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Biomedical subjects

P Wei

Publications and source records attributed to P Wei.

At least 19 recordsLinked to original sources
PubMed2004

Glomerular structural and functional changes in a high-fat diet mouse model of early-stage Type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes often results in diabetic nephropathy, which is preceded by an elevated glomerular filtration rate (GFR). This study was designed to develop a mouse model of Type 2 diabetes and to elucidate the glomerular events in the early stages of diabetic nephropathy. METHODS: Four-week-old mice were fed a normal or high-fat (42% of total calories from fat) diet, and body weight, blood glucose, insulin, leptin, lipids and GFR were monitored from 9 to 21 weeks or longer after the feeding programme. Mesangial cell dedifferentiation was accessed by alpha-smooth muscle actin staining. Glomerular hypertrophy was determined using image analysis with haematoxylin-eosin staining. Matrix deposition was determined by type IV collagen staining. RESULTS: After 9 weeks, mice fed a high-fat diet weighed more than mice fed a normal diet (30.5+/-1.2 vs 22.3+/-0.5 g, p<0.05), and mice fed a high-fat diet were hyperinsulinaemic (283.9+/-69.7 vs 102.9+/-36.4 pmol/l, p<0.05), hyperglycaemic (8.0+/-0.6 vs 6.5+/-0.2 mmol/l, p<0.05) and their leptin levels were increased six-fold (1.48+/-0.45 vs 0.25+/-0.03 ng/ml, p<0.05). After 13 weeks, mice fed a high-fat diet showed hyperfiltration (GFR; 440+/-60 vs 210+/-10 microl/min, p<0.05). During the early stages of diabetic nephropathy, mesangial cell dedifferentiation was evident, shown by increased expression of alpha-smooth muscle actin in the glomeruli. After 9 weeks, mice fed a high-fat diet already demonstrated increased type IV collagen deposition. After 13 weeks, they developed enlarged glomerular tufts compared with those of their age-matched controls. CONCLUSIONS/INTERPRETATION: The results of this study suggest that collagen IV deposition precedes the hyperfiltration and enlargement of glomeruli in early-stage diabetic nephropathy. Dedifferentiation of mesangial cells may be associated with collagen IV deposition.

Animals↗
PubMed2002

Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response.

The products of the cytochrome P450 (CYP) genes play an important role in the detoxification of xenobiotics and environmental contaminants, and many foreign chemicals or xenobiotics can induce their expression. We have previously shown that the nuclear hormone receptor CAR (Constitutive Androstane Receptor, NR113) mediates the well studied induction of CYP2B10 gene expression by phenobarbital (PB) and 1, 4-bis-[2-(3, 5,-dichloropyridyloxy)] benzene (TCPOBOP). We have used the CAR knockout mouse model to explore the broader functions of this xenobiotic receptor. In addition to the liver, CAR is expressed in the epithelial cells of the villi in the small intestine, and this expression is required for CYP2B10 induction in response to PB and TCPOBOP in those cells. In agreement with previous observations that CAR can bind to regulatory elements in CYP3A genes, CAR is also required for induction of expression of CYP3A11 in response to both PB and TCPOBOP in liver. In males, CAR is also required for induction of liver CYP2A4 expression. In wild type animals, pretreatment with the CAR inverse agonist androstenol blocks the response of both the CYP2B10 and CYP3A11 genes to PB and TCPOBOP, and decreases basal CYP3A11 expression. CAR is also required for the response of CYP2B10 to several additional xenobiotic inducers, including chlorpromazine, clotrimazole and dieldrin, but not dexamethasone, an agonist for both the xenobiotic receptor PXR (Pregnane X Receptor NR112) and the glucocorticoid receptor. Chlorpromazine induction of CYP3A11 is also absent in CAR-deficient animals, but the responses to clotrimazole and dieldrin are retained, indicating that both of these inducers can also activate PXR (Pregnane X Receptor NR112). We conclude that CAR has broad functions in xenobiotic responses. Some are specific to CAR but others, including induction of the important drug metabolizing enzyme CYP3A, overlap with those of PXR.

Animals↗
PubMed2001

Reactivity and derivatization of five-coordinate, chelated aluminum.

The convenient five-coordinate starting materials, Salen((t)Bu)AlCl (Salen((t)Bu) = N,N'-alkylene (or arylene) bis (3,5-di-tert-butyl-2-hydroxybenzylideneamine) (1-4) can be used in a wide range of reactions to form five-coordinate aluminum compounds. Herein, these reagents were used to produce new five-coordinate azides, LAlN(3) (L = Salen((t)Bu) (5), Salpen((t)Bu) (6), and Salomphen((t)Bu) (7)) through trimethylsilylhalide elimination. The decomposition of the azides produce first hydroxide (LAlOH (L = Salen((t)Bu) (8)) and, subsequently in the presence of chlorotrimethylsilane, the siloxide compounds, LAlOSiMe(3) (L = Salen((t)Bu) (9), Salpen((t)Bu) (10), and Salomphen((t)Bu) (11)). Alkane elimination reactions may also be used to access this type of compound as evidenced by the formation of Salomphen((t)Bu)AlOSiPh(3) (12). Additionally, the first structurally characterized five-coordinate monomeric amide, Salcen((t)Bu)AlN(SiMe(3))(2) (13), can prepared by a salt elimination utilizing Salcen((t)Bu)AlCl (4). The compounds were characterized by spectroscopic methods ((1)H and (27)Al NMR, MS, and IR) and, in the case of 2 (Salpen((t)Bu)AlCl), 3 (Salomphen((t)Bu)AlCl) 9, 11, 12, and 13, by X-ray analysis. Several of the compounds were explored as potential catalysts for the living polymerization of propylene oxide.

Journal Article↗
PubMed2001

Inhibitory antibodies against endopeptidase activity of human adamalysin 19.

Human adamalysin 19 (hADAM19)/meltrin beta is a member of the ADAM (a disintegrin and metalloproteinase) family and an active metalloproteinase. It is a new metalloproteinase and disintegrin dendritic cell antigen marker. Adamalysin 19 gene was expressed in normal and transformed tissues and cells such as placenta, brain, heart, leukocytes, and colorectal adenocarcinoma SW480. To develop specific tools to investigate the functions of hADAM19, peptide antigens were rationally selected and specific polyclonal antibodies (pAbs) were developed to modulate hADAM19 activity. Anti-metalloproteinase and anti-disintegrin domain IgG molecules inhibited the alpha-2-macroglobulin cleavage by hADAM19; however, their pre-immune and anti-pro-domain IgG molecules did not. Since anti-disintegrin IgG also neutralized the proteolytic activity, the disintegrin domain may affect the hADAM19 protein folding and/or substrate binding. These pAbs may be used to specifically localize the hADAM19 protein in tissues and cells and elucidate its biological and pathological functions such as processing pro-growth factors.

ADAM Proteins↗
PubMed2001

Monomeric uni-ligated aluminates.

The tetradentate ligand, common name Salban(But)H4 (N,N'-bis(2-hydroxy-3,5-di-tert-butylbenzyl)-1,4-diaminobutane) combines with appropriate amounts of LiAlH4 to produce the unique monomeric, uni-ligated aluminate [Salban(But)Al]Li(thf)2 (1) and the bimetallic derivative Salban(But)(AlH2Li(thf)2)2 (2).

Journal Article↗
PubMed2001

Proliferation of NG2-positive cells and altered oligodendrocyte numbers in the contused rat spinal cord.

Given the numerous reparative roles glia may play after spinal cord injury (SCI), glial proliferation and cell number were examined in a model of traumatic SCI. Emphasis was placed on analysis of oligodendrocytes and NG2-positive (NG2+) cells, an endogenous cell population that may be involved in oligodendrocyte replacement. Overall, proliferation (assessed by bromodeoxyuridine incorporation) was markedly elevated during the first 2 weeks after injury and declined thereafter; a large portion of these dividing cells likely consisted of microglia-macrophages. Although the total number of NG2+ cells in the epicenter was reduced by half, we noted protracted proliferation in surviving NG2+ cells, with values sevenfold greater than in uninjured controls. Elevated proliferation of NG2+ cells persisted throughout the first 4 weeks after injury. However, the absolute number of NG2+ cells was not increased over controls, suggesting that the daughter cells either did not survive or they differentiated into other cell types. As expected, oligodendrocyte numbers were drastically altered after SCI. By 7 d after injury, the number of oligodendrocytes at the impact site was reduced by 93%. Despite ongoing tissue loss, the number of oligodendrocytes in spared tissue rose threefold at 14 d after injury. Although the function of NG2+ cells within the spinal cord is not completely understood, several studies suggest that they may differentiate into oligodendrocytes. Thus, proliferating NG2+ cells may contribute to the increased oligodendrocyte number observed at 2 weeks after injury. Future studies are required, however, to definitively determine the role NG2+ cells play in oligodendrocyte genesis, remyelination, and other post-injury events.

Animals↗
PubMed2001

Expression and enzymatic activity of human disintegrin and metalloproteinase ADAM19/meltrin beta.

The adamalysins are involved in proteolysis, adhesion, fusion, and intracellular signaling. Human ADAM19/adamalysin-19 (A disintegrin and metalloproteinase 19) was identified from primary dendritic cell cDNA libraries. It has a signal sequence, a pro-domain with a "cysteine-switch" residue, a metalloproteinase domain with a zinc-binding site, a disintegrin, a cysteine-rich domain, an epidermal-growth-factor-like domain, a transmembrane domain, and a cytoplasmic domain with putative SH3 ligand binding sites. Its mRNA was expressed in the placenta, heart, bladder, lymph nodes, and leukocytes, colorectal adenocarcinoma SW 480, and other organs/cells. The hADAM19 recombinant protein was expressed in human cells. It formed a complex with and cleaved alpha-2 macroglobulin (alpha2-M). Its proteolytic activity was blocked by 1,10-phenanthroline, EDTA, EGTA, and a synthetic matrix metalloproteinase (MMP) inhibitor and not by the tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. It did not cleave the MMP substrates tested, e.g., type I collagen and gelatin, casein, and four peptide substrates. Thus, hADAM19 is an active metalloproteinase and may have a specific substrate profile.

ADAM Proteins↗
PubMed2001

Expression of matrix metalloproteinase-2, tissue inhibitors of metalloproteinase-1, -3 at the implantation site of rhesus monkey during the early stage of pregnancy.

We have examined the expression of MMP-2, TIMP-1, and TIMP-3 mRNA at the implantation site of rhesus monkeys during early stage of pregnancy using in situ hybridization and Northern blot analysis. The results indicate that MMP-2 mRNA was mainly localized in the chorinoic villi and epithelial plaque, suggesting that MMP-2 may be involved in the process of epithelial plaque and trophoblast invasion. TIMP-3 was specifically expressed in the cells around the spiral arteries and maternal-fetal interface. Therefore, TIMP-3 may be the main inhibitor that restricts the trophoblast invasion. The TIMP-1 mRNA was detected in trophoblast villi and maternal decidua; however, its distribution was not cell-specific, suggesting a general role in the protection of trophoblast villi and maternal decidua from proteolysis by the MMPs secreted by themselves.

Animals↗
PubMed2001

In vivo inhibition of Fas ligand-mediated killing by TR6, a Fas ligand decoy receptor.

TR6, a member of the tumor necrosis factor (TNF) receptor superfamily, has recently been shown to bind to Fas ligand (FasL) and inhibit FasL-mediated cell killing in vitro. In the current study, we demonstrate that TR6 can block the lethal activity of FasL in multiple in vitro systems, and extend this finding to an in vivo model of hepatitis. The binding of human TR6 to human FasL was verified with BIAcore chip technology. Human primary hepatocytes, HT-29 cells and Jurkat cells were assayed for viability to demonstrate TR6 inhibition of FasL-mediated cytotoxicity in vitro. Human TR6 was also shown to cross-react with membrane-bound mouse FasL, since the in vitro cytotoxic activity of L929 cells transfected with murine FasL was inhibited in the presence of human TR6. In vivo, FasL-induced acute, lethal, fulminant hepatic apoptosis resulting in death within 2 h of intravenous injection into Fas+ mice, but not Fas- MRL/lpr mice. Pretreatment of mice with TR6 blocked FasL-induced mortality, presumably by attenuating FasL-induced hepatic apoptosis. Thus, in both in vitro and in vivo systems, TR6 acts as a functional FasL decoy receptor and may be clinically useful in the treatment of hepatitis and other diseases associated with FasL-mediated tissue injury.

Animals↗
PubMed2001

Role of Fas/FasL genes in azoospermia or oligozoospermia induced by testosterone undecanoate in rhesus monkey.

AIM: To investigate role of apoptosis related genes Fas/FasL in azoospermia or oligozoospermia induced by testosterone undecanoate. METHODS: TUNEL was used to detect the apoptotic signal of testicular cells. Immunohistochemistry and Western blot were used to quantitatively or qualitatively analyze the expression of these apoptosis-related proteins. RESULTS: After injection of testosterone undecanoate, both the apoptotic signal in germ cells and the expression of Fas/FasL in testis increased correlatively in a time-dependent manner, reaching a maximum level on day 30. CONCLUSION: Fas system may initiate and regulate the germ cell apoptosis induced by testosterone undecanoate.

Animals↗
PubMed2001

[Changes in dietary pattern and certain nutrition-related diseases in urban and rural residents of Jiangsu province in 1990s].

A study on the relations of dietary pattern and mortality of some chronic diseases in urban and rural residents of Jiangsu Province in the past decade was made on the basis of the results of food consumption survey and disease surveillance. The results showed that food consumption and dietary pattern changed remarkably during the 1990s. Grain consumption was decreased, but the consumption of animal food was markedly increased. Though the score of desirable dietary pattern(DDP) in urban residents was more than 90, the deducted scores owing to over-consumption of animal food were increased. The mortality form infectious diseases was evidently decreased. While the death rates of some chronic diseases, such as diabetes, hypertension, coronary heart disease, colorectal cancer and breast cancer was increased rapidly in the urban residents. Sufficient attention should be paid to the negative effects of the change of dietary pattern on the health, especially of urban residents.

Breast Neoplasms↗
PubMed2000

Tumor necrosis factor (TNF) receptor superfamily member TACI is a high affinity receptor for TNF family members APRIL and BLyS.

An expression cloning approach was employed to identify the receptor for B-lymphocyte stimulator (BLyS) and identified the tumor necrosis factor receptor superfamily member TACI as a BLyS-binding protein. Expression of TACI in HEK293T cells confers on the cells the ability to bind BLyS with subnanomolar affinity. Furthermore, a TACI-Fc fusion protein recognizes both the cleaved, soluble form of BLyS as well as the membrane BLyS present on the cell surface of a recombinant cell line. TACI mRNA is found predominantly in B-cells and correlates with BLyS binding in a panel of B-cell lines. We also demonstrate that TACI interacts with nanomolar affinity with the BLyS-related tumor necrosis factor homologue APRIL for which no clear in vivo role has been described. BLyS and APRIL are capable of signaling through TACI to mediate NF-kappaB responses in HEK293 cells. We conclude that TACI is a receptor for BLyS and APRIL and discuss the implications for B-cell biology.

B-Cell Activation Factor Receptor↗
PubMed2000

The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism.

Organisms encounter a wide range of foreign compounds--or 'xenobiotics'--with potentially harmful consequences. The cytochrome P450 (CYP) enzymes metabolize xenobiotics and thus are a primary defence against these compounds. Increased expression of specific CYP genes in response to particular xenobiotics is a central component of this defence, although such induction can also increase production of toxic metabolites. Here we show that the nuclear receptor CAR mediates the response evoked by a class of xenobiotics known as the 'phenobarbital-like inducers'. The strong activation of Cyp2b10 gene expression by phenobarbital, or by the more potent TCPOBOP, is absent in mice lacking the CAR gene. These animals also show decreased metabolism of the classic CYP substrate zoxazolamine and a complete loss of the liver hypertrophic and hyperplastic responses to these inducers. Cocaine causes acute hepatotoxicity in wild-type mice previously exposed to phenobarbital-like inducers and this toxicity is also absent in the CAR-deficient animals. Thus, loss of CAR function alters sensitivity to toxins, increasing or decreasing it depending on the compound. Modulation of CAR activity in humans may significantly affect metabolism of drugs and other xenobiotics.

Alanine Transaminase↗
PubMed2000

Traumatic spinal cord injury produced by controlled contusion in mouse.

Previous work from this laboratory has described a rat spinal cord injury (SCI) model in which the mid-thoracic spinal cord is subjected to a single rapid and calibrated displacement at the site of a dorsal laminectomy. Injury is initiated at the tip of a vertical shaft driven by an electromagnetic shaker. Transducers arranged in series with the shaft record the patterns of displacement and force during the impact sequence. In the present study, this device and the relevant surgical procedures were adapted to produce a spinal contusion injury model in laboratory mice. The signal generator for the injury device has also been converted to a computer-controlled interface to permit extension of the model to other laboratories. Mice were subjected to SCI across a range of severities by varying the amplitude of displacement and the magnitude of measured preload force on the dural surface. A moderate injury produced by displacement of 0.5 mm over 25 msec resulted in initial paralysis and recovery of locomotion with chronic deficits in hindlimb function. The magnitude of the peak force, impulse, power, and energy generated at impact were correlated with behavioral outcome at 1 day postinjury, while peak displacement and impulse were the best predictors of behavioral outcome at 28 days postinjury. The shape of the force recording proved to be a highly sensitive measure of subtle variations in the spinal compartment that were otherwise difficult to detect in this small species. The results demonstrate that the electromagnetic spinal cord injury device (ESCID) can be used to produce a well-controlled contusion injury in mice. The unique features of controlled displacement and monitoring of the biomechanical parameters at the time of impact provide advantages of this model for reducing outcome variability. Use of this model in mice with naturally occurring and genetically engineered mutations will facilitate understanding of the molecular mechanisms of pathophysiology following traumatic spinal cord injury.

Animals↗
PubMed2000

Leukemia inhibitory factor, leukemia inhibitory factor receptor, and glycoprotein 130 in rhesus monkey uterus during menstrual cycle and early pregnancy.

This goal of this study was to examine immunohistochemical distribution of leukemia inhibitory factor (LIF), LIF receptor (LIFR), and glycoprotein (gp) 130 in rhesus monkey uterus during the menstrual cycle and early pregnancy. Pregnancy rate was significantly reduced in the control group from 66.7% (12 of 18) to 22.2% (4 of 18) with an injection of goat anti-human recombinant LIF immunoglobulin G into the uterine lumen on Day 8 of pregnancy. LIF was mainly localized in glandular and luminal epithelium. LIF immunostaining during the luteal phase was stronger than it was during the proliferative phase. LIF staining gradually increased from Day 3 of pregnancy and reached its highest level on Day 9. LIFR was mainly localized in the glandular and luminal epithelium. LIFR staining during the luteal phase was stronger than it was during the proliferative phase. LIFR staining began to increase from Day 3 of pregnancy and reached a high level on Days 9 and 11. Gp130, a signal-transducing receptor component of LIF, was mainly localized in the glandular epithelium. A high level of gp130 was found on Days 16 and 20 of menstrual cycle, and from Days 5 to 11 of pregnancy. These results suggest that LIF may play an important role in monkey implantation, as it does in mice.

Animals↗
PubMed1999

Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury.

Traumatic injury to the spinal cord initiates a series of destructive cellular processes which accentuate tissue damage at and beyond the original site of trauma. The cellular inflammatory response has been implicated as one mechanism of secondary degeneration. Of the various leukocytes present in the spinal cord after injury, macrophages predominate. Through the release of chemicals and enzymes involved in host defense, macrophages can damage neurons and glia. However, macrophages are also essential for the reconstruction of injured tissues. This apparent dichotomy in macrophage function is further complicated by the overlapping influences of resident microglial-derived macrophages and those phagocytes that are derived from peripheral sources. To clarify the role macrophages play in posttraumatic secondary degeneration, we selectively depleted peripheral macrophages in spinal-injured rats during a time when inflammation has been shown to be maximal. Standardized behavioral and neuropathological analyses (open-field locomotor function, morphometric analysis of the injured spinal cord) were used to evaluate the efficacy of this treatment. Beginning 24 h after injury and then again at days 3 and 6 postinjury, spinal cord-injured rats received intravenous injections of liposome-encapsulated clodronate to deplete peripheral macrophages. Within the spinal cords of rats treated in this fashion, macrophage infiltration was significantly reduced at the site of impact. These animals showed marked improvement in hindlimb usage during overground locomotion. Behavioral recovery was paralleled by a significant preservation of myelinated axons, decreased cavitation in the rostrocaudal axis of the spinal cord, and enhanced sprouting and/or regeneration of axons at the site of injury. These data implicate hematogenous (blood-derived) macrophages as effectors of acute secondary injury. Furthermore, given the selective nature of the depletion regimen and its proven efficacy when administered after injury, cell-specific immunomodulation may prove useful as an adjunct therapy after spinal cord injury.

Animals↗
PubMed1999

Interstrand cross-links induce DNA synthesis in damaged and undamaged plasmids in mammalian cell extracts.

Mammalian cell extracts have been shown to carry out damage-specific DNA repair synthesis induced by a variety of lesions, including those created by UV and cisplatin. Here, we show that a single psoralen interstrand cross-link induces DNA synthesis in both the damaged plasmid and a second homologous unmodified plasmid coincubated in the extract. The presence of the second plasmid strongly stimulates repair synthesis in the cross-linked plasmid. Heterologous DNAs also stimulate repair synthesis to variable extents. Psoralen monoadducts and double-strand breaks do not induce repair synthesis in the unmodified plasmid, indicating that such incorporation is specific to interstrand cross-links. This induced repair synthesis is consistent with previous evidence indicating a recombinational mode of repair for interstrand cross-links. DNA synthesis is compromised in extracts from mutants (deficient in ERCC1, XPF, XRCC2, and XRCC3) which are all sensitive to DNA cross-linking agents but is normal in extracts from mutants (XP-A, XP-C, and XP-G) which are much less sensitive. Extracts from Fanconi anemia cells exhibit an intermediate to wild-type level of activity dependent upon the complementation group. The DNA synthesis deficit in ERCC1- and XPF-deficient extracts is restored by addition of purified ERCC1-XPF heterodimer. This system provides a biochemical assay for investigating mechanisms of interstrand cross-link repair and should also facilitate the identification and functional characterization of cellular proteins involved in repair of these lesions.

Animals↗