Biomedical subjects

Y Z Zhu

Publications and source records attributed to Y Z Zhu.

At least 19 recordsLinked to original sources

PubMed2006

A comparison study of cerebral protection using Ginkgo biloba extract and Losartan on stroked rats.

It has been well documented that oxidative stress is involved in stroke. Currently, many neuroprotective strategies have been targeted at molecules that are able to act as an oxidant to intervene with free-radical mediated apoptosis in the ischemic penumbra. In particular, natural products which contain antioxidant properties have undoubtedly efficacious for stroke treatment. In the current study, therapeutic effects of Ginkgo biloba extract (EGb) against cerebral protection in Wistar rats underwent middle cerebral artery occlusion (MCAO) was evaluated. A comparison study was conducted by using Losartan, an antihypertensive drug. Gene expression levels of pro-apoptotic genes (AT2 receptor, Fas, Bax and Bcl-xS) have shown to have significant reduction by EGb- and Losartan-treated groups as compared to vehicle group. Significant reduction of immunoreactivity of protein production of these genes, together with least nuclear green fluorescence observed in TUNEL, EGb, as an antioxidant drug, is concluded to have potent and promising therapeutic effect for stroke treatment.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Peroxynitrite-modified collagen-II induces p38/ERK and NF-kappaB-dependent synthesis of prostaglandin E2 and nitric oxide in chondrogenically differentiated mesenchymal progenitor cells.

OBJECTIVE: Peroxynitrite (ONOO(-)) is formed in the inflamed and degenerating human joint. Peroxynitrite-modified collagen-II (PMC-II) was recently discovered in the serum of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Therefore we investigated the cellular effects of PMC-II on human mesenchymal progenitor cells (MPCs) as a model of cartilage and cartilage repair cells in the inflamed and degenerating joint. DESIGN: MPCs were isolated from the trabecular bone of patients undergoing reconstructive surgery and were differentiated into a chondrogenic lineage. Cells were exposed to PMC-II and levels of the proinflammatory mediators nitric oxide (*NO) and prostaglandin E(2) (PGE(2)) measured. Levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), phosphorylated mitogen activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappaB) activation were measured by enzyme linked immunosorbent assay (ELISA) together with specific MAPK and NF-kappaB inhibitors. RESULTS: PMC-II induced ()NO and PGE(2) synthesis through upregulation of iNOS and COX-2 proteins. PMC-II also lead to the phosphorylation of MAPKs, extracellularly regulated kinase 1/2 (ERK1/2) and p38 [but not c-Jun NH(2)-terminal kinase (JNK1/2)] and the activation of proinflammatory transcription factor NF-kappaB. Inhibitors of p38, ERK1/2 and NF-kappaB prevented PMC-II induced ()NO and PGE(2) synthesis, iNOS and COX-2 protein expression and NF-kappaB activation. CONCLUSION: iNOS, COX-2, NF-kappaB and MAPK are known to be activated in the joints of patients with OA and RA. PMC-II induced iNOS and COX-2 synthesis through p38, ERK1/2 and NF-kappaB dependent pathways suggesting a previously unidentified pathway for the synthesis of the proinflammatory mediators, ()NO and PGE(2), further suggesting that inhibitors of these pathways may be therapeutic in the inflamed and degenerating human joint.

Arthritis↗

PubMed2006

Role of transforming growth factor-beta in the progression of heart failure.

Transforming growth factor (TGF-beta) is a multifunctional peptide growth factor that has an important role in the regulation of cell growth, differentiation, and repair in a variety of tissues. In mammals, the cytokine has three isoforms, TGF-beta1, TGF-beta2, and TGF-beta3. TGF- beta1 is up-regulated by Ang II and induction of TGF-beta1 causes cardiac fibrosis. The stimulus that triggers the expression of TGF-beta1 may be repeated causing continual injury, which is associated with an increase in the activity of Ang II in heart tissue. The interplay between Ang II and TGF-beta1 causes continued activation that may result in chronic hypertension and progressive myocardial fibrosis, leading to heart failure. The regulation of TGF-beta1 secretion and action involves complex transcriptional events. Overproduction of TGF-beta1 underlies tissue fibrosis. Understanding the actions and signaling transduction of TGF-beta could lead to the development of therapeutic options that may be effective in inhibiting myocardial fibrosis triggered by TGF-beta1 in heart failure.

Angiotensin II↗

PubMed2005

Molecular basis of cardiotoxicity upon cobra envenomation.

Various clinical manifestations leading to death have been documented in most cases of bites caused by venomous snakes. Cobra envenomation is an extremely variable process and known to cause profound neurological abnormalities. The complexity of cobra venom can induce multiple-organ failure, leading to death in case of severe envenomation. Intramuscular administration of Malayan spitting cobra (Naja sputatrix) crude venom at 1 microg/g dose caused death in mice in approximately 3 h. Analysis of gene expression profiles in the heart, brain, kidney, liver and lung revealed 203 genes whose expression was altered by at least 3-fold in response to venom treatment. Of these, 50% were differentially expressed in the heart and included genes involved in inflammation, apoptosis, ion transport and energy metabolism. Electrocardiogram recordings and serum troponin T measurements indicated declining cardiac function and myocardial damage. This not only sheds light on the cardiotoxicity of cobra venom but also reveals the molecular networks affected during envenomation.

Animals↗

PubMed2004

Antioxidants in Chinese herbal medicines: a biochemical perspective.

Recently, intense interest has focused on the antioxidant properties of natural products. In particular, Chinese herbal medicines (CHM) have become hot topics for life science researchers since many are reported to possess cardioprotective compounds, many of which remain to be identified. Indeed, the exact mechanisms by which CHM work remain unknown. Although many of these herbal remedies are undoubtedly efficacious, few have been scientifically investigated for their active chemical constituents and biological activities. We have previously reported higher activities of antioxidant defence enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferases in the liver of rats treated with the herb Salvia miltiorrhiza in a model of acute myocardial infarction. Using well established in vitro antioxidant assays employing 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and diphenyl-l-picrylhydrazyl (DPPH) we have shown that in addition to elevating endogenous antioxidant enzyme activity, Salvia miltiorrhiza and other CHM traditionally used for cardiovascular disorders (such as Rhizoma ligustici, Herba leonuri, Radix achyranthis bidentatae, and Camellia sinensis) contain potent antioxidant moieties in addition to their phenolic constituents. Furthermore, these novel non-phenolic components are effective inhibitors of oxidative reactions mediated by the inflammatory oxidants, peroxynitrite,hypochlorous acid and hydroxyl radical as well as iron-dependent lipid peroxidation. In this review, we discuss the various antioxidant properties of CHM in the context of their biochemical mechanisms.

Antioxidants↗

PubMed2004

Analysis of strain difference in behavior to Cholecystokinin (CCK) receptor mediated drugs in PVG hooded and Sprague-Dawley rats using elevated plus-maze test apparatus.

This study investigated the behavioral mechanisms underlying the anxiogenic, or anxiolytic mediated effects of CCK(2) receptor mediated agonist (CCK-4) and antagonist drugs (LY225910, LY288513, CR2945) in PVG hooded and Sprague-Dawley (SD) rats using the elevated plus maze test apparatus. In addition, the effects of a CCK(1) antagonist (CR1409) were investigated for its possible mediation in anxiety behavior between PVG hooded and SD rats. PVG hooded rats treated with CCK-4, decreased the time spent in the open arm and increased the time spent in the closed arm and correspondingly showed increase in the number of entries in the open arms while the number of entries in closed arm was insignificant, whereas SD rats decreased the time spent in the closed arm, while other parameters remained insignificant. PVG hooded rats administered with various CCK(2) antagonists (LY225910, LY288513, and CR2945) significantly increased the time spent in the open arm and correspondingly decreased the time spent in the closed arm, while the number of entries in the open or closed arm was insignificant, in contrast, SD rats failed to show any reliable significance. PVG hooded rats administered with the CCK(1) antagonist (CR1409), failed to show any reliable significance, in contrast, SD rats significantly increased the time spent in the open arm. The strain differences observed in this study suggests that CCK plays mainly as a neuromodulator, in which the various CCK(2) antagonists may not affect baseline anxiety state, but instead they modulate heightened states of anxiety through differential effects of CCK(1)/CCK(2) receptors.

Animals↗

PubMed2004

Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts.

Wound healing is a complex process involving a number of related genes and receptors. Using cDNA microarrays, we explored the global gene expression profile of phenytoin (20microg/ml) induced changes to human dermal fibroblasts. Microarray data analysis revealed approximately 1500 genes were differentially expressed by 2.5-fold. At 3, 6, 12, and 24h, the transcripts of the major growth factors involved in wound healing and their receptors were increased. This was further confirmed by RT-PCR. Genes encoding other proteins with roles in signal transduction (NFkappaB), extracellular matrix (MMP1) including type I collagen, fibronectin, and laminin were strongly induced at 6h and onwards. Genes involved in cell cycle regulation (CCND1 and CDKN1A) were down-regulated consistent with our finding that phenytoin per se did not have cell proliferation activity. Notably, phenytoin accelerates the autocrine and paracrine activity of growth factors by up-regulating the related receptors.

Cell Cycle↗

PubMed2004

The CCK2 agonist BC264 reverses freezing behavior habituation in PVG hooded rats on repeated exposures to a cat.

Our previous studies (NeuroReport 12 (2001) 2717) showed that PVG hooded and not Sprague-Dawley (SD) rats exhibit remarkable freezing behavior on exposure to a cat in the cat freezing test apparatus. In the present study, we further examined the differences between these two strains of rats in response to repeated daily exposure to a cat in the cat freezing test apparatus. Freezing behavior habituation was observed in both PVG hooded (days 5-7) and SD rats (days 3-7). A selective CCK(2) agonist (BC264, 0.3 microg/kg, i.p.) on day 8 reversed habituated freezing behavior and locomotor activity in PVG hooded rats, but not in SD rats. These results suggest that CCK2 receptors mediate habituation to an anxiety-inducing stimulus in PVG hooded rats and further suggest that differential expression of these CCK2 receptors underlies this strain difference.

Animals↗

PubMed2003

cDNA microarray analysis of gene expression in anxious PVG and SD rats after cat-freezing test.

To identify genes involved in the development of anxiety or fear, we analyzed the gene expression profiles of the cortex of anxious hooded PVG and Sprague-Dawley (SD) rats after exposure to the cat-freezing test apparatus. These two rat strains showed a marked difference in the extent of anxious behavior on the cat-freezing test; the hooded PVG rats showed highly anxious behavior while a low anxiety state was observed in SD rats. A cDNA microarray consisting of 5,931 genes was employed to investigate the global mRNA expression profiles of anxiety-related genes. According to the assumption that an abundance ratio of > or =1.5 is indicative of a change in gene expression, we detected 16 upregulated and 38 downregulated genes in PVG hooded and SD rats. Some of these genes have not yet been associated with anxiety (e.g. FGF), while other genes were recently found to be expressed in an anxious state (e.g., rat nerve growth factor-induced gene, NGFI-A). Our study also focused on the expression of some neurotransmitter receptors that have already been proven to be relevant to anxiety or fear, e.g., gamma-aminobutyric acid (GABA), cholecystokinin (CCK) and 5-HT(3) receptors. To further confirm the microarray data, the mRNA expressions of three genes: rat activity-regulated cytoskeleton-associated gene (Arc), rat NGFI-A gene and rat 5-HT(3) receptor (5-HT(3)R) mRNA, were studied by reverse transcription-polymerase chain reaction (RT-PCR). The results of RT-PCR were basically consistent with those from cDNA microarray. Our study therefore demonstrated that the microarray technique is an efficient tool for analyzing global expression profiles of anxiety-related genes, which may also provide further insight into the molecular mechanisms underlying the states of anxiety and fear.

Animals↗

PubMed2003

Genetic variations in CCK2 receptor in PVG hooded and Sprague-Dawley rats and its mRNA expression on cat exposure.

This study examined differential freezing behavior, mediated by cholecystokinin-2 (CCK2) receptors (J. M. Farook et al., 2001), in PVG hooded and Sprague-Dawley (SD) rats exposed to a predator. The authors confirmed by reverse transcription polymerase chain reaction that CCK2 receptor expression in the PVG rats was increased in the hippocampus and cerebral cortex compared with that of SD rats. In addition, 4 variations in the coding region of the CCK2 receptor gene were detected between the PVG hooded and SD rats: 1 in Exon 4, 1 in Intron 2, and 2 in Intron 3. Acute treatment with a CCK2 agonist (CCK-4) or antagonist (LY225910) did not alter the level of CCK2 receptor expression, indicating no difference between the 2 strains in sensitivity of the CCK2 receptor to drugs.

Animals↗

PubMed2001

Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila.

Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms.

Acetylation↗

PubMed2001

Strain differences in freezing behavior of PVG hooded and Sprague-Dawley rats: differential cortical expression of cholecystokinin2 receptors.

PVG hooded, but not Sprague-Dawley (SD), rats showed remarkable freezing behavior on cat exposure. Experiments using cDNA microarray and reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that cholecystokinin (CCK)2 receptors were expressed to a greater extent in the PVG hooded rats. A CCK2 antagonist, LY225910, inhibited freezing behavior in the PVG hooded rats while a CCK2 agonist, CCK-4, increased freezing behavior in the SD rats. These results strongly suggest that CCK2 receptors mediate the freezing behavior and the differential expression of these receptors underlie the strain difference in such behavior.

Animals↗

PubMed2001

Time-dependent apoptotic development and pro-apoptotic genes expression in rat heart after myocardial infarction.

We investigated the apoptotic development and apoptotic-related gene expression after myocardial infarction (MI) at different time points in the current study. Bax gene expression was increased at 12 h after MI and peaked at 24 h. Fas gene started to over-express at 12 h after MI as well but it reached maximum at 72 h. In the MI groups, strongest staining of apoptosis was detected in rats 3 days post operation. Our results demonstrate that apoptotic development after MI is time dependent in the ischemic area and there could be some linkage with the over expression of angiotensin II receptors post MI.

Animals↗

PubMed2001

[Experimental study on effect of fuzheng yiliu decoction on tumor cell cycle and telomerease].

OBJECTIVE: To study the mechanism of anti-tumor effect of Fuzheng Yiliu Decoction (FZYLD). METHODS: S180 neoplasm strain was inoculated in Kunming mice to establish model of S180 solid tumor. The model animals were treated with FZYLD by gastrogavage, the cell cycle of tumor were checked up by flow cytometer and the telomerease kit was used to test telomerease activity. RESULTS: The stage G0/1 ratio of tumor cells in model animals treated with FZYLD increased, while cells of S stage decreased, with telomerease activity inhibited. These changes were different significantly from those in the model animals treated with normal saline (P < 0.001). CONCLUSION: FZYLD could block the tumor cell proliferation procedure and inhibit the DNA synthesis and duplication in tumor cell. And the suppression of telomerease activity might be one of the mechanisms affecting the tumor cell proliferation cycle.

Animals↗

PubMed2000

The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.

Huntington's Disease (HD) is caused by an expansion of a polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequences to nuclear function of a pathogenic amino-terminal region of htt (httex1p) including aggregation, protein-protein interactions, and transcription. httex1p was found to coaggregate with p53 in inclusions generated in cell culture and to interact with p53 in vitro and in cell culture. Expanded httex1p represses transcription of the p53-regulated promoters, p21(WAF1/CIP1) and MDR-1. httex1p was also found to interact in vitro with CREB-binding protein (CBP) and mSin3a, and CBP to localize to neuronal intranuclear inclusions in a transgenic mouse model of HD. These results raise the possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD.

Animals↗

PubMed2000

Expression of angiotensin II AT2 receptor in the acute phase of stroke in rats.

A male Wistar rat model of stroke (middle cerebral artery occlusion; MCAO) was used to study the angiotensin II (Ang II) receptor subtype 2 (AT2) gene expression by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining. After permanent occlusion of the middle cerebral artery (MCA), AT2 receptor gene expression was found to increase in the infarct cortex by 2.7-fold (1 day) and 1.7-fold (3 days), respectively. Positive AT2 immunostaining was also observed in the infarct area of the cerebral cortex. Apoptotic markers were detected in the necrotic area of the stroke cerebral cortex 1 day after MCAO. This demonstrated up-regulation of AT2 receptor may be involved in the apoptosis of tissue repair after stroke.

Acute Disease↗

PubMed2000

Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila.

Several dominant, late-onset neurodegenerative diseases (e.g. Huntington's disease) are caused by expansion of polyglutamine (polyQ) repeats within specific proteins. The diverse, yet overlapping, pathology of these diseases could be due to novel deleterious functions unique to each protein or to a common pathophysiology mediated by the long polyQ chains themselves. By engineering Drosophila to express different polyQ peptides, we find that expanded polyQ chains alone are intrinsically cytotoxic and cause neuronal degeneration and early adult death. We further find that this intrinsic toxicity is dependent on cell type and polyQ length and that the inclusion of other amino acids modifies and reduces toxicity. This is the first in vivo evidence that polyQs, when removed from their disease gene context, cause neurotoxicity. These studies provide a basis for understanding the diverse clinical presentations in terms of the intrinsic cytotoxic effect of polyQ peptides being modulated by protein context. Parallel experiments in which cytotoxic polyQ expansions were engineered into Dishevelled, a Drosophila protein containing a naturally occurring polyQ tract, strongly suggest that the effect of a toxic polyQ peptide can be neutralized by protein context. This animal model provides a simple and effective means of screening for therapeutics that relieves the polyQ-induced lethality, independent of any particular disease gene. By quantifying the degree of lethality in several transgenic lines, we have identified a number of genetically modified strains that are suitable for eventual testing of compounds or genes that ameliorate the pathology of polyQ peptides.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Identification of regulated genes in rat heart after myocardial infarction by means of differential mRNA display.

In order to testify the hypothesis that unknown mechanisms are involved in the process of cardiac remodeling after myocardial infarction (MI), we employed differential display reverse transcription-polymerase chain reaction (DDRT-PCR) as our primary inspection tool. An animal model of MI was established by ligation of the left anterior descending coronary artery (LAD) in rat. Fifty upregulated candidate cDNA fragments were obtained in the right ventricle (RV) of the heart six weeks after MI. Eight cDNA fragments isolated from DD denaturing gel were extracted and reamplified, cloned into pCR II vector and sequenced. A Genbank search of these clones showed that three of them have a high homology with known genes not previously associated with cardiac remodeling, i.e., mouse interleukin-4 receptor gene, rat ferritin mRNA, and T-cell receptor beta chain V beta 5. The remaining clones have no similarity to known sequences. These data suggest that certain genes which were not previously being associated with cardiac hypertrophy are turned on during the process of cardiac remodeling after MI.

Animals↗