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Biomedical subjects

M Liang

Publications and source records attributed to M Liang.

At least 37 records · Page 2Linked to original sources
PubMed2001

A phase I and pharmacologic study of 9-aminocamptothecin administered as a 120-h infusion weekly to adult cancer patients.

PURPOSE: To define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion. METHODS: 9-AC was administered over 120 h weekly to 55 adult cancer patients with solid tumors over doses ranging from 0.41 to 0.77 mg/m2 per day in a phase I and pharmacologic study. 9-AC formulated in dimethylacetamide/polyethylene glycol (DMA) was administered on a 3 of 4-week schedule, and the newer colloidal dispersion (CD) formulation was given on a 2 of 3-week schedule. RESULTS: Overall, 193 courses of therapy were administered over 122 dose levels. On the 3 of 4-week schedule, 9-AC DMA infused at > or = 0.6 mg/m2 per day for 120 h weekly produced dose-limiting neutropenia, thrombocytopenia, and diarrhea, or resulted in 1-2-week treatment delays. Shortening treatments to 2 of 3 weeks resulted in dose-limiting neutropenia and fatigue at infusion rates > 0.72 mg/m2 per day. The ratio of 9-AC lactone to total (carboxylate + lactone) drug plasma concentrations at steady-state was 0.15 +/- 0.07. Clinical toxicities and drug pharmacokinetics were not substantially different between the DMA and CD formulations. One objective response was observed in a patient with bladder cancer and minor responses were observed in patients with lung and colon cancers. Plasma area under the concentration versus time curve for 9-AC lactone modestly correlated with the degree of thrombocytopenia (r=0.51) using a sigmoid Emax pharmacodynamic model. CONCLUSION: The recommended phase II dose for the 9-AC DMA formulation is 0.48 mg/m2 per h over 120 h for 3 of 4 weeks and for the 9-AC CD formulation is 0.6 mg/m2 per day over 120 h for 2 of 3 weeks. Both regimens were well tolerated and feasible to administer.

Adult↗
PubMed2001

Role of gender on renal interstitial hydrostatic pressure and sodium excretion in rats.

The objective of this study was to compare renal interstitial hydrostatic pressure (RIHP) and sodium excretion in female and male Sprague-Dawley (SD) rats. The RIHP and pressure natriuresis responses were determined in female (n=13) and male (n=8) SD rats. Renal perfusion pressure (RPP) was controlled at two levels (100 and 120 mm Hg). Clearances were taken at each level and RIHP was measured with a chronically implanted polyethylene matrix in all rats. At the lower RPP level, RIHP was similar in both groups of rats (5.2+/-0.2 mm Hg for female, and 5.5+/-0.4 mm Hg for male), whereas fractional excretion of sodium (FENa) was significantly lower (P < .05) in male (1.10+/-0.27%) as compared to female (2.23+/-0.32%) rats at similar lower RPP. Allowing RPP to increase from 100 to 120 mm Hg resulted in similar increases in FENa (deltaFENa), urine flow rate (deltaV), and RIHP (deltaRIHP) in both groups of rats. The deltaFENa, deltaV, and deltaRIHP were 1.67+/-0.43%, 38.45+/-4.74 microL/min/g kidney weight, and 2.7+/-0.2 mm Hg for female, and 1.79+/-0.42%, 30.40+/-4.37 microl/min/g kidney weight, and 2.8+/-0.3 mm Hg for male rats. In conclusion, RIHP is similar in female and male SD rats at similar RPP levels. Both female and male SD rats increase RIHP and sodium excretion similarly in response to increases in RPP. The lower basal FENa in male as compared to female rats may play an important role in the more significant elevation of blood pressure in males with age.

Animals↗
PubMed2001

Intrarenal serotonin, dopamine, and phosphate handling in remnant kidneys.

BACKGROUND: Serotonin (5-HT) and dopamine (DA) are intrarenal autocrine/paracrine substances that regulate phosphate reabsorption. The present studies explored intrarenal serotonin and DA metabolism and the implications for phosphate homeostasis in rats with remnant kidneys, a model for renal failure. METHODS: The intrarenal productions of serotonin and DA were determined from measurements of renal interstitial fluid (microdialysate) and urine in rats with remnant or intact kidneys. In clearance studies, the effects of infusion of methiothepin, a serotonin receptor antagonist, or gludopa, a renal selective DA precursor, on phosphate and sodium excretion were determined in rats with a remnant or intact kidneys. RESULTS: Renal interstitial serotonin (5-HT, 3.4 +/- 0.9 pg/min) was fourfold higher than DA (0.6 +/- 0.1 pg/min) in remnant kidneys. Conversely, urinary excretion of serotonin was fourfold less than DA in rats with a remnant kidney (5-HT 0.4 +/- 0.02 vs. DA 1.5 +/- 0.1 ng/min). Infusion of methiothepin or gludopa significantly increased the fractional excretion of phosphate (FE(Pi)) in rats with a remnant kidney from 54 +/- 3 to 67 +/- 7% (P < 0.05) and from 36 +/- 10% to 51 +/- 13% (P < 0.05), respectively. CONCLUSION: We conclude that serotonin preferentially accumulates in the renal interstitium, whereas DA exits primarily via the tubular lumen. Phosphate excretion is increased by both the acute infusion of the serotonin receptor antagonist and the infusion of gludopa, suggesting that both serotonin and DA modulate phosphate excretion in rats with remnant kidneys.

Animals↗
PubMed2001

Mechanism underlying diuretic effect of L-NAME at a subpressor dose.

The diuretic effects of nitric oxide (NO) synthase inhibitors administered at subpressor dose in rats are controversial, and the tubular segments involved are not known. In the present study, we examined the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME) at a subpressor dose on renal interstitial NO and cGMP activity and on renal tubular segmental reabsorption of fluid in the rat. Intravenous infusion of L-NAME at 1 microg. kg(-1). min(-1) in Sprague-Dawley rats (N = 8), which did not alter mean arterial pressure or glomerular filtration rate, significantly increased urine flow rate (U(v); from 78.2 +/- 12.7 to 117.1 +/- 14.9 microl/min, P < 0.05). Paradoxically, this effect of L-NAME was concomitant with significant increases in nitrite/nitrate (from 10.79 +/- 1.20 to 16.50 +/- 2.60 microM, P < 0.05) and cGMP (from 0.65 +/- 0.09 to 0.98 +/- 0.18 nM, P < 0.05) concentrations in renal cortical microdialysate as well as the nitrite/nitrate concentration in the medullary microdialysate. Micropuncture studies in the superficial nephron revealed that L-NAME significantly increased the flow rate (from 8.3 +/- 0.9 to 12.2 +/- 1.2 nl/min, P < 0.05) and fractional delivery of fluid to the distal tubule, but not those in the late proximal tubule. In conclusion, L-NAME, at the subpressor dose used in this study, increased renal nitrate/nitrite and cGMP and inhibited fluid reabsorption in tubular segments between the late proximal tubule and the distal tubule of superficial nephrons.

Animals↗
PubMed2001

Stimulation of vascular protein synthesis by activation of oestrogen receptor beta.

The objective of this study was to investigate the effects of oestrogen receptor (ER) beta activation on vascular protein synthesis and protein expression. Nuclear immunoreactivity towards ER beta was observed abundantly in vascular smooth muscle and endothelial cells of mouse aorta. No ER alpha-positive cell nuclei were observed. In aorta from ovariectomized mice, treatment with the selective ER beta agonist genistein (100 nM) for 24 h increased [(3)H]leucine incorporation by about 30%. This effect was prevented by the ER blocker ICI 182780 (10 microM). Although genistein treatment stimulated protein synthesis, it caused no change in total protein determined either by the Lowry method on tissue homogenate or by densitometric scanning of protein bands (10-220 kDa) separated by SDS-PAGE. Separation of [(35)S]methionine-labelled proteins by SDS-PAGE did not reveal the protein(s) stimulated by genistein. DNA synthesis was not affected by 100 nM genistein, suggesting that genistein-induced stimulation of protein synthesis is not part of a growth response. Protein expression, determined by SDS-PAGE, was similar in aorta from ER beta-knockout and wild-type mice, suggesting that expression of vascular proteins does not depend solely on a functional ER beta gene. We suggest that activation of vascular ER beta stimulates synthesis of proteins and that this response is not associated with vascular growth.

Animals↗
PubMed2001

[The efficiency of algae removal from drinking water by ferrate].

This paper studied the efficiency of algae removal by ferrate from two kinds of raw water which were collected from Donghu and Tiegang reservoir respectively. The experimental results showed that the removal efficiency of algae reached about 95% only through PAC coagulation when the raw water was extracted from Donghu reservoir in which most of algae was Chlorella. But dealing with Tiegang raw water in which the majority of algae were Oscillatoria, terrate was used as pre-oxidant coupling with PAC coagulation not only using PAC to flocculate and the efficiency of algae removal could be up to 97.85%. However this treatment method using ferrate as pre-oxidant overmatched the traditional method prechlorination for algae removal.

Eukaryota↗
PubMed2001

[Generation of human recombinant antibody Fab fragment to influenza virus from combined antibody library].

OBJECTIVE: To acquire the recombinant human monoclonal antibodies to influenza virus which can be used in mucous membrane treatment to prevent the infection of virus in animal model in the future. METHODS: Construct and pan human Fab antibody library to influenza virus Sydney strain (H3N2) from vaccinated donors by using phage display technology and secreted expression in E. Coli system. The positive Fab clones with neutralization activity to influenza virus were selected and characterized through HI test, IFA and VN test. RESULTS: Separate two Fab clones, IV-2 and IV-6, appear positive responses in ELISA and IFA. These two clones can inhibit hemagglutination in HI test and can decrease viral titer by 30 and 20 times in viral neutralization assay, respectively. CONCLUSION: We have got two clones of Fab fragments with neutralization activity to influenza virus Sydney strain (H3N2).

Cells, Cultured↗
PubMed2001

[The metabolism of trehalose and intracellular glycerol in Candida krusei responding to high osmosis].

The trehalose and intracellular glycerol contents of osmotolerant yeast Candida krusei cells rapidly increased in response to the medium containing NaCl. Addition of NaCl at early exponential phase or steady phase increased trehalose content only, but the content of extracellular glycerol increased gradually. Development of resistance was accompanied by accumulation of trehalose and was apparently unrelated to intracellular glycerol content which was always low under these conditions. There seems to be an overlap function between trehalose and glycerol in Candida krusei cells in response to the osmotic conditions.

Candida↗
PubMed2001

[Determination of roxithromycin in serum by high-performance liquid chromatography with ultraviolet detection].

OBJECTIVE: To make better the RP-HPLC method for the determination of roxithromycin(RM) in human serum. METHODS: RM and clarithromycin (internal standard) were extracted from alkalinized serum sample (500 microliters) with methylene chloride. After evaporation of the organic layer, the residue was dissolved in 100 microliters of acetonitrile-ammonium phosphate (1:1, pH 6.0) and washed with n-hexane, then 20 microliters was injected onto a column (5 microns, 15 cm x 4.6 mm) of Penomenex luna C18. The mobile phase was acetonitrile-0.05 mol/L phosphoric acid (39:19:42, adjusted to pH 7.2 with ammonia water) pumped at 1.2 ml/min through the column. The variable wavelength UV detector operated at 0.01 aufs and the wavelength was set at 210 nm. RESULTS: The retention times for RM and clarithromycin were 4.4 min and 5.0 min, respectively. Standard curve was linear in the concentration range of 0.25 to 32 mg/L. The detection limit in serum was 0.06 mg/L; the average method recovery 97.4%; the inter-day RSD less than 3.0%. CONCLUSION: This method was found to be simple, rapid, sensitive and accurate for determination of RM in human serum.

Chromatography, High Pressure Liquid↗
PubMed2001

[Determination of warfarin in plasma by HPLC and an investigation of monitoring patients after cardiac valve replacement].

OBJECTIVE: A simple HPLC method was established for the determination of warfarin in plasma to investigate the relationship between warfarin concentration and anticoagulant effect. METHODS: The mixture of dichloromethane and hexane (1:9) was used as extracting solvent for the plasma samples. The chromatographic separation was on C18 column with a mobile phase consisting of methanol and 50 mmol/L ammonium acetate buffer (pH2.5, 70:30). RESULTS: The calibration curve was linear within 50-2000 ng/ml. The extraction recoveries of warfarin were 78.0%-81.6%. The recoveries of methodology were 103.1%-106.5%. Inter-day and intra-day RSD were 2.33%-5.46% and 5.29%-7.73%, respectively. This method was used for determining warfarin in 70 patients after cardiac valve replacement. The results showed that 44 cases had their INR within the safety range (1.31-2.35) recommended to Chinese, and of them 37(84.1%) cases had a warfarin level at 616.2 +/- 154.8 ng/ml. CONCLUSION: This method is useful in monitoring warfarin concentration during anticoagulant therapy.

Anticoagulants↗
PubMed2000

Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling.

Smads are important intracellular signaling effectors for transforming growth factor-beta (TGF-beta) and related factors. Proper TGF-beta signaling requires precise control of Smad functions. In this study, we have identified a novel HECT class ubiquitin E3 ligase, designated Smurf2, that negatively regulates Smad2 signaling. In both yeast two-hybrid and in vitro binding assays, we found that Smurf2 could interact with receptor-activated Smads (R-Smads), including Smad1, Smad2, and Smad3 but not Smad4. Ectopic expression of Smurf2 was sufficient to reduce the steady-state levels of Smad1 and Smad2 but not Smad3 or Smad4. Significantly, Smurf2 displayed preference to Smad2 as its target for degradation. Furthermore, Smurf2 exhibited higher binding affinity to activated Smad2 upon TGF-beta stimulation. The ability of Smurf2 to promote Smad2 destruction required the HECT catalytic activity of Smurf2 and depended on the proteasome-dependent pathway. Consistent with these results, Smurf2 potently reduced the transcriptional activity of Smad2. These data suggest that a ubiquitin/proteasome-dependent mechanism is important for proper regulation of TGF-beta signaling.

Cell Line↗
PubMed2000

A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection.

Chemokines like RANTES appear to play a role in organ transplant rejection. Because RANTES is a potent agonist for the chemokine receptor CCR1, we examined whether the CCR1 receptor antagonist BX471 is efficacious in a rat heterotopic heart transplant rejection model. Treatment of animals with BX471 and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself ineffective in prolonging transplant rejection, is much more efficacious in prolonging transplantation rejection than animals treated with either cyclosporin or BX471 alone. We have examined the mechanism of action of the CCR1 antagonist in in vitro flow assays over microvascular endothelium and have discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelium. Together, these data demonstrate a significant role for CCR1 in allograft rejection.

Animals↗
PubMed2000

Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1.

The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl ]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471). Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis. This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases.

Administration, Oral↗
PubMed2000

ADP-Ribosyl cyclase in rat vascular smooth muscle cells: properties and regulation.

We investigated whether ADP-ribosyl cyclase (ADPR-cyclase) in rat vascular smooth muscle cells (VSMCs) has enzymatic properties that differ from the well-characterized CD38-antigen ADPR-cyclase, expressed in HL-60 cells. ADPR-cyclase from VSMCs, but not CD38 ADPR-cyclase from HL-60 cells, was inhibited by gangliosides (10 micromol/L) GT(1B), GD(1), and GM(3). Preincubation of membranes from CD38 HL-60 cells, but not from VSMCs, with anti-CD38 antibodies increased ADPR-cyclase activity; CD38 antigen was detected both in VSMCs and in HL-60 cells. ADPR-cyclase in VSMC membranes was more sensitive than CD38 HL-60 ADPR-cyclase to inactivation by N-endoglycosidase F and to thermal inactivation at 45 degrees C. The specific activity of ADPR-cyclase in membranes from VSMCs was >20-fold higher than in membranes from CD38 HL-60 cells. Most importantly, VSMC ADPR-cyclase was inhibited by Zn(2+) and Cu(2+) ions; the inhibition by Zn(2+) was dose dependent, noncompetitive, and reversible by EDTA. In contrast, Zn(2+) stimulated the activity of CD38 HL-60 ADPR-cyclase and other known types of ADPR-cyclases. Retinoids act either via the nuclear receptor retinoic acid receptor or retinoid X receptor, including all-trans retinoic acid (atRA), and panagonist 9-cis-retinoic acid-upregulated VSMC ADPR-cyclase; the stimulatory effect of atRA was blocked by actinomycin D and cycloheximide. 1,25(OH)(2)-Vitamin D(3) (calciferol) stimulated VSMC ADPR-cyclase dose dependently at subnanomolar concentrations (ED(50) congruent with 56 pmol/L). Oral administration of atRA to rats resulted in an increase of ADPR-cyclase activity in aorta ( congruent with+60%) and, to a lesser degree, in myocardium of left ventricle (+18%), but atRA had no effect on ADPR-cyclases in lungs, spleen, intestinal smooth muscle, skeletal muscle, liver, or testis. Administration of 3,5,3'-triiodothyronine (T(3)) to rats resulted in an increase of ADPR-cyclase activity in aorta ( congruent with+89%), but not in liver or brain. We conclude the following: (1) ADPR-cyclase in VSMCs has enzymatic properties distinct from "classic" CD38 ADPR-cyclase, especially sensitivity to inhibition by Zn(2+) and Cu(2+); (2) ADPR-cyclase in VSMCs is upregulated by various retinoids, calcitriol, and T(3) in vitro; and (3) administration of atRA and T(3) increases ADPR-cyclase in aorta in vivo. We suggest that the cADPR signaling system plays an important role in the regulation of VSMC functions in response to steroid superfamily hormones.

ADP-ribosyl Cyclase↗
PubMed2000

Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor.

The species specificity of a small molecule antagonist for the human CCR1 chemokine receptor, 2-2-diphenyl-5-(4-chlorophenyl)piperidin-1-yl)valeronitrile (CCR1 antagonist 1), has been examined using cloned CCR1 receptors from various species. The compound was able to bind to rabbit, marmoset, and human CCR1, and was able to block the functional activation of these receptors. However, it failed to significantly displace radiolabeled macrophage inflammatory protein-1alpha (MIP-1alpha) binding to mouse CCR1 at concentrations up to 10 microM. These data suggested that the antagonist binding site is well-conserved in rabbit, marmoset and human CCR1, but not in mouse CCR1. The functional selectivity and mechanism of action for CCR1 antagonist 1 were further characterized. CCR1 antagonist 1 blocked the increase in intracellular Ca(2+) stimulated by CCR1 agonists, but had no effect on N-formyl-Met-Leu-Phe (FMLP), monocyte chemotactic protein-1 (MCP-1) and stromal-derived factor 1alpha (SDF1alpha)-induced Ca(2+) mobilization, demonstrating functional selectivity for CCR1. Since CCR1 antagonist 1 is a functional antagonist of marmoset and rabbit CCR1 receptors, it should be possible to test its efficacy in animal models of disease.

Amino Acid Sequence↗
PubMed2000

Partial rescue of the ocular retardation phenotype by genetic modifiers.

The or(J) allele of the murine ocular retardation mutation is caused by a premature stop codon in the homeodomain of the Chx10 gene. When expressed on an inbred 129/Sv strain, the or(J) phenotype is characterized by microphthalmia and a thin, poorly differentiated retina in which the peripheral portion is affected to a greater extent than the central portion. Such mutant retinae lack differentiated bipolar cells and the optic nerve typically fails to form, leading to blindness. Here, we show that progeny from an outcrossed backcross between 129/Sv-or(J) /or(J) and Mus musculus castaneus produce animals that are homozygous for the or(J) mutation and exhibit a much ameliorated eye phenotype. Although not of normal size, such modified or(J) eyes are significantly larger than those in 129/Sv-or(J) /or(J) mice, and contain a better organized retina which includes bipolar cells. Furthermore, optic nerves are frequently present, and the eyes show a degree of function as reflected by electroretinogram and pupillary response. As in 129/Sv-or(J) /or(J) mice, however, modified or(J) eyes show incomplete growth and a lack of cell differentiation in the periphery of the retina. The selective, and apparently nonmodifiable, effect of the ocular retardation phenotype on the periphery of the retina indicates that Chx10 plays an important role in the central-to-peripheral gradient of retinal development. These findings demonstrate that the ocular retardation phenotype can be greatly modified by the genetic background, and help to define a role for Chx10 in ocular development.

Animals↗
PubMed2000

Production and functional roles of nitric oxide in the proximal tubule.

A significant role for nitric oxide (NO) in proximal tubule physiology and pathophysiology has been revealed by a series of in vivo and in vitro studies. Whether the proximal tubule produces NO under basal conditions is still controversial; however, evidence suggests that the proximal tubule is constantly exposed to NO that might include NO from nonproximal tubule sources. When challenged with a variety of stimuli, including hypoxia, the proximal tubule is able to produce large quantities of NO. In vivo studies generally indicate that NO inhibits fluid and sodium reabsorption by the proximal tubule. However, the final effect of NO on proximal tubular reabsorption appears to depend on the concentration of NO and involve interaction with other regulatory mechanisms. NO regulates Na(+)-K(+)-ATPase, Na(+)/H(+) exchangers, and paracellular permeability of proximal tubular cells, which may contribute to its effect on proximal tubular transport. Enhanced production of NO, perhaps depending on macrophage type inducible NO synthase, participates in hypoxic/ischemic proximal tubular injury. In conclusion, NO plays a fundamental role in both physiology and pathophysiology of the proximal tubule.

Absorption↗