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Biomedical subjects

X M Li

Publications and source records attributed to X M Li.

At least 91 records · Page 5Linked to original sources
PubMed1998

Modulation of nonprotein sulphydryl compounds rhythm with buthionine sulphoximine: relationship with oxaliplatin toxicity in mice.

The relationship between the rhythm in tissue nonprotein sulphydryl groups (NPSH) and that in 1,2-diamine (trans-I)-cyclohexane oxalatoplatinum (1-OHP) toxicity was investigated in a total of 266 male B6D2F1 mice, using buthionine sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. Mice were synchronized with an alternation of 12 h light (L) and 12 h darkness (D; LD 12:12), and circadian time was expressed in hours after light onset (HALO). NPSH was measured in liver, jejunum and bone marrow at 0, 8 and 16 HALO. Dosing 1-OHP at these times achieved intermediate. high or low toxicity respectively. The physiological circadian rhythm in NPSH content was statistically significant in all tissues studied, with a maximum at the transition from D to L (0 HALO). BSO administration (450 mg/kg i.p., 4 h before sampling) induced a large depletion in liver and jejunum NPSH at their physiological peak (0 HALO), but exerted no significant effect at their trough (8 HALO). As a result, 24 h rhythm was suppressed in liver and jejunum, but remained similar to the physiological one in bone marrow. BSO enhanced 1-OHP-induced mortality and jejunal toxicity, but exerted no significant effect upon bone marrow toxicity. Despite these differences, 1-OHP remained least toxic at 16 HALO, near the middle of the dark span, which corresponds to maximum activity in the circadian rest/activity cycle. Our results show that mean NPSH levels in liver seem to account for the mean level of 1-OHP toxicity, while jejunal NPSH rhythm plays an important role in the intestinal toxicity rhythm of this drug.

Analysis of Variance↗
PubMed1998

Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum.

The in vivo effects of olanzapine on the extracellular monoamine levels in rat prefrontal cortex (Pfc), nucleus accumbens (Acb) and striatum (Cpu) were investigated by means of microdialysis. Sequential doses of olanzapine at 0.5, 3 and 10 mg/kg (s.c.) dose-dependently increased the extracellular dopamine (DA) and norepinephrine (NE) levels in all three brain areas. The increases appeared 30 min after olanzapine administration, reached peaks around 60-90 min and lasted for at least 2 h. The highest DA increases in the Acb and Cpu were induced by olanzapine at 3 mg/kg but at 10 mg/kg in the Pfc. The peak DA increase in the Pfc (421% +/- 46 of the baseline) was significantly larger than those in the Acb (287% +/- 24) and Cpu (278% +/- 28). Similarly, the highest NE increase in the Pfc (414% +/- 40) induced by 10 mg/kg olanzapine was larger than those in the Acb (233% +/- 39) and Cpu (223% +/- 24). The DA and NE increases in the Pfc induced by olanzapine at 3 and 10 mg/kg (s.c.) were slightly larger than those induced by clozapine at the same doses. In contrast, haloperidol (0.5 and 2 mg/kg, s.c.) did not change Pfc DA and NE levels. Extracellular levels of a DA metabolite, DOPAC, and tissue concentrations of a released DA metabolite, 3-methoxytyramine, were also increased by olanzapine, consistent with enhanced DA release. However, olanzapine at the three sequential doses did not alter the extracellular levels of either 5-HT or its metabolite, 5-HIAA, in any of the three brain areas. In conclusion, the present studies demonstrate that in the case of sequential dosing olanzapine more effectively enhances DA and NE release in the Pfc than in the subcortical areas, which may have an impact on its atypical antipsychotic actions.

Animals↗
PubMed1998

Controlled release microparticles as a single dose diphtheria toxoid vaccine: immunogenicity in small animal models.

Diphtheria toxoid (DT) was encapsulated in microparticles prepared from polylactide-co-glycolide (PLG) polymers using a solvent evaporation technique. Combinations of small and large sized microparticles with controlled release characteristics were used to immunize Sprague Dawley rats and the antibody responses were monitored for one year. For comparison, control groups of rats were immunized at 0, 1 and 2 months with DT adsorbed to alum. The antibody responses generated by the microparticles were comparable to the alum immunized control groups from 32 weeks. Microparticles with a single entrapped antigen (DT) induced better antibody responses than microparticles with two antigens entrapped simultaneously (DT + TT). Microparticles prepared from a single polymer were less effective for long term antibody induction than a combination of microparticles prepared from three different polymers. A combination vaccine consisting of antigen absorbed to alum and also entrapped in microparticles gave the best response. In an inhibition assay designed to determine the relative binding of antisera to the antigen, the sera from the microparticle and the alum immunized animals showed comparable binding. An intradermal challenge study was performed in rabbits, which showed similar levels for the alum and the microparticle immunized animals at 4, 12 and 32 weeks after immunization.

Animals↗
PubMed1998

Effects of La3+ on lipid fluidity and structural transitions in human erythrocyte membranes.

The effects of La3+ on the structure and function of human erythrocyte membranes were investigated by fluorescence polarization, spin-labeled electron spin resonance (ESR) and differential scanning calorimetry (DSC). The results showed that increasing concentrations of La3+ inhibited (Na(+) + K+)-ATPase and Mg(2+)-ATPase activities. La3+ lowered the lipid fluidity of erythrocyte membranes and induced structural transitions in erythrocyte membranes.

Ca(2+) Mg(2+)-ATPase↗
PubMed1998

Circadian-based effects of AcSDKP, with or without rhG-CSF on hematologic toxicity of chemotherapy in mice.

The hematologic toxicity of arabinosylcytosine (Ara-C) and carboplatin (CBDCA) as well as the stimulating effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on murine bone marrow vary according to their dosing time along the 24-h time scale. In the present study, we investigated whether the tolerability of Ara-C or CBDCA, given at their least toxic circadian time, could be improved further with AcSDKP, a negative regulator of hemopoiesis, rhG-CSF or both. A total of 228 B6D2F1 mice received once-daily injection of either Ara-C (42 mg/kg/d s.c.) for 7 d (d 0-6) at 8 hours after light onset - HALO) or CBDCA (40 mg/kg/d i.p.) for 5 d (d 2-6) at 16 HALO. AcSDKP (24 microg/d) was continuously infused for 7 d (d 0-6), using an osmotic minipump. rhG-CSF (400 microg/kg/d s.c.) was injected for 4 d (d 9-12) at 9 HALO. Subgroups of mice were sacrificed at 3 HALO on various days following treatment. AcSDKP significantly increased CFU-GM count on d 7 and leukocyte, neutrophil and monocyte counts on d 13 and d 16 compared to Ara-C alone. Also, rhG-CSF produced similar protective effects to those of AcSDKP with regard to leukocyte and CFU-GM counts. The combination of AcSDKP with rhG-CSF induced a further increase in total leukocytes and their subsets as compared to either agent alone, but did not alter the CFU-GM counts. Neither AcSDKP nor rhG-CSF nor their combination reduced CBD CA-induced hematological toxicity. In conclusion, AcSDKP or rhG-CSF administration further improved the tolerability of Ara-C beyond that already achieved with optimal circadian timing, while no such effect was observed in mice receiving CBDCA at the dose used. The results warrant further exploration of chronopharmacologic delivery schedules combining Ara-C with AcSDKP.

Analysis of Variance↗
PubMed1998

Pharmacological modulation of cisplatin toxicity rhythms with buthionine sulfoximine in mice bearing pancreatic adenocarcinoma (PO3).

In a previous report, we showed that the circadian rhythm of cisplatin (cis-diamminedichloroplatinum, CDDP) toxicity in healthy mice was modified by buthionine sulfoximine (BSO), a specific inhibitor of glutathione (GSH) synthesis. In the present study, the effects of BSO on the rhythms of CDDP toxicity and antitumor efficacy were investigated in mice bearing a transplantable pancreatic adenocarcinoma (PO3). B6D2F1 mice were inoculated with two 4 mm3 tumor fragments, one in each flank, then were synchronized with an alteration of 12 h of light (L) and 12 h of darkness (D) (LD 12:12). Three weeks later, a single dose of CDDP (12 mg/kg i.v.) was injected at 3 h, 7 h, 11 h, 15 h, 19 h, or 23 h after light onset (HALO) with or without prior BSO (450 mg/kg i.p. 4 h earlier). The antitumor activity of CDDP as assessed by tumor weight change and tumor growth delay was weak in this tumor model irrespective of prior BSO administration or CDDP dosing time. Nevertheless, toxic effects of CDDP as gauged by body weight loss or survival varied significantly according to CDDP dosing time. Body weight loss was least in mice receiving CDDP alone at the mid-to-late active span. Survival rate was 97% in mice treated with CDDP alone and 47% in those receiving prior BSO (chi 2 = 23.6, p < .0001). BSO pretreatment further shifted the period of survival or body weight change from 24 h to (10 + 24)h, an effect similar to that earlier reported in healthy mice. Thus, PO3 tumor at a measurable stage altered neither the circadian rhythm in CDDP toxicity nor the ultradian rhythm in the toxicity of BSO-CDDP combination. The results suggest that rhythms in target tissues for drug actions can be manipulated with biochemical modulators, thus partly escaping central clock control.

Adenocarcinoma↗
PubMed1998

Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma.

Vascular endothelial growth factor (VEGF) is an important mediator of vascular development in tumors. We aimed at clarifying the relationship between VEGF mRNA expression and invasion or metastasis of hepatocellular carcinoma (HCC). Reverse transcript-polymerase chain reaction (RT-PCR) was carried out on surgical specimens of 48 patients with HCC. The relative levels of VEGF mRNA expression were measured by determining a ratio between PCR products of VEGF and the endogenous internal standard gene beta-actin. Expression of VEGF mRNA in tumor was found in 76.5% (39/51) of patients, whereas it was 21.69% (11/51) in non tumorous liver. The levels of VEGF mRNA expression in tumors with tumorous emboli and in poor-encapsulated tumors were higher than that without tumorous emboli and in well-encapsulated tumors respectively (p < 0.05 t test). There was no significance in the expression of VEGF mRNA between large HCC (diameter > 5cm) and small HCC (diameter < or = 5cm) (p > 0.05). VEGF may play an important role in the invasion and metastasis of HCC. Angiogenesis in tumor correlates with progression of HCC.

Adult↗
PubMed1998

KAI1 gene expression in hepatocellular carcinoma and its relationship with intrahepatic metastases.

KAI1 gene is a novel metastasis suppressor gene. Its transcription level has been reported to be related with metastases in several kinds of tumors. The Authors used RT-PCR method to investigate the expression levels of KAI1 gene in hepatocellular carcinoma (HCC) tissues from 42 patients. The results demonstrated that 57.1% of tumor tissues were positive in KAI1 expression. There was no statistically significant difference on KAI1 gene expression rate between large (>5 cm) and small (<=5 cm) tumors, encapsulated and non-capsulated tumors, as well as alpha-fetoprotein (AFP) positive (>20 ug/ml) and negative (<=20 ug/ml) tumors; however, the expression rate was higher in tumors without intrahepatic metastasis than in those with intrahepatic metastasis (63.9% vs. 16.7%, P<0.05). It is suggested that KAI1 gene expression may be related to the metastases of hepatocellular carcinoma.

Adult↗
PubMed1997

Possible involvement of G-proteins in the regulation of striatal dopamine D2 receptor affinity by cholecystokinin octapeptide.

A G(i)-protein antibody AS/7 at 1:10 dilution significantly increased the K(d) values of the D2 agonist [3H]N-propylnorapomorphine (NPA) binding sites in the rat striatal membranes, and coincubation with sulphated cholecystokinin octapeptide (CCK-8; 1 nM) did not further increase the K(d) values. A GTP analogue guanylyl-imidodiphosphate (GMP-PNP) at 100 microM markedly increased the K(d) values of the [3H]NPA binding sites in the rat forebrain sections, and coincubation with CCK-8 (1 nM) again did not produce a further increase in the K(d) values. The present results indicate that abnormal activity of G-proteins abolished the ability of CCK-8 to reduce the D2 receptor affinity in the brain.

Animals↗
PubMed1997

Induction of preconvulsive behavior and Fos expression by dopamine-induced nigral lesion in the rat.

The substantia nigra pars reticulata (SNpr) has been proposed to play an important role in controlling the propagation and/or the generation of limbic seizures. Earlier work has shown that SN lesions have differential effects on seizure activity, suggesting that at least two discrete topographical regions mediate anticonvulsant or proconvulsant effects. The present investigation showed that exogenous dopamine (DA; 1.5-2.0 mumol) unilaterally injected into the anterior SNpr induced preconvulsive behavior (starting, immobilization, facial and mouth movements and wet-dog shakes). In addition, these rats showed Fos oncoprotein expression in the limbic system. These effects were observed in 90% of the rats with anterior SNpr DA injection. Rats with posterior SNpr injection did not show preconvulsive behavior nor Fos expression. These results show for the first time that unilateral DA lesion of the anterior portion of SNpr elicits Fos expression and preconvulsive behavior. In addition, the results suggest that lesion of the anterior and posterior regions of SNpr appear to exert different influences in the generation of preconvulsive behavior. The time course of behavior changes and Fos expression was also studied.

Animals↗
PubMed1997

Reciprocal regulation of the content of aromatic L-amino acid decarboxylase and tyrosine hydroxylase mRNA by NGF in PC12 cells.

Aromatic L-amino acid decarboxylase (AADC) and tyrosine hydroxylase (TH) are involved in the synthesis of dopamine and other monoamine neurotransmitters, and their activities can be regulated by a number of physiological stimuli. An interesting finding has been that (-)-deprenyl and some other irreversible monoamine B oxidase inhibitors increase AADC gene expression and that these compounds can exert neuronal protection/rescue effects. In this study, we have investigated the effects of nerve growth factor (NGF), and of (-)-deprenyl on AADC and TH gene expression in PC12 cells. Cells were treated with different doses of NGF (0.2-50 ng/ml) for up to 3 days. Northern and blot hybridizations were performed to detect AADC and TH mRNA. The results show that NGF can down-regulate AADC gene expression while increasing TH gene expression in a time- and dose-dependent fashion. Treatment with (-)-deprenyl alone increases the gene expression of AADC, and (-)-deprenyl further counteracts the reductions induced by NGF. This study introduces novel results with regard to the regulation of the gene expression of AADC in PC12 cells, which is not paralleled by the other catecholamine biosynthetic enzymes. These findings support the existence of an interaction between NGF and AADC gene expression that may be associated with the process of neuronal degeneration or regeneration.

Animals↗
PubMed1997

Identification of procaryotic developmental stages by statistical analyses of two-dimensional gel patterns.

Multivariate statistical comparisons of two-dimensional protein (2-D) gel patterns were used for the first time to define stages of a biological developmental system. The differentiating procaryote, Streptomyces coelicolor, was radiolabeled in liquid cultures at 16 intervals during development, and radioactive proteins were separated and quantified on 2-D gels. Cluster, principal component, and correlation analyses classified these gel patterns into four distinct groups, each reflecting a pattern of gene expression specific for a stage of development. These studies focused our attention on a phase of arrested growth as a key regulatory transition leading to secondary metabolism and a phase of renewed growth. Proteins whose synthesis was switched on or off during the "transitional" phase (some 21 and 18, respectively) were identified and will be the focus of future studies designed to identify their physiological or regulatory function.

Algorithms↗
PubMed1997

Pharmacologic modulation of reduced glutathione circadian rhythms with buthionine sulfoximine: relationship with cisplatin toxicity in mice.

The relationship between the rhythm in reduced glutathione (GSH) and that in cisplatin (CDDP) toxicity was investigated in a total of 560 male B6D2F1 mice, using buthionine sulfoximine (BSO). GSH was measured by high-performance liquid chromatography (HPLC) in four tissues, at each of six sampling times, 4 hr apart. A significant 24-hr rhythm was statistically validated in liver, jejunum, and colon, but not in bone marrow. Relative to liver, glutathione content was 56% in colon, 38% in bone marrow, 25% in jejunum, and negligible in kidney, where cysteine, a final product of GSH catabolism, displayed a 12-hr rhythmic variation. This rhythm may reflect that in the activity of GSH-degrading enzymes. BSO (450 mg/kg ip, 4 hr before sampling) reduced liver GSH threefold and kidney cysteine content was halved, but this pretreatment had no significant effect upon GSH content in the other organs. Furthermore, the period of the physiologic liver GSH rhythm changed from 24 hr to a composite (24 + 12 hr) period. This change in the period may result from an unmasking of the 12-hr rhythm in GSH-degrading enzyme activity by GSH synthesis blockade. Maximal values occurred in the mid-rest span and in the mid-active span after BSO administration. In the other tissues, the 24-hr period remained unchanged. BSO injection largely enhanced CDDP toxicity (as assessed by survival, leukopenia, and histologic lesions in kidney and bone marrow) and kidney mean platinum concentration. Furthermore, BSO pretreatment modified the period of CDDP toxicity rhythm: survival followed a significant 12-hr-rhythm, instead of a 24-hr rhythm. The cycling of GSH concentration results from a balance between synthesis and catabolism and likely constitutes one of the main components of the circadian rhythm in CDDP toxicity in mice.

Animals↗
PubMed1997

CTL induction using synthetic peptides delivered in emulsions--critical role of the formulation procedure.

Emulsions have been used with variable degrees of success to deliver antigen to stimulate immune responses. We have investigated three different ways of incorporating peptide antigen into soybean emulsions to induce CTL responses in mice. Two of these emulsions (oil-in-water, o/w, and water-in-oil-in-water, w/o/w) had peptide incorporated at the formulation stage, while the third had peptide added to a pre-formed o/w emulsion. High levels of CTL activity were induced when peptide was dispersed into the o/w or w/o/w emulsions, in contrast to addition of peptide to the pre-formed o/w emulsion, which did not stimulate a CTL response. Induction of CTL activity was independent of emulsion globule size but was correlated with a negative zeta potential and dispersion of peptide in the oil phase. The ability of peptide in soybean oil emulsion to induce CTL is critically dependent on dispersion of peptide at the time of emulsion formation.

Adjuvants, Immunologic↗
PubMed1997

Controlled release microparticles as a single dose hepatitis B vaccine: evaluation of immunogenicity in mice.

Hepatitis B surface antigen (HBsAg) was encapsulated in microparticles prepared from polylactide-co-glycolide (PLG) and polylactide (PLA) polymers using a solvent evaporation process. The immunoreactivity of the entrapped antigen was investigated by SDS-PAGE and Western blot. The microencapsulation process was modified to obtain both small (< 10 microns) and large microparticles (10-100 < microns). 80% of the antigen was encapsulated. Various combinations of small and large microparticles with controlled release characteristics were investigated in CD1 mice. Groups of animals were immunized with 30 micrograms equivalent of HBsAg in microparticles per animals. The control group received, three injections of 10 micrograms of HBsAg on alum at 0, 1 and 6 months. Results indicated that a single injection of HBsAg in microparticles could maintain the antibody response at a level comparable to the three-injection alum schedule for at least 1 year. An in vitro inhibition assay was developed to demonstrate that antigen-antibody reactivity were comparable for the microparticle immunized mice and the alum immunized mice. A competition assay with a monoclonal antibody specific for the neutralizing epitope of HBsAg demonstrated comparable binding for the sera from the microparticle and alum immunized mice.

Animals↗