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PubMed2005

Chromosomal telomere shortening of kidney cells in IgA nephropathy by the measurement of DNA in urinary sediment.

BACKGROUND: The histology and function of the kidney deteriorates with age and progressive renal failure, but the mechanisms involved in renal ageing are not known. In vitro studies suggest that telomere shortening is important in replicative senescence, and is accelerated by stress factors that increase replication. We investigated whether IgA nephropathy, a prototype chronic kidney disease, is associated with localized intrarenal cellular ageing. METHODS: We studied the mean length of terminal restriction fragments (TRF), a measure of average telomere size, in the DNA of peripheral blood mononuclear cells and urinary sediment of 15 patients with IgA nephropathy. RESULTS: The mean TRF lengths in peripheral blood is 7043.8 +/- 1 182.8 base pairs, and in urinary sediment is 6 749.7 +/- 636.5 base pairs. The mean TRF lengths of urinary DNA significantly correlate with the serum creatinine (r = -0.525, p = 0.044) and estimated glomerular filtration rate (GFR) (r = 0.651, p = 0.009). The mean TRF lengths of urinary DNA had an insignificant inverse correlation with patient age (r = -0.364, p = 0.2), and do not correlate with the degree of glomerulosclerosis (r = 0.004, p = 0.9) or tubulointerstitial scarring in renal biopsy (r =-0.032, p = 0.9). After 30 months of follow-up, the rate of decline of estimated GFR has an inverse correlation with the mean TRF lengths of urinary DNA (r = -0.699, p = 0.004). The TRF lengths of peripheral blood DNA do not correlate with any clinical or histological parameter or the rate of renal function decline. CONCLUSIONS: Although this is a pilot study, our observation indicates that the TRF lengths of genomic DNA extracted from urinary sediment is related to the degree of renal impairment. However, a long telomere length of genomic DNA in urinary sediment is associated with a more rapid decline of renal function. Our findings might be relevant to the pathogenesis of progressive renal failure.

Adult↗
PubMed1997

[Clinical significance of microtransferrinuria in diabetic patients].

We studied the relationship between the urinary microtransferrin (TRF) and early glomerular damage in diabetes mellitus. 61 patients with non-insulin-dependent diabetes mellitus and 40 healthy subjects were measured for urinary TRF with rate immunonephelometry assay. The Urinary TRF concentrations were found to be greatly elevated in patients with diabetes compared with those in the health subjects (P < 0.001). The increase of TRF was closely related to age and duration of diabetes mellitus, blood glucose, hypertension, retinopathy, and it was initial parameter to predict diabetic nephropathy. There was a significant correlation among urinary TRF concentration, microalbumin, and N-acetyl-beta-D-glucosaminidase. The urinary excretion of TRF was more elevated than that of microalbumin. It is suggested that excretion of TRF in urine is a more sensitive index of the glomerular dysfunction in diabetes mellitus.

Acetylglucosaminidase↗
PubMedDate not supplied

Epilepsy-related ambiguity in rating the child behavior checklist and the teacher's report form.

Although the child behavior checklist (CBCL) and the teacher's report form (TRF) were not designed for diagnosing psychopathology in children with chronic illnesses, they have become extensively used research tools to assess behavioural problems in paediatric populations, including children with epilepsy. When applied to children with epilepsy, items like "staring blankly" or "twitching" can be rated on the basis of seizure features rather than behaviour and, hence, render behavioural scores ambiguous. The aims were detection, and evaluation of the impact, of CBCL and TRF items eliciting ambiguity when applied to children with "epilepsy only" (idiopathic or cryptogenic epilepsy, attending normal schools). Experts identified items that give rise to interpretational ambiguity of the ratings in epilepsy. By treating ratings on these items as missing values, their effect was evaluated in CBCL and TRF scores of 59 schoolchildren with "epilepsy only" and age and gender matched healthy classmates. Seven items of the CBCL gave rise to ambiguity of which items 5 co-occur on the TRF. Rescoring reduced psychopathology scores in children with "epilepsy only", but not in those of healthy children: the percentage of patients trespassing the clinical cut off score, on at least one of the subscales, reduced from 46 to 23% on the CBCL and from 18 to 15% on the TRF. Parents and teachers run the risk of confusing behaviour and seizure features when filling out the CBCL and TRF. In "epilepsy only", prevalence estimates of psychopathology based on the CBCL and TRF, should be considered with some reserve.

Attention↗
PubMed2002

Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats.

This study determined the effects of palm vitamin E (TRF) diet on the levels of blood glucose, glycated hemoglobin (gHb), serum advanced glycosylation end-products (AGE) and malondialdehyde (MDA) of diabetic Sprague-Dawley rats. The rats received either control (normal rat chow), TRF diet (normal chow fortified with TRF at 1 g/kg) or Vitamin C diet (vitamin E-deficient but contained vitamin C at 45 g/kg). The animals were maintained on the respective diet for 4 weeks, made diabetic with streptozotocin (STZ), then followed-up for a further 8 weeks. At week-4, mean serum AGE levels of rats given TRF diet (0.7 +/- 0.3 units/ml) were significantly lower than those of control or Vitamin C diet rats (p pounds 0.03). The levels increased after STZ and became comparable to the other groups. At week 12, blood glucose (20.9 +/- 6.9 mM) and gHb (10.0 +/- 1.6%) of rats on TRF diet remained significantly low compared to that of control or Vitamin C diet rats (p pounds 0.03). MDA however, was not affected and remained comparable between groups throughout the study. This study showed that TRF may be a useful antioxidant; effectively prevented increase in AGE in normal rats, and caused decrease in blood glucose and gHb in diabetic rats. Further studies are needed to elucidate the mechanisms of action of TRF.

Animals↗
PubMed1992

Transferrin index: an alternative method for calculating the iron saturation of transferrin.

We surveyed 140 clinical chemistry laboratories in Australia to establish which laboratory methods they used to determine serum iron status: 125 measured serum iron (Fe), 85 measured transferrin (TRF), 47 measured total iron-binding capacity (TIBC), and 14 measured both TRF and TIBC. Of the 55 laboratories routinely reporting TRF saturation (TS), 16 calculated TS directly as (Fe/TIBC) x 100, and 9 used [Fe/(TRF x 2)] x 100. Thirty laboratories measured TRF and converted it to an equivalent TIBC concentration; the derived TIBC was then used to calculate TS. We measured iron, TIBC, and TRF concentrations in 94 control subjects, 59 patients with alcoholic liver disease (ALD), and 20 with proven genetic hemochromatosis (GH). TS was compared with a transferrin index (TI = Fe/TRF) to determine whether both methods were sensitive for GH screening and which method gave the fewest false-positive results with discrimination limits of > 55% and > 1.0, respectively. All GH patients were detected by both TS and TI at these limits. One control subject had a TI > 1.0, whereas three control subjects had a TS > 55%. Nine patients with ALD had a TI > 1.0 and 11 ALD patients had a TS > 55%. Some iron-overload patients had lower than expected TS values compared with TI, possibly because of ferritin interference in the TIBC assay. Also, the precision of the TRF assay was better than that of the TIBC assay: CVs of 1.85-3.68% vs 6.17%. We therefore recommend that calculated TI replace TS in screening for iron overload.

Australia↗
PubMed1982

Epidemiology of analgesic nephropathy in Belgium.

The incidence of analgesic nephropathy in patients with terminal renal failure (AN-TRF) was evaluated by questioning all the dialysis units in Belgium. The results were analyzed with respect to the distribution of the analgesic market in Belgium. Replies were received from 46 of the 49 dialysis units for adults. Of the 1,400 patients treated in these units, 258 (18.4%) have AN. Furthermore, AN was more frequent in the neighbourhood of Antwerp than in the other Belgian provinces (100 AN-TRF/million adults vs 19; 36% of TRF vs 14%, P less than 0.001). The number of patients treated by hemodialysis per million adults was correlated well with the number of AN-TRF/million adults in the various areas of Belgium (r = 0.73, P less than 0.05). 265 tons of analgesics (35 g/adult/year), including 55 tons of phenacetin (7 g/adult/year) are sold each year in Belgium. Among the five most popular drugs in Belgium, three are analgesics containing acetylsalicylate-phenacetin or phenazone or paracetamol-caffeine. These three analgesics are made in the neighbourhood of Antwerp, no such analgesics are made in other areas of Belgium. No correlation exists between the geographic distribution of AN-TRF and the distribution of other widely-used over-the-counter drugs such as laxatives, non-phenacetin-containing analgesics and even analgesics which contain phenacetin but which are not made in Belgium. Conversely, the distribution of AN-TRF was well correlated with that of the sale of an analgesics made in the neighbourhood of Antwerp (r = 0.79, P less than 0.001). Belgium thus has, after Australia, the second highest incidence of analgesic nephropathy in the world. The geographic distribution of AN-TRF inside Belgium correlates with the existence of analgesic factories in the neighbourhood of Antwerp.

Acetaminophen↗
PubMed2000

Human cytogenetic biomonitoring using flow-cytometric analysis of micronuclei in transferrin-positive immature peripheral blood reticulocytes.

We have developed a method to isolate and analyze nascent human reticulocytes in peripheral blood for the presence of micronuclei (MN). For a very short time peripheral reticulocytes show residual expression of the transferrin receptor. Using immunomagnetic separation of cells expressing the transferrin receptor, a population of immature reticulocytes (Trf-Ret) was isolated from peripheral blood. In humans, the spleen actively removes micronucleated erythrocytes but during the short lifetime of the isolated Trf-Ret only a fraction (less than about 20%) of the MN-containing reticulocytes will have been eliminated. Cells were stained with the fluorescent dyes Thiazole Orange for RNA and Hoechst 33342 for DNA and analyzed by flow cytometry and fluorescence microscopy. Baseline frequencies of MN-Trf-Ret on a group of healthy donors were found to be 1.1% for males and 1.4% for females; however, the gender difference was not significant. The frequency of MN-Trf-Ret in the studied group increased with age, and was dependent on blood group. In three donors studied over 4 months, the baseline level remained stable. In cancer patients treated with radiation or chemotherapy, the frequency of MN-Trf-Ret increased 10- to 20-fold after 1-4 days, depending on the treatment. A high correlation between flow and manual analysis of MN-Trf-Ret was seen. We believe the method has a high potential as a sensitive and rapid method for biological monitoring in presumed exposed groups and individuals.

Adult↗
PubMed1988

Direct combinatorial interaction between a herpes simplex virus regulatory protein and a cellular octamer-binding factor mediates specific induction of virus immediate-early gene expression.

We provide evidence for a novel mechanism of transcriptional regulation in which the immediate-early (IE) transactivating protein of herpes simplex virus, Vmw65, is assembled into a specific DNA-binding complex together with a cellular octamer-binding factor (TRF). The assembly of Vmw65/TRF complex requires not only the core TRF recognition site, but also flanking sequences which are dispensable for TRF binding alone. We show from functional analyses that TRF binding by a motif is required but not sufficient to confer induction on a heterologous promoter, and it is the ability of the motif to allow TRF/Vmw65 complex assembly which correlates with functional activity. Thus, for the induction of HSV IE expression, Vmw65 forms a complex with TRF by recognition of the specific subset of appropriately flanked TRF binding sites present in each of the IE genes. This mechanism may provide a paradigm for the selective utilization of the same transcription factor in differential gene expression.

Base Sequence↗
PubMed1979

Effect of thyrotropin releasing factor on body weight of the pond snail Lymnaea stagnalis.

Earlier studies had demonstrated that in Lymnaea stagnalis thyrotropin releasing factor (TRF) may be the secretory product of the so-called dark green neurosecretory cells. The dark green cells are believed to serve an osmoregulatory function. If TRF is the secretory product of the dark green cells, it should be capable of controlling the salt and water balance in L. stagnalis. In this study, the effect and fate of synthetic TRF injected in vivo into L. stagnalis was assessed. It was found that TRF caused an increase in the rate of loss of body water which normally occurs after anaesthesia. TRF also increased the loss of body water when it was administered to unanaesthetized animals. The peptide was accumulated and degraded by the tissues of the foot, mantle, and head regions, tissues which are believed to be the targets of the hormone of the dark green cells. Our results support the hypothesis that TRF may be the secretory product of the dark green cells and may be involved in osmoregulation in L. stagnalis.

Animals↗
PubMed1994

Alpha-interferon induces depletion of intracellular iron content and upregulation of functional transferrin receptors on human epidermoid cancer KB cells.

We have demonstrated that interferon-alpha (IFN alpha) upregulates the epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma cells. Here we report that IFN alpha induces growth inhibition and upregulation of transferrin receptor (TRF-R) on epidermoid cancer KB cells. IFN alpha does not alter TRF-R affinity for its ligand and induces a two-fold increase of TRF binding sites. IFN alpha does not modify receptor internalization and cycling. Intracellular iron levels are known to regulate TRF-R expression: we have, therefore, evaluated whether changes in the iron content could be determined by IFN alpha. Iron levels are transiently increased after addition of fresh growth medium in untreated controls but not in KB cells exposed for 48 h to IFN alpha. Iron depletion is however completely reversed 24 h later when maximal TRF-R upregulation occurs in IFN alpha-treated cells. We suggest that IFN alpha-induced iron depletion elicits a homeostatic cellular response through upregulation of TRF-R.

Cell Cycle↗
PubMed1998

Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status.

Potential antiproliferative effects of tocotrienols, the major vitamin E component in palm oil, were investigated on the growth of both estrogen-responsive (ER+) MCF7 human breast cancer cells and estrogen-unresponsive (ER-) MDA-MB-231 human breast cancer cells, and effects were compared with those of alpha-tocopherol (alphaT). The tocotrienol-rich fraction (TRF) of palm oil inhibited growth of MCF7 cells in both the presence and absence of estradiol with a nonlinear dose-response but such that complete suppression of growth was achieved at 8 microg/mL. MDA-MB-231 cells were also inhibited by TRF but with a linear dose-response such that 20 microg/mL TRF was needed for complete growth suppression. Separation of the TRF into individual tocotrienols revealed that all fractions could inhibit growth of both ER+ and ER- cells and of ER+ cells in both the presence and absence of estradiol. However, the gamma- and delta-fractions were the most inhibitory. Complete inhibition of MCF7 cell growth was achieved at 6 microg/mL of gamma-tocotrienol/delta-tocotrienol (gammaT3/deltaT3) in the absence of estradiol and 10 microg/mL of deltaT3 in the presence of estradiol, whereas complete suppression of MDA-MB-231 cell growth was not achieved even at concentrations of 10 microg/mL of deltaT3. By contrast to these inhibitory effects of tocotrienols, alphaT had no inhibitory effect on MCF7 cell growth in either the presence or the absence of estradiol, nor on MDA-MB-231 cell growth. These results confirm studies using other sublines of human breast cancer cells and demonstrate that tocotrienols can exert direct inhibitory effects on the growth of breast cancer cells. In searching for the mechanism of inhibition, studies of the effects of TRF on estrogen-regulated pS2 gene expression in MCF7 cells showed that tocotrienols do not act via an estrogen receptor-mediated pathway and must therefore act differently from estrogen antagonists. Furthermore, tocotrienols did not increase levels of growth-inhibitory insulin-like growth factor binding proteins (IGFBP) in MCF7 cells, implying also a different mechanism from that proposed for retinoic acid inhibition of estrogen-responsive breast cancer cell growth. Inhibition of the growth of breast cancer cells by tocotrienols could have important clinical implications not only because tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells could be growth-inhibited in the presence as well as in the absence of estradiol. Future clinical applications of TRF could come from potential growth suppression of ER+ breast cancer cells otherwise resistant to growth inhibition by antiestrogens and retinoic acid.

Breast Neoplasms↗
PubMed1987

Vectorial secretion of transferrin and androgen binding protein in Sertoli cell cultures: effect of extracellular matrix, peritubular myoid cells and medium composition.

We examined the effect of various culture conditions on the polarized secretion of androgen binding protein (ABP) and transferrin (Trf) by Sertoli cells (Sc) in vitro. Sc from 18-day-old rats were cultured as confluent monolayers on permeable membranes in two-compartment chambers for up to 11 days. Coating of the membranes with extracellular matrix (ECM) components: collagen IV + laminin (CL) or reconstituted basement membrane (RBM) enhanced ABP and Trf secretion (200% and 150%, respectively), with RBM being more effective than CL in stimulating ABP but not Trf secretion. Neither CL nor RBM significantly influenced the relative amounts of ABP and Trf secreted into the outer (OC) and inner (IC) compartments of the culture chamber (OC/IC ratio). All of these effects were not significantly influenced by the presence of testosterone and serum. Co-culture of Sc with peritubular myoid cells (Pc) significantly increased the secretion of both ABP and Trf, although the magnitude of stimulation and the time-response patterns were different for each protein. Co-culture with Pc also dramatically increased the OC/IC ratios for ABP and Trf. Testosterone (10(-6) M) enhanced the Pc effects. In cultures of Sc alone, presence of 2% fetal bovine serum increased the OC/IC ratios, whereas testosterone had no effect. Based on these results, we suggest a possible role of Pc in the regulation of Sc polarized secretions.

Androgen-Binding Protein↗
PubMed2005

Hypolipidemic and antioxidant properties of tocotrienol rich fraction isolated from rice bran oil in experimentally induced hyperlipidemic rats.

We investigated a dose-dependent hypolipidemic and antioxidant effect of tocotrienol rich fraction (TRF) isolated from rice bran oil on experimentally induced hyperlipidemic rats. Feeding of atherogenic diet (5% hydrogenated fat, 0.5% cholic acid and 1% cholesterol) for three weeks resulted in a significant increase in plasma triglyceride (3.3-fold) and total cholesterol (2.4-fold) levels. There was a 5-fold increase in the level of LDL cholesterol with only a small increase in HDL cholesterol. On the other hand, HMG-CoA reductase activity was significantly reduced in these animals. The formation of TBARS, thiobarbituric acid reactive substances, (86%) and conjugated dienes (78%) were also significantly higher in these rats compared to normals. After the induction of hyperlipidemia for three weeks, rats were supplemented with different doses of TRF for one week. TRF supplementation decreased the lipid parameters in a dose-dependent manner with an optimum effect at a dose of 8 mg TRF/kg/day. HMG-CoA reductase activity, which was increased after the withdrawal of atherogenic diet, remained significantly decreased during the TRF treatment. Feeding of TRF also decreased TBARS and conjugated dienes significantly. These results suggest that TRF supplementation has significant health benefits through the modulation of physiological functions that include various atherogenic lipid profiles and antioxidants in hypercholesterolemia.

Administration, Oral↗
PubMed2001

The combined effects of novel tocotrienols and lovastatin on lipid metabolism in chickens.

Both lovastatin (a fungal product) and a tocotrienol rich fraction (TRF(25), a mixture of tocols isolated from stabilized and heated rice bran containing desmethyl [d-P(21)-T3] and didesmethyl [d-P(25)-T3] tocotrienols) are potent hypocholesterolemic agents, although they suppress cholesterol biosynthesis by different mechanisms. To determine additive and/or synergistic effects of both agents, chickens were fed diets supplemented with 50 ppm TRF(25) or d-P(25)-T3 in combination with 50 ppm lovastatin for 4 weeks. Combinations of d-P(25)-T3 with lovastatin were found most effective in reducing serum total cholesterol and low-density lipoprotein (LDL) cholesterol compared to the control diet or individual supplements. The mixture of TRF(25)+lovastatin inhibited the activity of beta-hydroxy-beta-methylglutaryl coenzymeA reductase (21%) compared to lovastatin alone, which did not change its activity. Cholesterol 7alpha-hydroxylase activity was increased by lovastatin (11%) and by lovastatin plus TRF(25) (19%). TRF(25)+lovastatin decreased levels of serum total cholesterol (22%), LDL cholesterol (42%), apolipoprotein B (13-38%), triglycerides (19%), thromboxane B(2) (34%) and platelet factor 4 (26%), although high-density lipoprotein (HDL) cholesterol, and apolipoprotein A1 levels were unaffected. The mixture of TRF(25)+lovastatin showed greater effects than did the individual treatments alone, reflecting possible additive pharmacological actions. The effects, however, of the d-P(25)-T3/lovastatin combination were no greater than that of d-P(25)-T3 alone, possibly indicating that d-P(25)-T3 produced a maximum cholesterol lowering effect at the concentration used.

Animals↗
PubMed2001

Effects of subcutaneous IL-2 therapy on telomere lengths in PBMC in HIV-infected patients.

In this study we investigated the effect of interleukin-2 (IL-2) on mean terminal restriction fragment (TRF) lengths in peripheral blood mononuclear cells (PBMC). Ten human immunodeficiency virus (HIV)-infected individuals were included and IL-2 was administered subcutaneously with 3 x 106 IU three times a week for 24 weeks. Mean TRF length was decreased on average by 267 bp at week 4 (P = 0.03) and 286 bp at week 8 (P = 0.09). Individual TRF changes at weeks 12, 16, 20 and 24 were highly variable. However, in the 12 weeks following therapy, TRF lengths generally increased reaching baseline levels by the end of the study. At baseline, mean TRF lengths were positively correlated to the ratio of naïve and memory phenotype within both CD4+ and CD8+ cells. This study shows that IL-2 treatment induces transient shortened mean TRF lengths in PBMC from HIV-infected individuals, indicating that IL-2 enhances the lymphocyte count by peripheral proliferation or recruitment of memory T cells into the blood.

Adjuvants, Immunologic↗
PubMed2002

Comparative effects of a tocotrienol-rich fraction and tocopherol in aspirin-induced gastric lesions in rats.

This study examined the effects of a tocotrienol-rich fraction (TRF) obtained from palm oil on the healing of aspirin-induced gastric mucosal lesions. Thirty-six male Sprague-Dawley rats (200-250 g) were randomly divided into three groups. Group I was fed a vitamin E-deficient diet (control), Group II was fed a vitamin E-deficient diet supplemented with tocopherol (300 mg/kg food) and Group III was fed a vitamin E-deficient diet supplemented with TRF (300 mg/kg food). After eight weeks, the control and treated groups received a single intragastric dose of 400 mg/kg body weight aspirin. The rats were killed 24 h after exposure to aspirin. Assessment of gastric lesions showed a lower gastric lesion index in the TRF (P = 0.0005) and tocopherol groups (P = 0.0008) compared to the control. The gastric malondialdehyde (MDA) content was also lower in the TRF (P = 0.025) and tocopherol groups (P = 0.025) compared to control. There were, however, no significant differences in the gastric lesion index and gastric MDA content between the TRF and tocopherol-fed groups. There were no significant differences in the adherent gastric mucous concentration and gastric acid concentration among all groups. We conclude that the TRF and tocopherol are equally effective in preventing aspirin-induced gastric lesions. The most probable mechanism is through their ability to limit lipid peroxidation, which is involved in aspirin-induced gastric lesions.

Animals↗
PubMed1981

Culture supernatants of a stimulated T-cell line have helper activity that acts synergistically with interleukin 2 in the response of B cells to antigen.

Culture supernatants of an antigen-stimulated long-term alloreactive T cell line, C.C3.11.75, contain a T-cell-replacing factor (TRF) activity for the B-cell response to antigen. These same supernatants show little activity in the T-cell growth assay or the costimulator assay. TRF activity was assayed by using spleen cells that were rigorously depleted of both T cells and macrophages. In this assay preparations containing interleukin 2 and supernatants from stimulated C.C3.11.75 cells are relatively inactive if added alone but show marked synergy when added together. We conclude that the C.C3.11.75 TRF activity is not due to interleukin 1 or to interleukin 2 but to a third factor provisionally designated as (DL)TRF. This activity may be equivalent to the (late-acting) TRF described by Schimpl and Wecker. Evidence is presented suggesting that the helper activity (DL)TRF is a product of the T-cell line.

Animals↗
PubMed1994

Macromolecular permeability across the blood-nerve and blood-brain barriers.

The permeability of insulin (Ins), nerve growth factor (NGF), albumin (Alb), transferrin (Trf), and IgG across the blood-nerve barrier (BNB) and blood-brain barrier (BBB) in normal adult rats was quantified by measuring the (permeability coefficient x surface area) product (PS) with the i.v. bolus-injection technique in the cannulated brachial vein and artery using radioiodinated proteins. The PS values of the BNB for IgG and Alb were low: 0.079 +/- 0.029 x 10(-6) and 0.101 +/- 0.088 x 10(-6) ml.g-1.s-1, (mean +/- SD, respectively). The PS values for NGF and Trf were 16.1-fold and 25.5-fold higher than for Alb. The PS for Ins across the BNB was 33.190 +/- 2.053 x 10(-6) ml.g-1.s-1--a remarkable 329-fold increase compared with Alb. The PS values of the BBB for IgG and Alb in different brain regions were all low, from 0.028 +/- 0.017 to 0.151 +/- 0.035 x 10(-6) ml.g-1.s-1 (mean +/- SD). NGF and Trf had comparable PS values from 13- to 32-fold higher than for Alb, except for the brain stem, where the PS for Trf was 66-fold higher than for Alb. The mean PS for Ins across the BBB ranged from 15.78 +/- 5.45 x 10(-6) ml.g-1.s-1 for the cortex to 22.62 +/- 7.50 x 10(-6) ml.g-1.s-1 for the brain stem--again a remarkable 105- to 390-fold increase relative to Alb. Because reliable PS measurements were obtained for all proteins tested, the BBB and BNB cannot be considered impermeable to proteins--a concept that has plagued brain- and nerve-barrier research. The low PS values for IgG and Alb indicate low rates of transfer; however, Alb, in particular, is the major protein of endoneurial and ventricular fluid, which suggests that these PS values may be significant. Ins had the highest PS values, which likely reflect the mechanism of transport across the barriers--that is, receptor-mediated transport. Because NGF and Trf had PS values 13- to 66-fold higher than for Alb, whether this reflects receptor-mediated uptake, adsorptive-mediated transcytosis, or some other mechanism is unclear. That the PS values for NGF and Trf differ from Alb and IgG clearly suggests, however, a different uptake mechanism. Finally, the remarkably high PS values for Ins across the BBB and BNB identify this protein and its putative receptor on capillary endothelial cells as a potential target for drug delivery into the central and peripheral nervous systems.

Albumins↗