[Retrospection and Reflection on the Integrated Chinese and Western Medicine]

Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi = Chinese Journal of Integrated Traditional and Western Medicine / Zhongguo Zhong Xi Yi Jie He Xue Hui, Zhongguo Zhong Yi Yan Jiu Yuan Zhu Ban. Nov, 2010  |  Pubmed ID: 21275179

Integration of Chinese medicine and Western medicine is the necessary outcome in the reality of co-existence of the two medicines nowadays, also an inevitable tendency of cross-comprehensive, systematization, internationalization and diversification in the progress of science development and research. Experienced over half a century's self-innovation, lots of achievements in clinical and experimental studies have been achieved by the integrated Chinese and Western medicine (ICWM), but it still remains in the primary period of developing, and some deficiencies existed yet. So, we should have the foresight and mind of "Harmony in Diversity" and make effort to establish a series of independent and perfect theoretical system, for making more breakthrough development of ICWM.

Genetic Suppressor Screens in Haploids

Methods in Cell Biology. 2011  |  Pubmed ID: 21924160

As a vertebrate genetic model, the zebrafish has been well recognized for its strength in studying a variety of biological processes and human diseases. Traditional forward genetic screens in zebrafish have generated a large pool of mutants with interesting phenotypes resembling human diseases but the underlying mechanisms are not well understood. A powerful approach to elucidate the mechanisms of these mutants is the modifier screen, which identifies 2(nd)-site mutations that specifically enhance or block the phenotype of a given mutant. Here we described the first genetic suppressor screen in zebrafish, which identifies a novel transcriptional mechanism regulating erythropoiesis. In combination with the haploid genetics in zebrafish, we have shown the feasibility and strength of a modifier screen in zebrafish. This strategy will greatly broaden the utility of the zebrafish as a model for making original discoveries and establishing novel paradigms for understanding vertebrate biology.

Ryanodine Receptor Type 2 is Required for the Development of Pressure Overload-induced Cardiac Hypertrophy

Hypertension. Dec, 2011  |  Pubmed ID: 21986507

Ryanodine receptor type 2 (RyR-2) mediates Ca(2+) release from sarcoplasmic reticulum and contributes to myocardial contractile function. However, the role of RyR-2 in the development of cardiac hypertrophy is not completely understood. Here, mice with or without reduction of RyR-2 gene (RyR-2(+/-) and wild-type, respectively) were analyzed. At baseline, there was no difference in morphology of cardiomyocyte and heart and cardiac contractility between RyR-2(+/-) and wild-type mice, although Ca(2+) release from sarcoplasmic reticulum was impaired in isolated RyR-2(+/-) cardiomyocytes. During a 3-week period of pressure overload, which was induced by constriction of transverse aorta, isolated RyR-2(+/-) cardiomyocytes displayed more reduction of Ca(2+) transient amplitude, rate of an increase in intracellular Ca(2+) concentration during systole, and percentile of fractional shortening, and hearts of RyR-2(+/-) mice displayed less compensated hypertrophy, fibrosis, and contractility; more apoptosis with less autophagy of cardiomyocytes; and similar decrease of angiogenesis as compared with wild-type ones. Moreover, constriction of transverse aorta-induced increases in the activation of calcineurin, extracellular signal-regulated protein kinases, and protein kinase B/Akt but not that of Ca(2+)/calmodulin-dependent protein kinase II, and its downstream targets in the heart of wild-type mice were abolished in the RyR-2(+/-) one, suggesting that RyR-2 is a regulator of calcineurin, extracellular signal-regulated protein kinases, and Akt but not of calmodulin-dependent protein kinase II activation during pressure overload. Taken together, our data indicate that RyR-2 contributes to the development of cardiac hypertrophy and adaptation of cardiac function during pressure overload through regulation of the sarcoplasmic reticulum Ca(2+) release; activation of calcineurin, extracellular signal-regulated protein kinases, and Akt; and cardiomyocyte survival.

Heat Shock Transcription Factor 1 Protects Heart After Pressure Overload Through Promoting Myocardial Angiogenesis in Male Mice

Journal of Molecular and Cellular Cardiology. Nov, 2011  |  Pubmed ID: 21854784

Heat shock transcription factor 1 (HSF1) plays an important role not only in excise-induced cardiac hypertrophy but also in protection against pressure overload-induced cardiac dysfunction. However, the mechanism is not completely understood. We here elucidate the potential mechanisms by which HSF1 protects against pressure overload-induced cardiac remodeling and dysfunction. A sustained constriction of transverse aorta (TAC) was imposed to HSF1 transgenic (TG), knockout (KO) and their littermate wild type (WT) male mice. Four weeks later, adaptive responses to TAC, such as cardiac hypertrophy, contractility and angiogenesis evaluated by echocardiography, catheterization, coronary perfusion pressure and immunohistochemistry were well preserved in TG but not in KO compared with WT mice. An angiogenesis inhibitor TNP-470 abrogated all these adaptive responses in TG mice, while cardiac transfection of VEGF with angiopoietin-1 rescued the broken heart in KO mice. In response to TAC, p53 was downregulated and hypoxia-inducing transcription factor-1 (HIF-1) was upregulated not only in the heart but also in the cultured cardiac endothelial cells (EC) of TG mice as compared to WT mice whereas these changes became opposite in KO mice. A small interfering RNA (siRNA) of HIF-1 but not a p53 gene impaired the adaptive responses of the heart and EC in TG mice, and a siRNA of p53 but not a HIF-1 gene significantly reversed the heart and EC disorders in KO mice after TAC. We conclude that HSF1 promotes cardiac angiogenesis through suppression of p53 and subsequent upregulation of HIF-1 in endothelial cells during chronic pressure overload, leading to the maintenance of cardiac adaptation.

Nasotracheal Intubation Using the Blind Intubation Device in Anaesthetised Adults with Mallampati Class 3: a Comparison with the Macintosh Laryngoscope

European Journal of Anaesthesiology. Nov, 2011  |  Pubmed ID: 21885980

We hypothesised that the Blind Intubation Device (BID) would be effective for nasotracheal intubation (NTI) in anaesthetised adults with Mallampati class 3. We also hypothesised that BID may cause less haemodynamic changes due to the avoidance of direct stimulation induced by the Macintosh blade.

Extragastrointestinal Stromal Tumor in a Kidney Transplant Recipient

Clinical and Experimental Nephrology. Oct, 2011  |  Pubmed ID: 22009637

The occurrence of de novo malignant neoplasms has been shown in post-transplant recipients receiving immunosuppressive treatment. We present a case of a rare extragastrointestinal stromal tumor (EGIST) located in the pelvic cavity of a kidney transplant patient. A 57-year-old female patient was admitted to our department because of non-specific lower abdominal pain 6 months after renal transplantation. An abdominal computed tomography scan showed a 4.5 cm diameter pelvic tumor mass. The tumor was resected en bloc and confirmed as not being connected to the gastrointestinal wall. Microscopically, the tumor consisted of typical spindle cells with 2-3 mitotic figures per 50 high-power fields. Immunohistochemically, the tumor cells were strongly positive for CD117 (c-kit), and negative for CD34, SMA, s-100 protein, and desmin. Genetically, the tumor showed a silent mutation in exon 18 of the PDGFRA gene at codon 824 GTC > GTT (V824V) [rs2228230]. No recurrence was noted 24 months after the operation. This case draws our attention to the importance of considering EGISTs (including GISTs), even though they are extremely uncommon, in the differential diagnosis of mesenchymal neoplasms, especially in transplant patients.

Identification of PRRT2 As the Causative Gene of Paroxysmal Kinesigenic Dyskinesias

Brain : a Journal of Neurology. Dec, 2011  |  Pubmed ID: 22120146

Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1-q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder.

Broadband Superluminescent Diode-based Ultrahigh Resolution Optical Coherence Tomography for Ophthalmic Imaging

Journal of Biomedical Optics. Dec, 2011  |  Pubmed ID: 22191923

Spectral domain optical coherence tomography (SD-OCT) with ultrahigh resolution can be used to measure precise structures in the context of ophthalmic imaging. We designed an ultrahigh resolution SD-OCT system based on broadband superluminescent diode (SLD) as the light source. An axial resolution of 2.2 μm in tissue, a scan depth of 1.48 mm, and a high sensitivity of 93 dB were achieved by the spectrometer designed. The ultrahigh-resolution SD-OCT system was employed to image the human cornea and retina with a cross-section image of 2048 × 2048 pixels. Our research demonstrated that ultrahigh -resolution SD-OCT can be achieved using broadband SLD in a simple way.

FW523-3, a Novel Lipopeptide Compound, Induces Apoptosis in Cancer Cells

Molecular Medicine Reports. Jul-Aug, 2011  |  Pubmed ID: 21584500

FW523-3, a new lipopeptide compound, was recently isolated and purified from the culture broth of a marine Micromonospora chalcea. FW523-3 was shown to inhibit the proliferation of certain cancer cells. However, the spectra and the underlying mechanism of its antitumor activity are unclear. In this study, the MTT and colony formation assays were employed to determine the antitumor spectra of FW523-3 and its effect on cell proliferation, respectively. Apoptosis was analyzed using DNA laddering assay and flow cytometry and the involved pathways were explored by Western blotting. Results revealed that FW523-3 exhibited cytotoxicity in a panel of tumor cell lines including esophageal squamous cell carcinoma cells (EC109), lung cancer cells (A549 and 95D), gastric cancer cells (SGC7901), uterine cervix cancer cells (HeLa) and hepatocellular carcinoma cells (HepG2). Based on these results, FW523-3 inhibited the colony formation ability of tumor cells. Moreover, FW523-3 induced apoptosis via activation of caspases 9, 7 and 3. FW523-3 also blocked the ERK and p38 signaling pathways. Taken together, we propose that FW523-3 acts as a broad-spectrum antitumor drug. FW523-3 inhibits tumor cell growth and induces tumor cell apoptosis via the mitochondrial and MAPK pathways.

Epithelial Cells Lining Salivary Gland Ducts Are Early Target Cells of Severe Acute Respiratory Syndrome Coronavirus Infection in the Upper Respiratory Tracts of Rhesus Macaques

Journal of Virology. Apr, 2011  |  Pubmed ID: 21289121

The shedding of severe acute respiratory syndrome coronavirus (SARS-CoV) into saliva droplets plays a critical role in viral transmission. The source of high viral loads in saliva, however, remains elusive. Here we investigate the early target cells of infection in the entire array of respiratory tissues in Chinese macaques after intranasal inoculations with a single-cycle pseudotyped virus and a pathogenic SARS-CoV. We found that angiotensin-converting enzyme 2-positive (ACE2(+)) cells were widely distributed in the upper respiratory tract, and ACE2(+) epithelial cells lining salivary gland ducts were the early target cells productively infected. Our findings also have implications for SARS-CoV early diagnosis and prevention.

Human Adenovirus Type 5 Induces Cell Lysis Through Autophagy and Autophagy-triggered Caspase Activity

Journal of Virology. May, 2011  |  Pubmed ID: 21367888

Oncolytic adenoviruses, such as Delta-24-RGD, are promising therapies for patients with brain tumor. Clinical trials have shown that the potency of these cancer-selective adenoviruses should be increased to optimize therapeutic efficacy. One potential strategy is to increase the efficiency of adenovirus-induced cell lysis, a mechanism that has not been clearly described. In this study, for the first time, we report that autophagy plays a role in adenovirus-induced cell lysis. At the late stage after adenovirus infection, numerous autophagic vacuoles accompany the disruption of cellular structure, leading to cell lysis. The virus induces a complete autophagic process from autophagosome initiation to its turnover through fusion with the lysosome although the formation of the autophagosome is sufficient for virally induced cell lysis. Importantly, downmodulation of autophagy genes (ATG5 or ATG10) rescues the infected cells from being lysed by the virus. Moreover, autophagy triggers caspase activity via the extrinsic FADD/caspase 8 pathway, which also contributes to adenovirus-mediated cell lysis. Therefore, our study implicates autophagy and caspase activation as part of the mechanism for cell lysis induced by adenovirus and suggests that manipulation of the process is a potential strategy to optimize clinical efficacy of oncolytic adenoviruses.

Validation of the Simplified Criteria for Diagnosis of Autoimmune Hepatitis in Chinese Patients

Journal of Hepatology. Feb, 2011  |  Pubmed ID: 21056494

In 1999, the International Autoimmune Hepatitis Group (IAIHG) revised the diagnostic criteria for autoimmune hepatitis (AIH). It subsequently developed the simplified criteria in 2008 to enhance clinical applicability and practicability. In this study, we validated the simplified diagnostic criteria in Chinese patients with AIH or other chronic liver diseases in comparison with the revised original criteria.

Dual Effects of Statins Therapy in Systemic Lupus Erythematosus and SLE-related Atherosclerosis: The Potential Role for Regulatory T Cells

Atherosclerosis. Feb, 2012  |  Pubmed ID: 22417842

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease associated with accelerated atherosclerosis independent of traditional risk factors. Statins, the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been widely prescribed for hyperlipidemia, which could slow the atherosclerosis progression, and reduce cardiovascular disease events. Nonetheless, accumulated evidences suggested that statins exert immunomodulatory and anti-inflammatory functions independent of their lipid-lowering effects. By the virtue of pleiotropic immunomodulatory property, statins may be applied for the treatment of both autoimmunity and atherosclerosis in patients with SLE. Interestingly, it has been well documented that regulatory T cells (Tregs) are involved in the pathogenesis of SLE as well as atherosclerosis. Meanwhile, studies have shown that statins could induce augmented number of Tregs with increased functional inhibitory properties. Thus, we hypothesized that the effect of statins ameliorating lupus disease manifestations and lupus-mediated atherogenesis might be mediated, at least partly, via the activation of Tregs. To our knowledge, this is the first hypothesis focused on that Tregs might be involved in the immunomodulatory effect of statins on SLE and SLE-related atherosclerosis.

Baicalein, a Natural Product, Selectively Activating AMPKα(2) and Ameliorates Metabolic Disorder in Diet-induced Mice

Molecular and Cellular Endocrinology. Jun, 2012  |  Pubmed ID: 22698522

The aim of the present study was to determine the effect of baicalein on metabolic syndrome induced by a high-fat diet in mice. The mice developed obesity, dyslipidemia, fatty liver, diabetes and insulin resistance. These disorders were effectively normalized in baicalein-treated mice. Further investigation revealed that the inhibitory effect on inflammation and insulin resistance was mediated by inhibition of the MAPKs pathway and activation of the IRS1/PI3K/Akt pathway. The lipid-lowering effect was attributed to the blocking of synthesis way mediated by SERBP-1c, PPARγ and the increased fatty acid oxidation. All of these effects depended on AMPKα activation. These results were confirmed in the primary hepatocytes from wild type and AMPKα(2)(-/-) mice. However, the IRS-1/PI3K/AKT pathway showed no change, which may be due to the time of stimulation and concentration. Thus, these data suggested that baicalein protects mice from metabolic syndrome through an AMPKα(2)-dependent mechanism involving multiple intracellular signaling pathways.

CREB-binding Protein Silencing Inhibits Thrombin-induced Endothelial Progenitor Cells Angiogenesis

Molecular Biology Reports. Mar, 2012  |  Pubmed ID: 21670961

Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence from our group suggested that CREB-binding protein (CBP) plays an important role in thrombin-induced EPCs migration. However, whether CBP could regulate EPCs angiogenic properties is unknown. In the present study, we investigated whether CBP silencing could inhibit thrombin-induced EPCs angiogenesis. EPCs isolated from the bone marrow of Sprague-Dawley rats were cultured and identified, and then were treated by thrombin alone or combined with CBP-shRNA lentivirus. The effect of CBP silencing on EPCs proliferation was assessed using BrdU incorporation assay. Cell adhesion and tube formation were detected to evaluate the angiogenic functions. Finally, mRNA and protein expression of relevant angiogenic genes were examined by real-time PCR, western-blot, and enzyme-linked immunoassay respectively. Luciferase reporter gene assay was performed to evaluate NF-κB activity. Administration of thrombin significantly promoted EPCs proliferation and adhesion. Thrombin also increased the tube formation in Matrigel assay. However, these effects of thrombin were abolished by CBP gene silencing. CBP silencing also abrogated thrombin-induced increases of integrin β2 expression. In thrombin-induced EPCs, CBP silencing significantly decreased the secretion of VEGF, IL-6 and suppressed NF-κB activity. In conclusion, thrombin-induced EPCs proliferation, adhesion, and tube formation were inhibited by CBP silencing, indicating that CBP plays an important role in thrombin-induced EPCs neovascularization.

Meta-analysis: the Importance of a Proper Search Strategy

European Journal of Anaesthesiology. Jan, 2012  |  Pubmed ID: 22249154

Interaction of Transient Receptor Potential Vanilloid 4 with Annexin A2 and Tubulin Beta 5

Neuroscience Letters. Jan, 2012  |  Pubmed ID: 22309793

The aim of the present study was to investigate if there exists an interaction of TRPV4 with annexin A2 and with tubulin beta 5 in transfected human embryonic kidney (HEK293) cells in vitro. Coimmunoprecipitation of the rat dorsal root ganglion was performed to validly conform the interaction of TRPV4 with the other two proteins. Gene fragments coding for the amino acids in protein were obtained. We conducted coimmunoprecipitation and immunofluorescence on the transfected cell samples. Coimmunoprecipitation experiments of transfected HEK293 cells revealed that TRPV4 and tubulin beta 5 associated together in a complex, whereas TRPV4 and annexin A2 did not. The immunofluorescence microscopy revealed a colocalization of TRPV4 with both the tubulin beta 5 and annexin A2. These results indicate an interaction between TRPV4 and tubulin beta 5 by associating together. However, the association between TRPV4 and annexin A2 may be mediated by some intermediate elements or just exists in some physiological conditions. Thus, TRPV4 channel function may be modulated by tubulin beta 5 and annexin A2 and their interactions may play a role in the mechanosensation in the pathogenesis of neuropathic pain.

Naringin Ameliorates Metabolic Syndrome by Activating AMP-activated Protein Kinase in Mice Fed a High-fat Diet

Archives of Biochemistry and Biophysics. Feb, 2012  |  Pubmed ID: 22198281

Metabolic syndrome is a low-grade inflammatory state in which oxidative stress is involved. Naringin, isolated from the Citrussinensis, is a phenolic compound with anti-oxidative and anti-inflammatory activities. The aim of this study was to explore the effects of naringin on metabolic syndrome in mice. The animal models, induced by high-fat diet in C57BL/6 mice, developed obesity, dyslipidemia, fatty liver, liver dysfunction and insulin resistance. These changes were attenuated by naringin. Further investigations revealed that the inhibitory effect on inflammation and insulin resistance was mediated by blocking activation of the MAPKs pathways and by activating IRS1; the lipid-lowering effect was attributed to inhibiting the synthesis way and increasing fatty acid oxidation; the hypoglycemic effect was due to the regulation of PEPCK and G6pase. The anti-oxidative stress of naringin also participated in the improvement of insulin resistance and lipogenesis. All of these depended on the AMPK activation. To confirm the results of the animal experiment, we tested primary hepatocytes exposed to high glucose system. Naringin was protective by phosphorylating AMPKα and IRS1. Taken together, these results suggested that naringin protected mice exposed to a high-fat diet from metabolic syndrome through an AMPK-dependent mechanism involving multiple types of intracellular signaling and reduction of oxidative damage.

Cellular FLICE-inhibitory Protein Protects Against Cardiac Remodelling After Myocardial Infarction

Basic Research in Cardiology. Jan, 2012  |  Pubmed ID: 22202974

Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI.

Hydrogen-rich Saline Prevents Neointima Formation After Carotid Balloon Injury by Suppressing ROS and the TNF-α/NF-κB Pathway

Atherosclerosis. Feb, 2012  |  Pubmed ID: 22153150

Reactive oxygen species (ROS) play a pivotal role in neointima hyperplasia after balloon injury. Molecular hydrogen has emerged as a novel antioxidant and has been proven effective in treating many diseases.

Hypoxia Inducible Factor-1α is Involved in the Neurodegeneration Induced by Isoflurane in the Brain of Neonatal Rats

Journal of Neurochemistry. Feb, 2012  |  Pubmed ID: 22097881

More and more data show isoflurane, a commonly used volatile anesthetic has dual effects on neuron fate. However, the underlying mechanisms that can explain the apparent paradox are poorly understood. Hypoxia inducible factor (HIF)-1α, a transcription factor, has been found regulating both prosurvival and prodeath pathways in the CNS. Previously, we found that isoflurane can activate HIF-1α under normoxic conditions in vitro and HIF-1α has been found to be involved in the pre-conditioning effect of isoflurane in various organs. Here, we investigated whether HIF-1α is a contributing factor in the neurodegenration in rodent primary cultured neurons and in developing rat brain. Isoflurane dose-dependently induced apoptotic neurodegeneration in neonatal rats as assessed by S100β, cleaved caspase 3 and poly-(ADP-ribose) polymerase (PARP), respectively. Notably, isoflurane up-regulates HIF-1α protein levels in vivo and in vitro during induction of neurodegeneration. Likewise, isoflurane resulted in a significant elevation of cytosonic calcium levels in neuron cultures. Furthermore, knockdown of HIF-1α expression in cultured neurons attenuated isoflurane-induced neurotoxicity. Finally, Morris water maze (MWM) test showed neonatal exposure to isoflurane impaired juvenile learning and memory ability in rats. These findings indicate that HIF-1α is involved in the neurodegeneration induced by isoflurane in the brain of neonatal rats, suggesting HIF-1α may be a candidate for the dual effects of isoflurane on neuron fate.

Tumor Cell Cross Talk with Tumor-associated Leukocytes Leads to Induction of Tumor Exosomal Fibronectin and Promotes Tumor Progression

The American Journal of Pathology. Jan, 2012  |  Pubmed ID: 22067905

Exosomes participate in intercellular communication, but most data published are based on exosomes released from in vitro cultured cells that do not communicate with neighboring cells located in the same microenvironment as the exosomal-producing cells in vivo. In this study, our data show that co-culture of leukocytes isolated from breast tumor tissue leads to uptake of fibronectin (FN) on or in the tumor exosomes (Exo(fib+)). The induction of FN and exosomal uptake is tumor tissue derived and leukocyte specific, because leukocytes isolated from the peripheral blood of naïve mice failed to induce FN uptake by tumor exosomes. Furthermore, depletion of both CD25(+) cells and Gr-1(+) cells from tumor-associated leukocytes causes a reduction of Exo(fib+), suggesting that tumor-associated CD25(+) cells and Gr-1(+) cells participate in FN production and uptake by tumor exosomes, resulting in Exo(fib+). As a result of tumor cells absorbing Exo(fib+), two major events are induced: focal adhesion kinase/Src-dependent signaling pathways are activated, and the production of proinflammatory cytokines and metalloproteinase 9 is enhanced in response to absorbing exosomes. This, in turn, enhances tumor cell invasion in vitro and in vivo. Collectively, our findings provide evidence that exosomes released from freshly excised tumor tissue cells that have communicated/interacted with immune cells gain new immune evasion capacity.