Pathophysiology

Editorial Board

2009-10-01

The advances of Pathophysiology in China—Welcoming Global Collaboration

Jian-Zhi Wang — 2009-10-01

This special issue was aimed to share with the colleagues worldwide the most recent research progress in the Pathophysiology field in China. To reach this goal, we invited over twenty prestigious pathophysiologists to write reviews or original articles to demonstrate their research advances. Though many of them were not able to submit their work in the designated time frame, we still collected eleven papers for this special issue, which at least represent part of the researches carried out by the Chinese pathophysiologist. I am greatly appreciated to the contributions made by my colleagues.

Scorpion venom polypeptide accelerate irradiated hematopoietic cells proliferation

Yanjie He, Tianhan Kong, Weihua Dong — 2009-10-01

Abstract: Objective: To study the effects of Scorpion venom polypeptide (SVP) on the irradiated hematopoietic progenitor cells and the initial research of its mechanism.Methods and materials: (1) MTT array was used to select the effective concentration of SVP that had proliferate action on the irradiated early hematopoietic cells (K562), just like the doses of experiment in vitro; (2) The male BALB/c mice were divided into NS control group, SVP IV group and SVP V group. After treatment and sublethal irradiation, the C-KIT and IL-6Rα levels of bone marrow cells were detected by immunohistochemistry and tissue array; (3) The bone marrow cells of the normal BALB/c mice, given to SVP IV and SVP V after different action times respectively, were taken to extract the total proteins inside the cell, the phosphorylated STAT3 protein levels in JAK-STAT signal transduction pathway were detected by Western blot array.Results: (1) 30mg/L SVP IV has an obvious effect to accelerate K562 cell proliferation; (2) The C-KIT and IL-6Rα expression on bone marrow cell surfaces in SVP IV and SVP V groups were negative (control with the saline group, p>0.05); (3) The phosphorylated STAT3 protein levels in bone marrow cells of SVP IV group had a rise-and-fall trend within 30min, while the test of SVP V group showed that the phosphorylated STAT3 protein levels obviously elevated after 30min.Conclusions: The results show that certain SVP IV concentration can protect the hematopoietic progenitor cells after irradiation, and the underlying mechanism of SVP accelerating the hematopoietic recovery in irradiated mice may be related to the activation of the JAK-STAT signal pathway.

Hypermethylation of estrogen receptor-α gene in atheromatosis patients and its correlation with homocysteine

Yu-Shan Huang, Yan-Fang Zhi, Shu-Ren Wang — 2009-10-01

Abstract: Objective: To investigate the aberrant DNA methylation in promoter region of estrogen receptor α (ERα) in atherosclerosis (As) and the possible involvement of homocysteine (Hcy) in its pathogenesis.Methods: The blood samples were collected from 54 patients with As approved by carotid colorized ultrasound examination and 28 healthy control subjects. The methylation status of CpG islands in ER-α gene promoter region of genome DNA was analyzed by nested-methylation-specific PCR (nMSP). tHcy was examined by fluorescent-biochemical method. Spearman rank correlation was used to analyse the relationship between the degree of methylation in ER-α gene and the level of tHcy. Cultured smooth muscle cells of Homo sapiens were treated by Hcy with different concentrations and different treating time, again the DNA methylation status was assayed by nMSP, and the proliferation of SMC was assayed by MTT.Results: Hypermethylation of ER-α gene promoter region was found in 38 cases of atherosclerosis patients, and the methylation frequency was 70.4%. While in healthy controls, just 8 of 28 samples hypermethylation was found, only 28.6% methylation frequency was detected, much lower than the one in atherosclerosis group (p<0.05). Meanwhile, the level of tHcy in atherosclerosis group was significantly higher than that in control group (p<0.05). The spearman rank correlation analysis explored an obvious correlation between the degree of methylation in ER-α gene and the level of tHcy (r=0.809, p<0.05), and the severity of atherosclerotic lesion was also heightened along with the increment of plasma level of tHcy. The cultured SMCs treated by Hcy resulted in de novo methylation in promoter region of ERα gene with a concentration and treating time-dependent manner, and a dose-dependent promoting effect on SMC proliferation. The in vivo and in vitro data coincidently showed that the Hcy could promote the hypermethylation of ERα gene, which may be an important mechanism for the pathogenesis of As.Conclusion: Hypermethylation of CpG islands in ER-α gene promoter region was found in much higher frequency in atherosclerosis patients, which is positively correlated with the increased level of plasma tHcy and the severity of atherosclerotic lesion, and the in vitro experimental results further extended above clinical data that HHcy can lead to the hypermethylation of ER-α gene, and hence to promote the occurrence and development of As.

The anti-proliferation mechanism of glucocorticoid mediated by glucocorticoid receptor-regulating gene expression

Jian Lu — 2009-10-01

Abstract: Glucocorticoid (GC) hormones exert an antiproliferative effect on various cells. The effect is mainly mediated by glucocorticoid receptor (GR) which acts as a transcription factor. Ligand-bound GR translocates from the cytoplasm into the nucleus to modulate gene expression in a variety of ways. Although the framework of transcriptional regulation by the GC/GR has been described, the molecular mechanism of antiproliferative effect of GC is still largely unclear. In this article, we reviewed GC-induced changes in gene expression that are involved in GC-antiproliferative effect, and mainly focused on our recently identified glucocorticoid-responsive genes, TGF-β receptor type II (TβRII) and small GTP binding protein RhoB. We found that expressions of TβRII and RhoB were up-regulated by ligand-bound GR at mRNA and protein levels. Blocking the effect of TβRII by TβRII neutralizing antibody or reduction of RhoB mRNA expression by RNAi diminished dexamethasone-inhibitory effect on cell proliferation, thus confirming that these genes are involved in GC anti-proliferation effect. Collectively, GC up-regulating the expressions of RhoB and TβRII play an important role in GC anti-proliferation effect.

Protein phosphatase 2A in Alzheimer's disease

Rong Liu, Jian-Zhi Wang — 2009-10-01

Abstract: Protein phosphatase 2A (PP2A) is the predominant serine/threonine phosphatase in eukaryotic cells. In Alzheimer's disease (AD), PP2A activity is decreased. Decreased PP2A activity is suggested to be involved in NFT formation and neurodegeneration. PP2A is also involved in APP secreting pathway, thus probably participating the Aβ production. Based on our research and other previous findings, decreased PP2Ac level, decreased PP2A holoenzyme composition, increased level of PP2A inhibitors, increased PP2Ac Leu309 demethylation and Tyr307 phosphorylation could partly explain the mechanisms of PP2A inactivation in AD. Aβ over-production, estrogen deficiency and impaired homocysteine metabolism are the possible up-stream factors that inactivate PP2A in AD neurons. Further studies are needed to disclose the role of PP2A in Alzheimer's disease.

Possible mechanisms of Cyclosporin A ameliorated the ischemic microenvironment and inhibited mitochondria stress in tree shrews’ hippocampus

Shu-qing Li, Ying Zhang, Dai-bin Tang — 2009-10-01

Abstract: Objective: The ischemic brain damage is always accompanied by the significant accumulation of glutamate and calcium ions (Ca2+). Our objectives were to observe the effects of glutamate and Ca2+ overloading in tree shrew's hippocampal microenvironment on mitochondrial stress resulting in cytochrome C release and caspase apoptotic gene activation, and to explore the possible mechanism of Cyclosporin A (CsA) inhibiting mitochondrial stress. Methods: The thrombotic focal cerebral ischemia was induced by photochemical reaction in tree shrews. The extracellular contents of amino acidic neurotransmitters and Ca2+ were determined, respectively, with high performance liquid chromatography (HPLC) and atomic absorption spectrophotometry at 4, 24 and 72h after cerebral ischemia. The glutamate–calcium chloride solutions were microperfused into hippocampus by a kind of single-pumped push–pull perfusion (SPPP) system under three-dimensional orientation instrument in tree shrews. At 24h, the expression of cytochrome C was observed in perfused lateral hippocampus by immunochemistry. Also, the hippocampus was removed, then mitochondria and cytoplasmic fragment were divided by low temperature centrifugation and the distribution of cytochrome C was assessed through Western blot. Real time fluorescence polymerase chain reaction was used to evaluate the relative amounts of caspase-3 and caspase-9 mRNA. In the treated group, CsA (40mg/kg) was intravenously injected at 6h after the microperfuse or cerebral ischemia. The glutamate–calcium solutions were perfused into the hippocampus and inspected the above-mentioned items at 24h. Data were compared between the two groups (ischemia group vs. sham group, or ischemia group vs. CsA group). Results: Thrombotic cerebral ischemia led to significant increase in extracellular glutamate and Ca2+ level of hippocampus (P<0.01). The cerebral ischemia group and the microperfusion group, which cytochrome C immunoreactivity increased and Western blot analysis demonstrated that the cytochrome C content in the mitochondria of hippocampal cells decreased (P<0.01), but the cytochrome C in the cytosol increased (P<0.01). When CsA was intravenously injected at 6h after the microperfusion or cerebral ischemia, the cytochrome C expression weakened and its release was diminished to a lesser extent. By real time PCR, in relation to the control group, the caspase-3 and caspase-9 mRNA was higher in the glutamate–calcium chloride solution perfused group. CsA treatment cut down the contents of caspase-3 mRNA and caspase-9 mRNA (P<0.01). Conclusions: It is a primary factor that glutamate and Ca2+ accumulate in hippocampal microenvironment, which results in proapoptotic protein cytochrome C release from mitochondria into cytoplasm and caspase cascade activation, and finally mitochondria stress and neuronal secondary injury appear. The neuroprotection of CsA is in relation to inhibiting glutamate receptor overactivation and reducing the Ca2+ influx, which can decrease cytochrome C release and caspase mRNA transition.

Stem cells based transplantation for cardiovascular diseases in China

Yan-qiu Yu, Li-li Du — 2009-10-01

Abstract: Stem cells based therapy has been a realistic option for cardiovascular diseases. Since 1990s, Chinese researchers and doctors have been starting to seek for optimal stem cells sources, effective methods of stem cells proliferation and differentiation with traditional Chinese medicine and clinical application of stem cells based transplantation for cardiovascular diseases. This review will summarize the investigation of stem cells in the field of cardiovascular diseases in China.

Therapeutic strategies targeting the LPS signaling and cytokines

Hua-Dong Wang, Da-Xiang Lu, Ren-Bin Qi — 2009-10-01

Abstract: Lipopolysaccharide (LPS) has been recognized as a major player in the pathogenesis of sepsis and neutralization of LPS or inhibition of its signal transduction mechanism is promising new treatment strategy in preclinical experiments. However, these therapeutic approaches have been shown unsuccessful in clinical trials. LPS activates Toll-like receptor 4 (TLR4) and induces pro-inflammatory and anti-inflammatory responses, the altered innate and adaptive immune responses eventually lead to the immunosuppressive state. The future therapeutic efforts in sepsis should focus on the immunosuppressive state. In this article, we will outline the current data on therapeutic strategies targeting LPS, TLR4 and single cytokine in sepsis and discuss the experimental and clinical evaluation of the immunomodulatory action of glycine and berberine. While we have demonstrated berberine in combination with yohimbine can modulate host immune responses in endotoxemia, it seems worthwhile to conduct clinical trials on the safe and efficacy of this new immunomodulatory therapy.

Hypoxia-HIF-1α-C/EBPα/Runx1 signaling in leukemic cell differentiation

Jing Zhang, Guo-Qiang Chen — 2009-10-01

Abstract: Acute myeloid leukemia (AML), a class of prevalent hematopoietic malignancies, is caused by the acquisition of gene mutations that confer deregulated proliferation, impaired differentiation and a survival advantage of hematopoietic progenitors. More recently, we reported that cobalt chloride (CoCl2)/iron chelator desferrioxamine (DFO)-mimicked hypoxia or moderate hypoxia (2% and 3% O2) can directly trigger differentiation of many subtypes of AML cells. Also, intermittent hypoxia significantly prolongs the survival of the transplanted leukemic mice with differentiation induction of leukemic cells. Additionally, these hypoxia-simulating agents selectively stimulate differentiation in acute promyelocytic leukemic cells induced by arsenic trioxide, an effective second-line drug for this unique type of leukemia. Based on this interesting evidence in vitro and in vivo, the ongoing investigations showed the role of hypoxia-inducible factor-1alpha (HIF-1α) protein through its non-transcriptional activity in myeloid cell differentiation, as evidenced by chemical interference, the conditional HIF-1α induction, the specific short hairpin RNAs (shRNAs) against HIF-1α and HIF-1β, an essential partner for transcription activity of HIF-1. Furthermore, HIF-1α and two hematopoietic transcription factors CCAAT/enhancer binding protein alpha (C/EBPα) and Runx1/AML1 interact directly with each other. Such interactions increase the transcriptional activities of C/EBPα and Runx1/AML1, while C/EBPα competes with HIF-1β for direct binding to HIF-1α protein, and significantly inhibits the DNA-binding ability of HIF-1. As a protein is rapidly responsive to all-trans retinoic acid (ATRA), a classical clinical differentiation-inducing drug for AML, HIF-1α also plays a role in ATRA-induced differentiation of leukemic cells.

Negative growth regulators of the cell cycle machinery and cancer

Man Zhang, Huiling Yang — 2009-10-01

Abstract: Cell cycle dysregulation is a critical feature of tumor cells. Numerous cell cycle regulators act either as oncogenes or tumor suppressors and their aberrations result in proliferative advantage for cancer cells. Many molecular targets and their use in either abrogating the growth advantage of oncogenic mediators or enhancing the growth suppressive activity of tumor suppressors, have been filed for patents. The molecular targets associated with cell cycle inhibition are of particular interest because they are potential therapeutic agents of promise in the control of inappropriate cellular proliferation. This review focuses on the recent discovery of potential molecular targets involved in cell cycle inhibition and their evaluation as therapeutic agents for cancers. In this review, the strategies employed to control oncogenesis and their possible clinical applications are discussed.

Hyperphosphorylation of microtubule-associated tau protein plays dual role in neurodegeneration and neuroprotection

Yao Zhang, Qing Tian, Qi Zhang, Xinwen Zhou, Shijie Liu, Jian-Zhi Wang — 2009-10-01

Abstract: The microtubule-associated protein tau plays a major role in maintaining the normal morphology of the neurons. The major biological activity of tau is to promote microtubule assembly and stabilize the microtubules. In the brain of Alzheimer's disease (AD) patients, tau protein is abnormally hyperphosphorylated and thus become incompetent in promoting microtubule assemble and maintaining the stability of the microtubules. These detrimental effects of tau may lead the neurons to degeneration. Recent studies show that tau hyperphorylation may be neuroprotective in the early stages of the disease process. The primary aim of this review is to summarize the latest developments and perspectives in our understanding about the roles of tau hyperphosphorylation in neurodegeneration and neuroprotection.

Calcium sensing receptor and heart diseases

Weihua Zhang, Changqing Xu — 2009-10-01

Abstract: Background: Calcium ion is the first identified endogenous substance to function as both a first and second messenger via the stimulation of an extracellular calcium sensing receptor (CaR). CaR is a seven transmembrane G-protein-coupled receptor, which activates intracellular effectors, for example, it causes inositol phosphate (IP) accumulation to increase the release of intracellular calcium. Furthermore, more and more evidence shows that CaR is related to mediating the cellular functions in various cells. Recent findings: Since 2003, CaR has been detected to be functionally expressed in the atria and ventricle of the rat hearts. Recently, increasing evidence suggests that CaR has been involved in apoptosis in the ischemia/reperfusion heart through caspase-3-Cytochrome c and FasL/Fas and endoplasmic reticulum stress pathways and also involved in cardiac hypertrophy-induced by AngII through CaN pathway in neonatal rat cardiomyocytes. Summary: These results suggested that CaR in cardiac tissue might have a physiological and pathophysiological role in heart disease. This review revealed CaR's structure and function and emphasized the role of CaR in the cardiac tissues.