical strains of Scaptodrosophila coracina, Drosophila bizonata and D. daruma were less tolerant to cold than their temperate strains. However, the difference of cold tolerance between these two geographic strains was much smaller than the difference between the species restricted to the subtropical region and those occurring in the temperate region. In D. auraria and D. suzukii, no difference was observed in thermal tolerance between their cool- and warm-temperate strains. Thus, geographic variation in thermal tolerance within species was low or negligible. Interspecific comparisons by phylogenetic independent contrasts revealed that species which had the northern boundaries of their distributions at higher latitudes were generally more tolerant to cold than those which had their boundaries at lower latitudes. However, the data for some species did not agree with this trend. The use of man-protected warm places for overwintering, competition or predation would also affect their distributions. It also appeared that species which had their southern boundaries at higher latitudes were generally more cold-tolerant. The acquisition of cold tolerance may lower a fly's capacity to compete, survive or reproduce in warmer climates. On the other hand, no relation was observed between heat tolerance and latitudinal distribution. Heat tolerance was higher in species inhabiting openlands or the forest canopy than in those inhabiting the forest understorey.

Adaptation, Physiological↗
PubMed1997

Cardiovascular risk factors prior to the development of non-insulin-dependent diabetes mellitus in persons with impaired glucose tolerance: the Hoorn Study.

The aim of the study was to analyze cardiovascular risk factors as predictors for developing non-insulin-dependent diabetes mellitus (NIDDM) in people with impaired glucose tolerance. A cross-sectional survey of glucose tolerance was conducted in people, aged 50-74, who were randomly selected from the registry of the middle-sized town Hoorn (The Netherlands). Based on the mean values of two oral glucose tolerance tests, people were classified in glucose tolerance categories according to the WHO criteria. The mean follow-up time was 36 months (range 13-55 months). The cumulative incidence of NIDDM was 34% (95% CI 16.9-45.1). In multiple logistic regression analysis, cardiovascular risk factors at baseline did not predict the conversion from impaired glucose tolerance to NIDDM, in contrast with the two-hour plasma glucose level (odds ratio 3.56, p < 0.001) and the fasting proinsulin level, as one of the determinants of beta-cell dysfunction (Odds ratio 2.1, p < 0.05). The baseline HDL-cholesterol level, one of the components of the insulin resistance syndrome, was associated with the conversion from impaired glucose tolerance to normal glucose tolerance (Odds ratio 1.58, p < 0.05). The results of our study seem to support the hypothesis that conversion from impaired glucose tolerance to normal glucose tolerance depends on insulin resistance and the development of NIDDM from impaired glucose tolerance depends on beta-cell dysfunction.

Aged↗
PubMed2002

Tolerance of bacteria to organic solvents.

Organic-solvent-tolerant bacteria are a relatively novel group of extremophilic microorganisms. They overcome the toxic and destructive effects of organic solvents due to the presence of various adaptive mechanisms. Extensive studies done on the toluene tolerance of certain Pseudomonas strains have led to an understanding of the mechanisms of organic solvent tolerance involving novel adaptations such as the toluene efflux pumps, cis-trans isomerisation of membrane fatty acids, rapid membrane repair mechanisms, etc. Organic-solvent-tolerant mutants of Escherichia coli have been constructed and genes enhancing such tolerance characterised. However, there is practically no information available on the tolerance mechanisms of the reported Gram-positive organic-solvent-tolerant bacterial strains like Bacillus, Rhodococcus and Arthrobacter. This review discusses the general aspects of organic-solvent-tolerant bacteria, their history, biodiversity, mechanisms of tolerance and proposes certain probable adaptations of Gram-positive bacteria in tolerance to organic solvents.

Bacterial Outer Membrane Proteins↗
PubMed1999

Properties of an L-glutamate-induced acid tolerance response which involves the functioning of extracellular induction components.

Escherichia coli became more acid tolerant following incubation for 60 min in a medium containing L-glutamate at pH 7.0, 7.5 or 8.5. Several agents, including cAMP, NaCl, sucrose, SDS and DOC, prevented tolerance appearing if present with L-glutamate. Lesions in cysB, hns, fur, himA and relA, which frequently affect pH responses, failed to prevent L-glutamate-induced acid tolerance but a lesion in L-glutamate decarboxylase abolished the response. Induction of acid tolerance by L-glutamate was associated with the accumulation in the growth medium of a protein (or proteins) which was able to convert pH 7.0-grown cultures to acid tolerance, and the original L-glutamate-induced tolerance response was dependent on this component(s). Acid tolerance was also induced by L-aspartate at pH 7.0 and induction of such tolerance was dependent on an extracellular protein (or proteins). The L-glutamate and L-aspartate acid tolerance induction processes are further examples of a number of stress tolerance responses which differ from most inductions in that extracellular components, including extracellular sensors, are required.

Aspartic Acid↗
PubMed2000

A strategy of clinical tolerance for the prevention of HIV and AIDS in China.

HIV infection and AIDS create many dilemmas in Chinese AIDS/HIV prevention policy. A strategy of clinical tolerance is proposed to address these dilemmas. The immediate purpose of the strategy of clinical tolerance is to win the cooperation of members of stigmatized groups at high risk for contracting HIV infection and AIDS, which occurs as a result of acts done in private and thus beyond the reach of regulation. The strategy of clinical tolerance differs from both tolerance as liberal tolerance and tolerance as a moral ideal of tolerance. A strategy of clinical tolerance does not ask the government, health worker, health official or the public to change either laws or the disapproval of prostitution, homosexuality and drug use. A strategy of clinical tolerance asks, instead, that we weigh what we may regard as the wrong involved in prostitution, homosexuality, and drug use against the greater evil of an HIV/AIDS epidemic. A strategy of clinical tolerance offers the most effective and practical way to confront a growing and significant public health problem in China.

China↗
PubMed2004

Tolerance to vancomycin in pneumococci: detection with a molecular marker and assessment of clinical impact.

BACKGROUND: Vancomycin is often added to therapy for meningitis caused by Streptococcus pneumoniae. Tolerant bacteria without classic resistance that escape killing by multiple antibiotics have been reported sporadically. We determined the prevalence of tolerance to vancomycin in pneumococci and its effect on the outcome of meningitis. METHODS: Archival samples of 215 nasopharyngeal (NP) and 113 meningitis isolates were tested for the killing efficacy of vancomycin. Specific DNA sequence changes in a transporter locus were identified for tolerant isolates. Similar tests were conducted prospectively on 517 NP isolates from healthy children. RESULTS: In archival isolates, tolerance to vancomycin was detected in 3.7% of NP and 10.6% of invasive isolates. Patients with meningitis caused by tolerant isolates had a worse estimated 30-day survival than did patients with meningitis caused by nontolerant isolates (49% vs. 86%; P = .048); 62.5% of tolerant archival NP isolates harbored a specific sequence change for pep27 and vex2 (P = .021). Prospective analysis of 517 carriage isolates indicated that 8.1% were tolerant to vancomycin and that 82.1% of tolerant isolates harbored the specified marker gene sequences (P = .001). CONCLUSIONS: Tolerance to vancomycin exists in the population of pneumococci. Tolerant isolates are associated with meningitis of increased mortality, and these isolates can be tracked by specific marker sequences in 2 genes.

Alleles↗
PubMed2003

Thai jasmine rice carrying QTLch9 (SubQTL) is submergence tolerant.

Submergence tolerance is an important agronomic trait for rice grown in South-East Asia, where flash flooding occurs frequently and unpredictably during the monsoons. Although mapping locations of one major and several minor quantitative trait loci (QTL) were known previously, improving submergence tolerance in agronomically desirable types of rice has not been achieved. KDML105 is jasmine rice widely grown in rain-fed lowland regions of Thailand. This cultivar is very intolerant of submergence stress. To improve submergence tolerance in this cultivar, three submergence-tolerant cultivars, FR13A, IR67819F2-CA-61 and IR49830-7-1-2-2, were cross-pollinated with KDML105. Transferring the major QTL for submergence tolerance was facilitated by four back-crossings to the recipient KDML105. Molecular markers tightly linked to the gene(s) involved were developed to facilitate molecular genotyping. We demonstrated that individuals of a BC4F3 line that retained a critical region on chromosome 9 transferred from tolerant lines were also tolerant of complete submergence while retaining all the agronomically desirable traits of KDML105. In addition, effects of secondary QTLch2 were detected statistically in back-cross progenies. Effects of secondary QTLch7 were not statistically significant. The close association between tightly linked markers of the tolerance locus on chromosome 9 and submergence tolerance in the field demonstrates the considerable promise of using these markers in lowland rice breeding programmes for selecting increased submergence tolerance.

Adaptation, Physiological↗
PubMed1987

Significance of in-vitro penicillin tolerance in experimental enterococcal endocarditis.

Although penicillin tolerance has been increasingly recognized among clinical isolates of many Gram-positive organisms, the significance of this phenomenon in vivo is not clear. The present study was performed to characterize penicillin-tolerant enterococci by several in-vitro parameters and to examine the significance in vivo in a rabbit model of infective endocarditis. Tolerant enterococci exhibited several characteristics which distinguished them from non-tolerant bacteria: significantly greater ratios of MIC to MBC of penicillin, resistance to penicillin-induced lysis and killing, and growth in areas of superinhibitory concentrations of penicillin upon transfer from penicillin gradient to penicillin-free plates. In-vivo studies of aortic valve endocarditis in rabbits treated with procaine penicillin G (300 mg/kg/day) revealed strikingly different responses between infections due to one tolerant and one non-tolerant strain. Animals infected with a tolerant enterococcus showed consistently greater bacterial counts in vegetations during ten days of therapy and significantly lower rates of vegetation sterilization. Serum penicillin levels were not significantly different between the two groups, but serum bactericidal titres were significantly lower for the tolerant than for the non-tolerant strains. These findings indicate that penicillin tolerance identified by several in-vitro criteria is a significant determinant of the in-vivo response of enterococci to penicillin therapy.

Animals↗
PubMed1994

Paradoxical dose effect of continuously administered cloxacillin in treatment of tolerant Staphylococcus aureus endocarditis in rats.

The efficacies of different doses of cloxacillin administered by continuous infusion were compared in the treatment of endocarditis in rats caused by a beta-lactam tolerant strain of Staphylococcus aureus and its non-tolerant variant. In-vitro killing of the tolerant strain was maximal at a concentration near the MIC, while at higher concentrations the rate of killing gradually decreased, a paradoxical effect, not found for the non-tolerant strain. During treatment of endocarditis caused by a tolerant strain, the reduction of bacterial numbers in the infected vegetations decreased significantly with increasing doses of cloxacillin. Thus for the tolerant strain a paradoxical dose effect was also apparent in vivo. For the non-tolerant strain this paradoxical effect was not found. Furthermore, continuous administration of cloxacillin was significantly less effective in reducing bacterial numbers in the vegetations for the tolerant strain than for the non-tolerant strain. The results of this study suggest that the phenomenon of tolerance, demonstrated in vitro, may have a significant influence on the outcome of treatment of S. aureus endocarditis with continuously administered cloxacillin, particularly when high doses of antibiotic are used.

Animals↗
PubMed2002

Response of rice to Al stress and identification of quantitative trait Loci for Al tolerance.

Rice (Oryza sativa L.) shows the highest tolerance to Al toxicity among small-grain cereal crops, however, the mechanisms and genetics responsible for its high Al tolerance are not yet well understood. We investigated the response of rice to Al stress using the japonica variety Koshihikari in comparison to the indica variety Kasalath. Koshihikari showed higher tolerance at various Al concentrations than Kasalath. The Al content in root apexes was less in Koshihikari than in Kasalath, suggesting that exclusion mechanisms rather than internal detoxification are acting in Koshihikari. Al-induced secretion of citrate was observed in both Koshihikari and Kasalath, however, it is unlikely to be the mechanism for Al tolerance because there was no significant difference in the amount of citrate secreted between Koshihikari and Kasalath. Quantitative trait loci (QTLs) for Al tolerance were mapped in a population of 183 backcross inbred lines (BILs) derived from a cross of Koshihikari and Kasalath. Three putative QTLs controlling Al tolerance were detected on chromosomes 1, 2 and 6. Kasalath QTL alleles on chromosome 1 and 2 reduced Al tolerance but increased tolerance on chromosome 6. The three QTLs explained about 27% of the phenotypic variation in Al tolerance. The existence of QTLs for Al tolerance was confirmed in substitution lines for corresponding chromosomal segments.

Adaptation, Physiological↗
PubMed2000

Studies on the mechanisms of arsenic-induced self tolerance developed in liver epithelial cells through continuous low-level arsenite exposure.

Arsenic (As) is a human carcinogen. Our prior work showed that chronic (>18 weeks) low level (500 nM) arsenite (As3+) exposure induced malignant transformation in a rat liver epithelial cell line (TRL 1215). In these cells, metallothionein (MT) is hyper-expressible, a trait often linked to metal tolerance. Thus, this study examined whether the adverse effects of arsenicals and other metals were altered in these chronic arsenite-exposed (CAsE) cells. CAsE cells, which had been continuously exposed to 500 nM arsenite for 18 to 20 weeks, and control cells, were exposed to As3+, arsenate (As5+), dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), antimony (Sb3+), cadmium (Cd2+), cisplatin (cis-Pt), and nickel (Ni2+) for 24 h and cell viability was determined by metabolic integrity. The lethal concentration for 50% of exposed cells (LC50) for As3+ was 140 microM in CAsE cells as compared to 26 microM in control cells, a 5.4-fold increase in tolerance. CAsE cells were also very tolerant to the acute toxic effects of As5+ (LC50 > 4000 microM) compared to control (LC50 = 180 microM). The LC50 for DMA was 4.4-fold higher in CAsE cells than in control cells, but the LC50 for MMA was unchanged. There was a modest cross-tolerance to Sb3+, Cd2+, and cis-Pt in CAsE cells (LC50 1.5-2.0-fold higher) as compared to control. CAsE cells were very tolerant to Ni2+ (LC50 > 8-fold higher). Culturing CAsE cells in As(3+)-free medium for 5 weeks did not alter As3+ tolerance, implicating an irreversible phenotypic change. Cellular accumulation of As was 87% less in CAsE cells than control and the accumulated As was more readily eliminated. Although accumulating much less As, a greater portion was converted to DMA in CAsE cells. Altered glutathione (GSH) levels were not linked with As tolerance. A maximal induction of MT by Zn produced only a 2.5-fold increase in tolerance to As3+ in control cells. Cell lines derived from MT normal mice (MT+/+) were only slightly more resistant (1.6-fold) to As3+ than cells from MT null mice (MT-/-). These results show that CAsE cells acquire tolerance to As3+, As5+, and DMA. It appears that this self-tolerance is based primarily on reduced cellular disposition of the metalloid and is not accounted for by changes in GSH or MT.

Animals↗
PubMedDate not supplied

Prospects for increasing the salt tolerance of forest trees: a review.

Three major themes related to the improvement of salt tolerance in forest tree species are examined. First, evidence demonstrating that substantial intraspecific variation in salt tolerance exists in many species is presented. This evidence is important because it suggests that efforts to improve salt tolerance through conventional plant breeding techniques are justified. Second, the physiological and genetic mechanisms controlling salt tolerance are discussed briefly. Although salt tolerance involves the integration of numerous physiological processes, there is considerable evidence that differences in the ability to exclude Na(+) and Cl(-) from leaves are the most important factors underlying intraspecific differences in tolerance. It is also becoming apparent that, although salt tolerance is a multigenic trait, major genes play an important role. Third, progress to date in improving salt tolerance of forest tree species is assessed. Compared with agricultural crops, relatively little progress has been made with either conventional or biotechnological methods, but field trials designed to test clones identified as salt tolerant in screening trials are underway now in several countries. We conclude that there is justification for cautious optimism about the prospects for improving salt tolerance in forest tree species.

Journal Article↗
PubMed2004

Responses of eucalypt species to aluminum: the possible involvement of low molecular weight organic acids in the Al tolerance mechanism.

Aluminum (Al) tolerance mechanisms in crop plants have been extensively researched, but our understanding of the physiological mechanisms underlying Al tolerance in trees is still limited. To investigate Al tolerance in eucalypts, seedlings of six species (Eucalyptus globulus Labill., Eucalyptus urophylla S.T. Blake, Eucalyptus dunnii Maiden, Eucalyptus saligna Sm., Eucalyptus cloeziana F. J. Muell. and Eucalyptus grandis w. Hill ex Maiden) and seedlings of six clones of Eucalyptus species were grown for 10 days in nutrient solutions containing Al concentrations varying from 0 to 2.5 microM (0 to 648 microM Al3+ activities). Root elongation of most species was inhibited only by high Al3+ activities. Low to intermediate Al3+ activities were beneficial to root elongation of all species and clones. Among the species tested, E. globulus and E. urophylla were more tolerant to Al toxicity, whereas E. grandis and E. cloeziana were more susceptible to Al-induced damage. Although E. globulus seedlings were tolerant to Al toxicity, they were highly sensitive to lanthanum (La), indicating that the tolerance mechanism is specific for Al. Fine roots accumulated more Al and their elongation was inhibited more than that of thick roots. In E. globulus, accumulation of Al in root tips increased linearly with increasing Al concentration in the nutrient solution. The majority of Al taken up was retained in the root system, and the small amounts of Al translocated to the shoot system were found mainly in older leaves. No more than 60% of the Al in the thick root tip was in an exchangeable form in the apoplast that could be removed by sequential citrate rinses. Gas chromatography/mass spectrometry and ion chromatography analyses indicated that root exposure to Al led to a greater than 200% increase in malic acid concentration in the root tips of all eucalypt species. The increase in malate concentration in response to Al treatment correlated with the degree of Al tolerance of the species. A small increase in citric acid concentration was also observed in all species, but there were no consistent changes in the concentrations of other organic acids in response to Al treatment. In all eucalypt species, Al treatment induced the secretion of citric and malic acid in root exudates, but no trend with respect to Al tolerance was observed. Thus, although malate and citrate exudation by roots may partially account for the overall high Al tolerance of these eucalypt species, it appears that tolerance is mainly derived from the internal detoxification of Al by complexation with malic acid.

Aluminum↗
PubMed1997

Donor-specific tolerance by perioperative intrathymic injection of bone marrow cells in the rat cardiac allograft model: use of FK506 can shorten the necessary duration of pretransplant intrathymic conditioning.

BACKGROUND: Many strategies of tolerance induction by intrathymic (IT) injection of donor alloantigens have been reported to date; however, the timing of IT injection is usually 1-3 weeks before transplantation. METHODS: To apply IT injection to cadaveric organ transplantation, 1 x 10(8) fully allogeneic bone marrow cells (BMC) of Buffalo (BUF; RT1b) rats were intrathymically injected into Wistar Furth (WF; RT1u) rats at the time of BUF cardiac allografting with short-course therapy of antilymphocyte serum (ALS) and FK506 in our experimental model. RESULTS: Allogeneic IT injection of BUF BMC with ALS and FK506 indefinitely prolonged graft survival (mean survival time > 210 days) in all WF rats. On day 130 after grafting, tolerant WF rats accepted donor BUF skin grafts (> 120 days) but not third-party Lewis skin grafts. In control groups, syngeneic IT injection of WF BMC or intravenous injection of donor BUF BMC in combination with ALS/FK506 therapy failed to induce tolerance. In vivo testing was performed during induction (1 month) or during maintenance (6 months of tolerance. In the mixed lymphocyte reaction (MLR), spleen T cells of tolerant rats at 1 month after grafting displayed hyporesponsiveness after stimulation with donor cells. The addition of interleukin (IL)-2 to MLR culture did not restore T-cell responsiveness. Tolerant rats had a significantly decreased frequency of T cytotoxic cell precursors (fTcp) of 1:4,926, and frequency of IL-2-producing T helper cell precursors (fThp) of 1:23,925, compared with naive rats (1: 2,158 and 1:4,266, respectively). By 6 months after grafting, however, the anti-donor MLR proliferative responses of tolerant rats had been restored to the levels of naive splenic T cells. These tolerant rats displayed restoration of the (fTcp) of 1:2,842 and of the (fThp) of 1:5,630, which were comparable frequencies of naive rats. Suppressor T cells did not contribute in this model. In cardiac grafts of tolerant rats induced by IT injection, expression of both Th1 (interferon-gamma and IL-2) and Th2 (IL-4 and IL-10) cytokines was detected in the early phase; thereafter, expression was completely inhibited, except for interferon-gamma in the chronic phase. CONCLUSIONS: Perfect donor-specific tolerance was obtained by IT injection of donor BMC at the time of transplantation, while alloimmune responses were maintained at levels similar to those of naive rats.

Adoptive Transfer↗
PubMed1989

Tolerance to the behavioural effects of the selective 5-HT(1A) agent, ipsapirone.

Effects of ipsaprione on rats were studied in procedures in which tolerance was assessed with operant responding and in feeding tests. Initially, the suppressant effect of ipsapirone on Fixed Ratio 20 behaviour was studied. During 33 days treatment (7.5mg/kg daily) no tolerance developed. Subsequently, the same rats received ipsapirone (7.5mg/kg) three times daily, at intervals of 2.5h, the first injection preceding operant sessions. Over 10 further days of treatment, there was still no evidence of tolerance. In a second study, ipsapirone was again administered at 7.5mg/kg before operant sessions, followed by 2 daily injections of 20mg/kg, at at 2.5h intervals after operant sessions. Under these conditions, some tolerance developed although it was incomplete and rapidly lost. The effects of ipsapirone on operant responding were found to be short-lasting. The suppressant action of 7.5mg/kg of ipsapirone (to 50% of baseline) was abolished if the drug was injected 4h before sessions. In other studies, we confirmed that tolerance develops very rapidly to hyperphagic actions of ipsapirone (see Kennett et al., 1987). We conclude that: 1) tolerance develops at differing rates to various effects of ipsapirone; 2) only those effects of ipsapirone (and related agents) which involve activation of presynaptic autoreceptors show rapid tolerance; 3) tolerance develops to effects on operant responding only if high doses are administered frequently. Since ipsapirone is short-acting, tolerance to such effects develops only when drug is continuously present in body tissue. The tolerance observed (to effects on operant behaviour) was probably of a pharmacodynamic nature and did not involve learning processes.

Journal Article↗
PubMed2005

Contribution of MKP-1 regulation of p38 to endotoxin tolerance.

Endotoxin tolerance has been characterized as diminished TNF-alpha expression after a second LPS stimulus and is dependent on new protein synthesis. LPS-induced expression of TNF-alpha is partly regulated by the p38 mitogen-activated protein (MAP) kinase, which post-transcriptionally stabilizes TNF-alpha mRNA. The dual-specific phosphatase, MKP-1, has been shown to negatively regulate p38 via dephosphorylation. We hypothesized that MKP-1 expression induced during tolerance regulates TNF-alpha expression by inhibiting p38 activity. To test this hypothesis, tolerance was induced in THP-1 cells, and naive or tolerized cells were rechallenged 18 h later with LPS (1 microg/mL) and TNF-alpha production was measured. Under similar conditions, nuclear proteins were isolated after LPS stimulation and were analyzed for phospho-p38 and MKP-1 by Western blot. Transient overexpression of MKP-1 was achieved using an adenoviral expression strategy and infected cells subsequently treated with LPS for TNF-alpha production and p38 activation. Results showed that LPS tolerance was induced as reflected by decreased TNF-alpha. Induction of LPS hyporesponsiveness could be mimicked by overexpression of MKP-1 but not beta-gal. MKP-1 expression was noted only in LPS-tolerized or Ad-MKP-1 infected cells. In the canonical and Ad-MKP-1-mediated tolerance models, decreased phospho-p38 activity was observed. MKP-1s role in mediating endotoxin tolerance was further confirmed by demonstrating the inability to fully tolerize peritoneal macrophages isolated from MKP-1 null mutant (vs. wild type) mice (24% vs. 72% reductions, respectively). These data demonstrate that the dual specific phosphatase MKP-1 is an important mediator of endotoxin tolerance via p38 regulation.

Adenoviridae↗