Xiang M.,University of Pittsburgh |
Xiang M.,Fudan University |
Yuan Y.,University of Pittsburgh |
Fan L.,University of Pittsburgh |
And 10 more authors.
Shock | Year: 2012
The release of hematopoietic progenitor cells (HPCs) from bone marrow (BM) is under tight homeostatic control. Under stress conditions, HPCs migrate from BM and egress into circulation to participate in immune response, wound repair, or tissue regeneration. Hemorrhagic shock with resuscitation (HS/R), resulting from severe trauma and major surgery, promotes HPC mobilization from BM, which, in turn, affects post-HS immune responses. In this study, we investigated the mechanism of HS/R regulation of HPC mobilization from BM. Using a mouse HS/R model, we demonstrate that the endogenous alarmin molecule high-mobility group box 1 mediates HS/R-induced granulocyte colony-stimulating factor secretion from macrophages (M in a RAGE [receptor for advanced glycation end products] signaling-dependent manner. Secreted granulocyte colony-stimulating factor, in turn, induces HPC egress from BM. We also show that activation of β-adrenergic receptors on M by catecholamine mediates the HS/R-induced release of high-mobility group box 1. These data indicate that HS/R, a global ischemia-reperfusion stimulus, regulates HPC mobilization through a series of interacting pathways that include neuroendocrine and innate immune systems, in which M play a central role. © 2012 by the Shock Society.
Xie H.-H.,Shanghai University |
Xie H.-H.,University of Pittsburgh |
Zhou S.,Shanghai University |
Zhou S.,University of Pittsburgh |
And 7 more authors.
Hypertension | Year: 2010
Endothelial progenitor cells (EPCs) are both reduced and dysfunctional in hypertension that correlates inversely with its mortality, but the mechanisms are poorly understood. Endothelial nitric oxide synthase (eNOS) critically regulates EPC mobilization and function but is uncoupled in salt-sensitive hypertension because of the reduced cofactor tetrahydrobiopterin (BH4). We tested the hypothesis that GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme of BH4 de novo synthesis, protects EPCs and its function in deoxycorticosterone acetate (DOCA)-salt mice. EPCs were isolated from peripheral blood and bone marrow of wild-type (WT), WT DOCA-salt, endothelial-specific GTPCH transgenic (Tg-GCH), GTPCH transgenic DOCA-salt, and BH4-deficient hph-1 mice. In WT DOCA-salt and hph-1 mice, EPCs were significantly decreased with impaired angiogenesis and adhesion, which were restored in Tg-GCH DOCA-salt mice. Superoxide (O2) and nitric oxide (NO) levels in EPCs were elevated and reduced, respectively, in WT DOCA-salt and hph-1 mice; both were rescued in Tg-GCH DOCA-salt mice. eNOS-/-GCH+/- hybrid mice demonstrated that GTPCH preserved the circulating EPC number, reduced intracellular O2 in EPCs, and ameliorated EPC dysfunction independent of eNOS in DOCA-salt hypertension. Secreted thrombospondin-1 (TSP-1; a potent angiogenesis inhibitor) from EPCs was elevated in WT DOCA-salt and hph-1 but not DOCA-salt Tg-GCH mice. In vitro treatment with BH4, polyethylene glycol-superoxide dismutase (PEG-SOD), or Nomega-nitro-L-arginine (L-NNA) significantly augmented NO and reduced TSP-1 and O2 levels from EPCs of WT DOCA-salt mice. These results demonstrated, for the first time, that the GTPCH/BH4 pathway critically regulates EPC number and function in DOCA-salt hypertensive mice, at least in part, via suppressing TSP-1 expression and oxidative stress. © 2010 American Heart Association, Inc.
PubMed | Sun Yat Sen University, Surgical Research, Shanghai JiaoTong University, University of California at Davis and University of Pittsburgh
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2015
Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2(-/-) mice. EST is a direct transcriptional target of Nrf2. In female mice, the I/R-responsive induction of EST compromised estrogen activity. EST ablation attenuated I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific because the EST(-/-) males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R-responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST(-/-) mice was associated with increased Nrf2 accumulation. Our results suggested a novel I/R-responsive feedback mechanism to limit the activity of Nrf2 in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen-responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury.
PubMed | Sun Yat Sen University, China Pharmaceutical University, Surgical Research, Zhejiang University and 3 more.
Type: | Journal: Nature communications | Year: 2015
Sepsis is the hosts deleterious systemic inflammatory response to microbial infections. Here we report an essential role for the oestrogen sulfotransferase (EST or SULT1E1), a conjugating enzyme that sulfonates and deactivates estrogens, in sepsis response. Both the caecal ligation and puncture (CLP) and lipopolysaccharide models of sepsis induce the expression of EST and compromise the activity of oestrogen, an anti-inflammatory hormone. Surprisingly, EST ablation sensitizes mice to sepsis-induced death. Mechanistically, EST ablation attenuates sepsis-induced inflammatory responses due to compromised oestrogen deactivation, leading to increased sepsis lethality. In contrast, transgenic overexpression of EST promotes oestrogen deactivation and sensitizes mice to CLP-induced inflammatory response. The induction of EST by sepsis is NF-B dependent and EST is a NF-B-target gene. The reciprocal regulation of inflammation and EST may represent a yet-to-be-explored mechanism of endocrine regulation of inflammation, which has an impact on the clinical outcome of sepsis.
News Article | December 10, 2015
A team of UCLA researchers found that there are several parts of California where, in a high percentage of people with thyroid cancer, the disease is already at an advanced stage by the time it is diagnosed. The research was led by Dr. Avital Harari, a member of the UCLA Jonsson Comprehensive Cancer Center and assistant professor of surgery. Approximately 63,000 people were diagnosed with thyroid cancer nationwide last year, and according to the National Cancer Institute, the incidence of thyroid cancer has increased across racial, ethnic and gender lines over the past several decades. When detected early, thyroid cancer is treatable and even curable. However, survival rates are much lower for people who are diagnosed at advanced stages of the disease. The UCLA scientists examined county-by-county data from the California Cancer Registry for 27,000 people who had been diagnosed with thyroid cancer from 1999 to 2008. To ensure that they were comparing similar population sizes, the researchers grouped together some smaller counties for the analysis. Nationally, about 29 percent of people with thyroid cancer have advanced-stage disease by the time it is diagnosed, according to data from the NCI’s surveillance, epidemiology, and end results program, also known as SEER. Of the 47 geographical areas the UCLA researchers analyzed, 20 had significantly higher percentages than that, ranging from 33 percent (Orange County) to 51 percent (for the combination of Alpine, Amador and Calaveras counties). Overall, in 35 percent of Californians with thyroid cancer — 6 percentage points higher than the national average — the disease has reached the regional and/or distant metastatic stage, meaning that it has spread beyond the thyroid to other tissues in the neck, regional lymph nodes or other parts of the body, by the time it is diagnosed. According to the UCLA findings, the California counties (or combined county groups) where people were most likely to have advanced thyroid cancer at the time of diagnosis were: Alpine, Amador and Calaveras (combined): Disease was advanced in 51 percent of those with thyroid cancer Imperial: 48 percent Sutter: 45 percent San Francisco: 41 percent Santa Barbara: 40 percent Southern California counties outside of the top five were San Bernardino, which ranked 12th (37 percent of people with thyroid cancer had advanced-stage disease), San Diego (13th, 36 percent), Los Angeles (14th, 35 percent), Fresno (17th, 34 percent), Ventura (18th, 34 percent) and Orange (20th, 33 percent). The counties with the highest percentages of people with advanced cancer were not grouped together in any obvious geographic pattern, meaning that none of the larger regions within the state seem to have a higher risk for the disease than any other. Harari said it is not clear why the incidence of advanced-stage thyroid cancer is that much higher in California than the national average, but her research suggests there might be an environmental component. “California has the largest amount of farmland in the country, so this type of exposure could very well contribute to our thyroid cancer rates,” she said. However, the only known environmental risk factor for thyroid cancer is radiation exposure, and that alone is unlikely to fully explain the phenomenon. The next stage of Harari’s research will evaluate possible links between thyroid cancer and exposure to pesticides and radon. The study was published online by the Journal of Surgical Research.
News Article | December 7, 2016
A new study published in the just-published "Oncotarget" peer-reviewed medical journal has concluded that “in the setting of previously treated, advanced pancreatic cancer, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test.” The study was conducted by a team of researchers and clinicians from Perthera, Inc., a precision medicine company based in McLean, VA, the Pancreatic Cancer Action Network (PanCAN), Lombardi Comprehensive Cancer Center of Georgetown University, Cedars-Sinai Medical Center, Ohio State University, City of Hope Cancer Center, Virginia Mason Medical Center, and the Sidney Kimmel Cancer Center at Thomas Jefferson University. The study is entitled "a pilot study evaluating concordance between blood-based and patient-matched tumor molecular testing within pancreatic patients participating in the Know Your Tumor (KYT) Initiative." Know Your Tumor is a benchmark precision cancer therapy program of the Pancreatic Cancer Action Network that is executed by Perthera. The study asserted that “molecular profiling of the tumor itself should remain the gold standard,” or as approved by the FDA. Liquid biopsies can "go wrong" in a variety of ways: mainly because the tumor isn't dumping DNA into the blood, or because the detection assays aren't sensitive enough to detect the DNA when it is too low in abundance to see. The investigators assessed the ability of the circulating genomic information obtained from a blood sample of 34 consecutively screened pancreatic cancer patients with metastatic disease to accurately recapitulate the genomic information obtained by direct analysis of a tumor biopsy obtained from the same patient taken at the same time. They used the high frequency of KRAS mutation (~90%) in pancreatic cancer as a benchmark for comparison, and they found that KRAS mutations “were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies." Dr. Jonathan Brody, the last author on the study and Director of Surgical Research and Co-director of the Jefferson Pancreas, Biliary and Related Cancer Center and on the scientific advisory board at Perthera, cautioned that "the results of this study should give people some pause; we need to be very careful about the state of the liquid biopsy field right now." He said, "we need to be very circumspect- in this study, we detected DNA with KRAS mutations in only a third of the patients that you should see the genomic alteration, so what does it say about being able to reliably detect actionable alterations that doctors would use to make critical treatment decisions?” Dr. Michael Pishvaian, the first author of the study and Perthera’s CMO as well as the Director of the Phase I Clinical Program and Co-Director of the Ruesch Center Pancreatic Cancer Program at Georgetown University added that “there will be times when a tumor biopsy is unable to be performed due to medical issues, and then could a liquid biopsy be considered. Pishvaian says: “There are papers that show good but not perfect concordance between the genomic information in tumor samples and blood samples, and our study in pancreatic cancer reveals something different. Some of the disparate results from these studies come from differences in the clinical aspects of the patients studied, but ultimately if liquid biopsies are to be used routinely for precision medicine applications then the field needs more improvements.” In the meantime, Emanuel “Chip” Petricoin, PhD, Perthera’s Chief Science Officer said, “Central to Perthera’s medical philosophy is that the patient should have as extensive molecular profiling as relevant, and blood-based testing will be great to add to our arsenal of testing options as it becomes more reliable and sensitive. So, we are committed to implementing molecular profiling technologies that have the best evidence of impact to patients' precision cancer therapy outcome and we will be constantly monitoring the state of the field on this topic. As the liquid biopsy technologies and approaches improve and become more sensitive, then we can validate them and implement them." ABOUT PERTHERA, INC.: Perthera is a founder- and venture-backed precision medicine company based in McLean, VA, that has achieved more than 1,000 case histories since it was founded about five years ago, often working in an alliance with cancer advocacy agencies as well as hospitals, community oncology practices, and academia. In every patient instance, the Company seeks to become the precision medicine partner on their cancer care team, providing the widest, deepest, and most independent range of service possible.
News Article | February 15, 2017
MONTREAL, QUEBEC--(Marketwired - Feb. 10, 2017) - Relevium Technologies Inc. (TSX VENTURE:RLV)(FRANKFURT:6BX) (the "Company" or "Relevium") a consolidator of e-commerce assets in Health and Wellness in conjunction with its board of directors, is pleased to announce the addition of Dr. Tina Sampalis to the Company's Board of Directors. Tina Sampalis, M.D., Ph.D., is an oncology surgeon trained in physiology at McGill University in Montreal, medicine at the University of Patras (Greece), dermatology at Göttingen University (Germany) and Marselisborg University (Denmark), pediatric, general and oncology surgery at the University of Athens (Greece), graduate training (Ph.D.) in Surgical Research at the University of Athens and a second Ph.D. in Epidemiology and Experimental Surgery at McGill University. Dr. Sampalis' leading work in Nutraceuticals includes Neptune Technologies & Bioressources, where she discovered one of the primary reasons krill oil is so beneficial to human health: Phospholipids. Dr. Sampalis is the named inventor of Neptune's composition and application patents. As the former President of Acasti Pharma Inc. she led the development of a novel patented active pharmaceutical ingredient targeting the prevention and treatment of hypertriglyceridemia and cardio metabolic-disorders. She is the Founder and President of the AGOO Children's Health & Wellness Center, a state-of-the-art multidisciplinary comprehensive, pediatric-adolescent medical center and accredited McGill University teaching site in Quebec. Dr. Sampalis has received several international scholarships and awards for her work on the clinical implementation of retinols for skin and breast cancer, including the Helen Hutchison Award for geriatric medicine. Her work on scintimammography resulted in her appointment at the International Educational Speakers Bureau, the Canadian and U.S. Faculty of Medical Speakers for Breast Imaging. As an international scholar, Dr. Sampalis leads the development and implementation of innovative micro-invasive and stereotactic robotic surgical techniques for breast cancer, for which a U.S. and Canadian patent application has been filed. She is a member of the American Association of Naturopathic Medicine. Dr. Sampalis has published papers in multiple peer-reviewed publications. She was named one of the 10 most successful women in Quebec (Les Affaires, 18-24 September 2010) and one of the 100 most successful globally by the Princeton Global Network. Relevium Technologies Inc. (TSX.V - "RLV") President and CEO, Aurelio Useche, stated, "We are very honored to have Dr. Sampalis join our Company. The addition of Dr. Sampalis closes the value chain by providing deep expertise in scientific and evidence based nutraceutical and medical trends, which can be leveraged through the consolidation of e-commerce assets such as BioGanix as announced on December 22, 2016." Relevium is a TSX Venture listed issuer focused on growth through the acquisition of businesses, products and/or technologies with a focus on e-commerce in the growing health and wellness sector, specifically under three important verticals: Pain Relief, Recovery and Performance. Relevium Technologies Inc. currently holds patented intellectual property for application of static magnetic fields on direct-to-consumer devices, which aid in decreasing pain, improving recovery time and enhancing overall physical performance. BioGanix (http://www.bioganix.com/) was founded with customer results in mind, to provide the best quality, best researched, and most potent formulas at competitive prices, while providing excellent and personal customer care. BioGanix puts our customers first, and do everything we can to keep them happy. BioGanix prides itself on using only the best and purest ingredients in our manufacturing processes. BioGanix only provides premium quality products, and doesn't cut any corners in manufacturing processes. All BioGanix products have been 3rd Party Laboratory tested and verified, and are manufactured in GMP Certified and FDA inspected facilities in the USA. BioGanix currently has over 16 of the best-selling dietary supplement products available, varying from trending weight loss products, to proven health supporting supplements that supports various processes in the body, including digestive health, heart health, brain health, blood sugar, as well as anti-aging supplements. Neither TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release. This release includes certain statements and information that may constitute forward-looking information within the meaning of applicable Canadian securities laws or forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. All statements in this news release, other than statements of historical facts, including statements regarding future estimates, plans, objectives, assumptions or expectations of future performance, including the timing and completion of the proposed acquisitions, are forward-looking statements and contain forward-looking information. Generally, forward-looking statements and information can be identified by the use of forward-looking terminology such as "intends" or "anticipates", or variations of such words and phrases or statements that certain actions, events or results "may", "could", "should", "would" or "occur". Forward-looking statements are based on certain material assumptions and analysis made by the Company and the opinions and estimates of management as of the date of this press release, including the assumptions that the Company will obtain stock exchange approval of the Offering, the proposed acquisition will occur as anticipated, that the Company will raise sufficient funds, and that the Company will obtain all requisite approvals of the acquisition. These forward-looking statements are subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of the Company to be materially different from those expressed or implied by such forward-looking statements or forward-looking information. Important factors that may cause actual results to vary, include, without limitation, the risk that the proposed acquisitions may not occur as planned; the timing and receipt of requisite approvals and failure to raise sufficient funds under the Offering. Although management of the Company has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking statements or forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. There can be no assurance that such statements will prove to be accurate, as actual results and future events could differ materially from those anticipated in such statements. Accordingly, readers should not place undue reliance on forward-looking statements and forward-looking information. Readers are cautioned that reliance on such information may not be appropriate for other purposes. The Company does not undertake to update any forward-looking statement, forward- looking information or financial outlook that are incorporated by reference herein, except in accordance with applicable securities laws. We seek safe harbor. On Behalf of the Board of Directors
Dehne N.,Goethe University Frankfurt |
Kerkweg U.,Institute of Physiological Chemistry |
Flohe S.B.,Surgical Research |
Brune B.,Goethe University Frankfurt |
Fandrey J.,University of Duisburg - Essen
Shock | Year: 2011
Skeletal muscle damage provokes complex repair mechanisms including recruitment of leukocytes as well as activation of myogenic precursor cells such as satellite cells. To study muscle cell repair mechanisms after muscle fiber damage, we used an in vitro model of scrape-injured myotubes. Exposing vital C2C12 myoblasts and myotubes to cell debris of damaged myotubes revealed mRNA upregulation of adrenomedullin (ADM), insulin-like growth factors 1 and 2, metallopeptidase 9, and monocyte chemoattractant protein11. When cell debris was treated with ultrasound, frozen in liquid nitrogen, or heat inactivated before addition to C2C12 cells, gene expression was drastically reduced or completely absent. Moreover, incubations of myoblasts with debris separated by transwell inserts indicated that direct cell contact is required for gene induction. Incubation with albumin and PolyIC ruled out that ADM induction by cell debris simply results from increased protein or nucleic acid concentrations in the supernatant. Because the genes, which were upregulated by cell debris, are potential target genes of hypoxia-inducible factor (HIF), cells were analyzed for HIF-1α expression. Western blot analysis showed accumulation of the α-subunit upon contact to cell debris. Knockdown of HIF-1α in C2C12 cells proved that activation of HIF-1 in response to cell debris was responsible for upregulating ADM and monocyte chemoattractant protein 1. Furthermore, by incubating cells on gas-permeable culture dishes, we excluded a reduced pericellular pO2 induced by cell debris as the cause for ADM upregulation. Our data suggest that damaged myofibers activate HIF-1 in neighboring myotubes and precursor myoblasts by direct contact, concomitantly upregulating factors necessary for angiogenesis, tissue regeneration, and phagocyte recruitment. Copyright © 2011 by the Shock Society.
Pivotal advance: The pattern recognition receptor ligands lipopolysaccharide and polyinosine-polycytidylic acid stimulate factor B synthesis by the macrophage through distinct but overlapping mechanisms
Kaczorowski D.J.,University of Pittsburgh |
Afrazi A.,University of Pittsburgh |
Scott M.J.,University of Pittsburgh |
Kwak J.H.,University of Pittsburgh |
And 7 more authors.
Journal of Leukocyte Biology | Year: 2010
TLRs and complement are critical to the host response in sepsis, trauma, and ischemia/reperfusion. We hypothesize that TLR stimulation leads to synthesis and release of complement components by macrophages, an important source of extrahepatic complement. RAW264.7 macrophages or peritoneal macrophages from WT and TLR4-, TLR3-, TRIF-, or MyD88-deficient mice were cultured under standard conditions. In some experiments, cells were pretreated with inhibitors of MAPKs or a NF-κB inhibitor. Cells were stimulated with TLR ligands at known stimulatory concentrations. Intratracheal and i.p. injections were also performed in mice. RT-PCR, Western blotting, and immunocytochemistry were used for analysis. Using a RT-PCR-based panel, we demonstrate that of 18 complement components tested, factor B of the alternative pathway is the most robustly up-regulated complement component in macrophages in response to LPS. This up-regulation results in release of factor B into the media. Up-regulation of factor B by LPS is dependent on TLR4, TRIF, JNK, and NF-κB. A screen of other TLR ligands demonstrated that stimulation with poly I:C (dsRNA analog) also results in up-regulation of factor B, which is dependent on JNK and NF-κB but independent of TLR3 and TRIF. Up-regulation of factor B is also observed after intratracheal and i.p. injection of LPS or poly I:C in vivo. PRR stimulation profoundly influences production and release of factor B by macrophages. Understanding the mechanisms of PRR-mediated complement production may lead to strategies aimed at preventing tissue damage in diverse settings, including sepsis, trauma, and ischemia/reperfusion. © Society for Leukocyte Biology.
Sun Q.,University of Pittsburgh |
Gao W.,University of Pittsburgh |
Loughran P.,University of Pittsburgh |
Shapiro R.,University of Pittsburgh |
And 4 more authors.
Journal of Biological Chemistry | Year: 2013
Caspase 1 activation can be induced by oxidative stress, which leads to the release of the proinflammatory cytokines IL1β and IL18 in myeloid cells and a potentially damaging inflammatory response. However, little is known about the role of caspase 1 in non-immune cells, such as hepatocytes, that express and activate the inflammasome but do not produce a significant amount of IL1β/IL18. Here we demonstrate that caspase 1 activation protects against cell death after redox stress induced by hypoxia/reoxygenation in hepatocytes. Mechanistically, we show that caspase 1 reduces mitochondrial respiration and reactive oxygen species by increasing mitochondrial autophagy and subsequent clearance of mitochondria in hepatocytes after hypoxia/reoxygenation. Caspase 1 increases autophagic flux through up-regulating autophagy initiator beclin 1 during redox stress and is an important cell survival factor in hepatocytes. We find that during hemorrhagic shock with resuscitation, an in vivo mouse model associated with severe hepatic redox stress, caspase 1 activation is also protective against liver injury and excessive oxidative stress through the up-regulation of beclin 1. Our findings suggest an alternative role for caspase 1 activation in promoting adaptive responses to oxidative stress and, more specifically, in limiting reactive oxygen species production and damage in cells and tissues where IL1β/IL18 are not highly expressed. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.