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Biomedical subjects

H Lin

Publications and source records attributed to H Lin.

At least 73 records · Page 4Linked to original sources
PubMed2001

A complex flow pattern of low shear stress and flow reversal promotes monocyte binding to endothelial cells.

Predilection sites for atherosclerosis within the vasculature are characterized by low shear stress and flow reversal. In this study, endothelial cells were exposed to a complex flow pattern that was characterized by particle velocity determination. Bovine aortic endothelial cells exposed to low shear stress and flow reversal demonstrated higher levels of monocyte binding compared to endothelial cells exposed to one-directional flow. In addition, endothelial cells exposed to low shear stress and flow reversal responded to inflammatory stimuli with substantial increases in monocyte binding, similar to that seen in cells exposed to one-directional flow. These findings suggest a mechanism by which areas of low shear stress and flow reversal are predisposed to the development of atherosclerotic lesions.

Animals↗
PubMed2001

A novel sterol from Chinese truffles Tuber indicum.

From the fruiting bodies of Ascomycetes Tuber indicum, a new steroidal glucoside with polyhydroxy ergosterol nucleus, tuberoside (2), has been isolated along with additional four known ergosterol derivatives, (22E, 24R)-ergosta-7, 22-dien-3beta, 5alpha, 6beta-triol (1), 5alpha, 8alpha-epidioxy-(22E, 24R)-ergosta-6, 22-dien-3beta-ol (3), (22E, 24R)-ergosta-5, 22-dien-3beta-ol (4), and (22E, 24R)-ergosta-4, 6, 8(14), 22-tetraen-3-one (5). The structure of new compound was established as 3-O-beta-D-glucopyranosyl-(22E, 24R)-ergosta-7, 22-dien-5alpha, 6beta-diol (2) on the basis of chemical and spectroscopic means ((1)H NMR, (13)C NMR, HMQC, HMBC, MS, and IR). This is the first example of isolation of a polyhydroxylated ergosterol glucoside from higher fungi in nature.

Ascomycota↗
PubMed2001

Asymmetric germ cell division and oocyte determination during Drosophila oogenesis.

Early oogenesis in Drosophila, with a stereotypic pattern of germ cell division and differentiation, provides an attractive model for studying cell lineage and patterning. Drosophila oogenesis is initiated when a germline stem cell divides asymmetrically to produce a daughter stem cell and a cytoblast. The cystoblast then undergoes four rounds of incomplete mitoses to form a 16-cell cyst, accompanied by the formation of the fusome. Within the cyst, one of the two cells with four intercellular bridges differentiates into an oocyte while the rest become nurse cells. The oocyte then translocates within the cyst to a posterior position, which defines the anterio-posterior axis of the future embryo. Recent studies have shown that the asymmetric germline stem cell division is controlled by somatic signaling involving piwi, fs(1)Yb, and the dpp pathway as well as by intrinsic mechanisms involving pumilio, nanos, arrest, bag-of-marbles, and the spectrosome-the fusome precursor in the stem cells and the cystoblast. The spectrosome in the cystoblast appears to play an important role in polarized fusome growth during cyst formation. The fusome may guide the formation of a polarized microtubule network for the intracyst transport of certain RNAs and proteins to the cystocyte destined to become the oocyte. Genes such as egalitarian, Bicaudal D, stonewall, and encore are important for oocyte determination, while differential adhesion between the oocyte and its surrounding prefollicle cells, as mediated by armadillo, alpha-catenin, shotgun, and the spindle genes, is crucial for oocyte translocation. Early oogenesis shares many parallel features to early spermatogenesis, although distinct differences are also observed at both the phenomenological and mechanistic levels. The study of oogenesis, progressing at an exciting rate, contributes significantly to our understanding of the mechanisms underlying proliferation, differentiation, and patterning.

Animals↗
PubMed2001

Aberrant receptor signaling in human malignant gliomas: mechanisms and therapeutic implications.

Alterations of the epidermal growth factor receptor (EGFR) occur frequently in malignant gliomas through gene amplification or rearrangement, especially in a large fraction of de novo type glioblastomas. The most common of these mutant EGFRs (variously named de2-7 EGFR, deltaEGFR or EGFRvIII) lacks a portion of the extracellular ligand-binding domain. Here, we review the evidence that shows that expression of deltaEGFR bestows in vivo growth advantages to human glioma cells through its constitutively active tyrosine kinase activity. Thus, deltaEGFR may provide a novel therapeutic target for the most aggressive type of glioblastoma.

Apoptosis↗
PubMed2001

Elevated potassium intake inhibits neointimal proliferation in the swine coronary artery.

BACKGROUND: Previously, we reported that elevated extracellular potassium concentration in vitro inhibited proliferation and migration of vascular smooth muscle cells, formation of free radical compounds by macrophages, and reduced platelet sensitivity to agonists. More recently, we described a reduction in neointimal proliferation after balloon angioplasty injury in the carotid arteries of rats associated with an elevation of dietary potassium intake during a 4-week experiment. In the present study we conducted a similar investigation in the swine coronary artery balloon angioplasty model. PROCEDURES: Two groups of seven castrated male swine were studied; for 28 days the normal potassium group consumed a diet containing 0.25% potassium and the high potassium group ate diet containing 2.0% potassium. After 14 days on the diet, balloon angioplasty was performed. After an additional 14 days on the same diets the hearts were removed, and normal and lesioned sections of the artery were analyzed histologically. RESULTS: The neointimal area was markedly less in the high potassium group than in the normal potassium group, 0.33+/-0.04 mm2 v 0.74+/-0.10 mm2 (P < .004). Neointimal area-to-total wall area ratio in the normal potassium group averaged 0.199+/-0.018, significantly greater than the ratio computed for the elevated potassium group, 0.120+/-0.015 (P < .006). CONCLUSION: These results support the hypothesis that a high level of dietary potassium intake inhibits neointimal proliferation after balloon angioplasty in the swine coronary artery.

Aldosterone↗
PubMed2001

Yb modulates the divisions of both germline and somatic stem cells through piwi- and hh-mediated mechanisms in the Drosophila ovary.

The coordinated division of distinctive types of stem cells within an organ is crucial for organogenesis and homeostasis. Here we show genetic interactions among fs(1)Yb (Yb), piwi, and hedgehog (hh) that regulate the division of both germline stem cells (GSCs) and somatic stem cells (SSCs), the two constituent stem cell populations of the Drosophila ovary. Yb is required for both GSC and SSC divisions; loss of Yb function eliminates GSCs and reduces SSC division, while Yb overexpression increases GSC number and causes SSC overproliferation. We also show that Yb acts via the piwi- and hh-mediated signaling pathways that emanate from the same signaling cells to control GSC and SSC division, respectively. hh signaling also has a minor effect in GSC division.

Animals↗
PubMed2001

N-nitrosodimethylamine-mediated formation of oxidized and methylated dna bases in a cytochrome P450 2E1 expressing cell line.

The metabolic activation of N-nitrosodimethylamine (NDMA) to reactive metabolites is a critical step for the expression of its toxic and carcinogenic potential. We have previously reported that a P450 2E1 expressing cell line, GM2E1, can metabolize NDMA to toxic reactive metabolites and cause apoptotic cell death. To investigate whether DNA is a critical target for the reactive metabolites of NDMA, we measured the levels of DNA adducts in untreated and NDMA-treated GM2E1 cells. 8-Hydroxydeoxyguanosine (8-OHdG), a biomarker for oxidative DNA damage, was analyzed following enzymatic hydrolysis of DNA. 7-Methylguanine (7-mGua), the most suitable marker for the DNA adducts formed by methylating agents, was released by thermal depurination of DNA. The modified guanine adducts were separated by HPLC and quantified using electrochemical detection. The levels of 8-OHdG and 7-mGua in GM2E1 cells treated with NDMA increased up to approximately 4- and 100-fold over those in the untreated cells, respectively. The addition of ascorbic acid, an antioxidant, to the NDMA-treated cells resulted in a significant decrease in the cytotoxicity with a concomitant decrease in the levels of 8-OHdG, but not the levels of 7-mGua. Our results demonstrate that the metabolism of NDMA in GM2E1 cells causes both DNA methylation and oxidation and support the hypothesis that NDMA-mediated DNA damage may play an important role in its toxic effects.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Modulation of expression of ribosomal protein L7a (rpL7a) by ethanol in human breast cancer cells.

Epidemiological studies indicate that there is a positive correlation between alcohol consumption and the risk of breast cancer. Experimental results demonstrate that ethanol is a tumor promoter and chronic ethanol exposure enhances metastasis and growth of breast cancer. The present study used an in vitro model to investigate the molecular mechanism(s) underlying tumor promoting effects of ethanol. With differential display reverse transcription polymerase chain reaction, we demonstrated that human ribosomal large subunit protein L7a (rpL7a) was an ethanol-responsive factor in T47D breast cancer cells. The results of northern blot hybridization revealed that the effect of ethanol on L7a expression was duration- and concentration-dependent. Initial exposure resulted in a 2-fold increase in rpL7a level, whereas a longer exposure period produced a down-regulation. Ethanol had little effect on the stability of rpL7a mRNA; however, the transcription rate of rpL7a was significantly increased by ethanol. Ethanol-induced up-regulation of rpL7a was not a simple stress response, because other stress inducers, such as heat shock, did not affect the expression of rpL7a. Furthermore, breast cancer cells expressed higher level of rpL7a than normal mammary epithelial cells. Ribosomal proteins are known to play an important role in translational regulation, and they have been implicated in the control of cellular transformation, tumor growth, aggressiveness and metastasis. Specially, rpL7a activates the trk oncogene by contributing an amino-terminal-activating sequence to the receptor kinase domain of trk. Thus, ethanol-induced alteration of rpL7a expression may mediate the promoting effects of ethanol on breast cancer development.

Alcohol Drinking↗
PubMed2001

Chinese medicinal herbs for chronic hepatitis B: a systematic review.

AIMS/BACKGROUND: Chronic hepatitis B is a serious health problem worldwide. Chinese medicinal herbs are widely used for treatment of chronic hepatitis B in China and many clinical trials have been conducted. This systematic review is to assess the efficacy and safety of Chinese medicinal herbs for chronic hepatitis B. METHODS: Randomised clinical trials comparing Chinese medicinal herbs versus placebo, no intervention, nonspecific treatment, or interferon treatment for chronic hepatitis B with > or = 3 months follow-up were included. No language and blinding limitations were applied. The electronic databases were searched, combined with handsearches on Chinese literature. Data were extracted independently by two reviewers. The methodological quality of trials was assessed by the Jadad-scale plus allocation concealment. RESULTS: Nine randomised trials (n=936) were included, with only one being of high quality. There was a funnel plot asymmetry (intercept 3.37, p=0.047). Compared to nonspecific treatment or placebo, the herbal compound Fuzheng Jiedu Tang showed an effect on clearance of serum HBsAg (relative risk 5.19, 95% CI 1.24-21.79), HBeAg (10.85, 3.56-33.06), and HBV DNA (8.50, 1.23-58.85). Polyporus umbellatus polysaccharide showed an effect on serum HBeAg (3.06, 1.13-8.29) and HBV DNA (4.14, 1.0-17.19); Phyllanthus amarus showed an effect on serum HBeAg (3.35, 1.49-7.56). Phyllanthus compound and kurorinone showed no significant difference on clearance of serum HBeAg and HBV DNA and on alanine aminotransferase normalisation compared to interferon. No serious adverse event was observed. CONCLUSIONS: Chinese medicinal herbs are not recommended for chronic hepatitis B because of the publication bias and low quality of the trials. Rigorously designed, randomised, double-blind, placebo-controlled trials are needed.

Drugs, Chinese Herbal↗
PubMed2001

Genus Phyllanthus for chronic hepatitis B virus infection: a systematic review.

To evaluate the efficacy and safety of genus Phyllanthus for chronic hepatitis B virus (HBV) infection we performed a systematic review of randomized clinical trials. Randomized trials comparing genus Phyllanthus vs. placebo, no intervention, general nonspecific treatment, other herbal medicine, or interferon treatment for chronic HBV infection were identified by electronic and manual searches. Trials of Phyllanthus herb plus interferon (IFN) vs. IFN alone were also included. No blinding and language limitations were applied. The methodological quality of trials was assessed by the Jadad scale plus allocation concealment. Twenty-two randomized trials (n=1947) were identified. The methodological quality was high in five double-blind trials and low in the 17 remaining trials. The combined results showed that Phyllanthus species had positive effect on clearance of serum HBsAg (relative risk 5.64, 95% CI 1.85-17.21) compared with placebo or no intervention. There was no significant difference on clearance of serum HBsAg, HBeAg and HBV DNA between Phyllanthus and IFN. Phyllanthus species were better than nonspecific treatment or other herbal medicines for the clearance of serum HBsAg, HBeAg, HBV DNA, and liver enzyme normalization. Analyses showed a better effect of the Phyllanthus plus IFN combination on clearance of serum HBeAg (1.56, 1.06-2.32) and HBV DNA (1.52, 1.05-2.21) than IFN alone. No serious adverse event was reported. Based on this review Phyllanthus species may have positive effect on antiviral activity and liver biochemistry in chronic HBV infection. However, the evidence is not strong due to the general low methodological quality and the variations of the herb. Further large trials are needed.

Adult↗
PubMed2001

Mechanisms of inverse agonism of antipsychotic drugs at the D(2) dopamine receptor: use of a mutant D(2) dopamine receptor that adopts the activated conformation.

The antipsychotic drugs have been shown to be inverse agonists at the D(2) dopamine receptor. We have examined the mechanism of this inverse agonism by making mutations in residue T343 in the base of the sixth transmembrane spanning region of the receptor. T343R, T343S and T343K mutant D(2) dopamine receptors were made and the T343R mutant characterized in detail. The T343R mutant D(2) dopamine receptor exhibits properties of a receptor that resides more in the activated state, namely increased agonist binding affinity (independent of G-protein coupling and dependent on agonist efficacy), increased agonist potency in functional tests (adenylyl cyclase inhibition) and increased inverse agonist effects. The binding of agonists to the mutant receptor also shows sensitivity to sodium ions, unlike the native receptor, so that isomerization of the receptor to its inactive state may be driven by sodium ions. The binding of inverse agonists to the receptor is, however, unaffected by the mutation. We conclude that inverse agonism at this receptor is not achieved by the inverse agonist binding preferentially to the non-activated state of the receptor over the activated state. Rather the inverse agonist appears to bind to all forms of the receptor but then renders the receptor inactive.

1-Methyl-3-isobutylxanthine↗
PubMed2001

The left ventricular stress-velocity relation in transgenic mice expressing a dominant negative CREB transgene in the heart.

OBJECTIVE: CREB(A133) transgenic mice that express a dominant negative CREB transcription factor in cardiomyocytes develop a dilated cardiomyopathy that is anatomically, physiologically, and clinically similar to human idiopathic dilated cardiomyopathy. The goals of this study were to quantitate left ventricular (LV) contractility and measure cardiac reserve in CREB(A133) mice by using the relation of end-systolic wall stress to the velocity of fiber shortening. METHODS: A total of 37 adult CD-1 mice (including both nontransgenic and CREB(A133) transgenic mice) were studied with simultaneously acquired high-fidelity instantaneous aortic pressures and 2-dimensionally targeted M-mode echocardiograms. RESULTS: CREB(A133) mice displayed significantly lower values of LV fiber shortening velocities over a wide range of afterloads, and they displayed smaller dobutamine-induced shifts from baseline contractility relations. Counterbalancing effects of differences in LV geometry and aortic pressures resulted in comparable levels of LV wall stress during ejection in both groups. CONCLUSION: These results demonstrate directly that CREB(A133) mice display reduced LV contractility at baseline and decreased cardiac reserve.

Animals↗
PubMed2001

Genetic control of horizontal virus transmission in the chestnut blight fungus, Cryphonectria parasitica.

Vegetative incompatibility in fungi has long been known to reduce the transmission of viruses between individuals, but the barrier to transmission is incomplete. In replicated laboratory assays, we showed conclusively that the transmission of viruses between individuals of the chestnut blight fungus Cryphonectria parasitica is controlled primarily by vegetative incompatibility (vic) genes. By replicating vic genotypes in independent fungal isolates, we quantified the effect of heteroallelism at each of six vic loci on virus transmission. Transmission occurs with 100% frequency when donor and recipient isolates have the same vic genotypes, but heteroallelism at one or more vic loci generally reduces virus transmission. Transmission was variable among single heteroallelic loci. At the extremes, heteroallelism at vic4 had no effect on virus transmission, but transmission occurred in only 21% of pairings that were heteroallelic at vic2. Intermediate frequencies of transmission were observed when vic3 and vic6 were heteroallelic (76 and 32%, respectively). When vic1, vic2, and vic7 were heteroallelic, the frequency of transmission depended on which alleles were present in the donor and the recipient. The effect of heteroallelism at two vic loci was mostly additive, although small but statistically significant interactions (epistasis) were observed in four pairs of vic loci. A logistic regression model was developed to predict the probability of virus transmission between vic genotypes. Heteroallelism at vic loci, asymmetry, and epistasis were the dominant factors controlling transmission, but host genetic background also was statistically significant, indicating that vic genes alone cannot explain all the variation in virus transmission. Predictions from the logistic regression model were highly correlated to independent transmission tests with field isolates. Our model can be used to estimate horizontal transmission rates as a function of host genetics in natural populations of C. parasitica.

Alleles↗
PubMed2001

The involvement of the proto-oncogene p120 c-Cbl and ZAP-70 in CD2-mediated T cell activation.

The CD2 co-receptor expressed on the surface of T lymphocytes is able to stimulate T cell activation, proliferation and cytokine production in the absence of direct engagement of the antigen-specific TCR. Engagement of human CD2 by mitogenic pairs of anti-CD2 mAb induces tyrosine phosphorylation of a number of intracellular proteins including a 120 kDa phosphoprotein that we identify as the proto-oncogene c-Cbl. Rapidly tyrosine phosphorylated following stimulation of a number of cell surface receptors, c-Cbl is an adaptor protein that has been shown to associate with a complex of intracellular signaling molecules, and to mediate both positive and negative regulatory effects. Here we show that, like TCR-CD3 stimulation, stimulation of CD2 enhanced the association of c-Cbl with both Crk(L) and the p85 subunit of phosphatidylinositol-3 kinase. Overexpression of wild-type c-Cbl protein inhibited both CD2and CD3-induced NF-AT transcriptional activity, suggesting that CD2 signaling is also negatively regulated by c-Cbl. The inhibitory effect of c-Cbl depended upon its N-terminal phosphotyrosine-binding domain, the domain that has been shown to be required for inhibition of the Syk/ZAP-70 family kinases. In Syk(-) Jurkat T cells stably expressing wild-type ZAP-70, CD2 stimulation induced only a minimal increase in ZAP-70 tyrosine phosphorylation. Nevertheless, ZAP-70 kinase was required for CD2-mediated NF-AT transcriptional activity. Thus, CD2-mediated NF-AT transcriptional activity appears to depend upon ZAP-70/Syk kinases and to be negatively regulated by c-Cbl.

Amino Acid Sequence↗
PubMed2001

Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology.

Amyloid beta protein (AbetaP) is the major constituent of senile plaques associated with Alzheimer's disease (AD). However, its mechanistic role in AD pathogenesis is poorly understood. Globular and nonfibrillar AbetaPs are continuously released during normal metabolism. Using techniques of atomic force microscopy, laser confocal microscopy, electrical recording, and biochemical assays, we have examined the molecular conformations of reconstituted globular AbetaPs as well as their real-time and acute effects on neuritic degeneration. Atomic force microscopy (AFM) of AbetaP1-42 shows globular structures that do not form fibers in physiological-buffered solution for up to 8 h of continuous imaging. AFM of AbetaP1-42 reconstituted in a planar lipid bilayer reveals multimeric channel-like structures. Consistent with these AFM resolved channel-like structures, biochemical analysis demonstrates that predominantly monomeric AbetaPs in solution form stable tetramers and hexamers after incorporation into lipid membranes. Electrophysiological recordings demonstrate the presence of multiple single channel currents of different sizes. At the cellular level, AbetaP1-42 allows calcium uptake and induces neuritic abnormality in a dose- and time-dependent fashion. At physiological nanomolar concentrations, rapid neuritic degeneration was observed within minutes; at micromolar concentrations, neuronal death was observed within 3-4 h. These effects are prevented by zinc (an AbetaP channel blocker) and by the removal of extracellular calcium, but are not prevented by antagonists of putative AbetaP cell surface receptors. Thus, AbetaP channels may provide a direct pathway for calcium-dependent AbetaP toxicity in AD.

Alzheimer Disease↗
PubMed2001

Fatty liver vulnerability to endotoxin-induced damage despite NF-kappaB induction and inhibited caspase 3 activation.

Fatty livers are sensitive to lipopolysaccharide (LPS) damage. This study tests the hypothesis that this vulnerability occurs because protective, antiapoptotic mechanisms are not upregulated appropriately. Genetically obese, leptin-deficient ob/ob mice, a model for nonalcoholic fatty liver disease, and their lean litter mates were treated with a small dose of LPS. General measures of liver injury, early (i.e., cytochrome c release) and late (i.e., activation of caspase 3) events that occur during hepatocyte apoptosis, and various aspects of the signal transduction pathways that induce nuclear factor-kappaB (NF-kappaB) and several of its antiapoptotic transcriptional targets (e.g., inducible nitric oxide synthase, bfl-1, and bcl-xL) were compared. Within 0.5-6 h after LPS exposure, cytochrome c begins to accumulate in the cytosol of normal livers, and procaspase 3 cleavage increases. Coincident with these events, kinases (e.g., AKT and Erk-1 and -2) that result in the degradation of inhibitor kappa-B are activated; NF-kappaB activity is induced, and NF-kappaB-regulated gene products accumulate. Throughout this period, there is negligible histological evidence of liver damage, and serum alanine aminotransferase values barely increase over baseline values. Although ob/ob livers have significant histological liver injury and 11-fold greater serum alanine aminotransferase values than those of lean mice by 6 h post-LPS, they exhibit greater activation of AKT and Erk, more profound reductions in inhibitor kappa-B, enhanced activation of NF-kappaB, and greater induction of NF-kappaB-regulated genes. Consistent with this heightened antiapoptotic response, increases in cytochrome c and procaspase 3 cleavage products are inhibited. Together with evidence that ob/ob hepatocytes have a reduced ATP content and undergo increased lysis after in vitro exposure to tumor necrosis factor-alpha, these findings suggest that fatty livers are sensitive to LPS damage because of vulnerability to necrosis, rather than because of apoptosis.

Adenosine Triphosphate↗
PubMed2001

Accuracy of echocardiographic estimates of left ventricular mass in mice.

Genetically modified mice have created the need for accurate noninvasive left ventricular mass (LVM) measurements. Recent technical advances provide two-dimensional images adequate for LVM calculation using the area-length method, which in humans is more accurate than M-mode methods. We compared the standard M-mode and area-length methods in mice over a wide range of LV sizes and weights (62-210 mg). Ninety-one CD-1 mice (38 normal, 44 aortic banded, and 9 inherited dilated cardiomyopathy) were imaged transthoracically (15 MHz linear transducer, 120 Hz). Compared with necropsy weights, area-length measurements showed higher correlation than the M-mode method (r = 0.92 vs. 0.81), increased accuracy (bias +/- SD: 1.4 +/- 27.1% vs. 36.7 +/- 51.6%), and improved reproducibility. There was no significant difference between end-systolic and end-diastolic estimates. The truncated ellipsoid estimation produced results similar in accuracy to the area-length method. Whereas current echocardiographic technology can accurately and reproducibly estimate LVM with the two-dimensional, area-length formula in a variety of mouse models, additional technological improvements, rather than refinement of geometric models, will likely improve the accuracy of this methodology.

Animals↗