PubMed | Center for Translational Research on Inflammatory Diseases and Baylor College of Medicine
Type: Journal Article | Journal: Cardiovascular endocrinology | Year: 2015
Non-alcoholic fatty liver disease (NAFLD) is a condition where there is excess accumulation of triglycerides in the liver in the absence of excess alcohol consumption. It ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD, one of the most common causes of chronic liver disease in Western populations, is the hepatic component of the metabolic syndrome (MetS) and is associated with increased visceral adipose tissue (VAT), insulin resistance, and dyslipidemia. Studies have also shown that testosterone deficiency is associated with increased VAT and insulin resistance in males while hyperandrogenemia has been associated with increased risk of insulin resistance and VAT in females. Thus, the aims of this review are to discuss the available experimental and epidemiological data evaluating the association between testosterone and NAFLD, to discuss the potential clinical relevance of these data, and to identify gaps in the literature.
Da Q.,Baylor College of Medicine |
Da Q.,Center for Translational Research on Inflammatory Diseases |
Teruya M.,Baylor College of Medicine |
Guchhait P.,Regional Center for Biotechnology |
And 4 more authors.
Blood | Year: 2015
Intravascular hemolysis occurs in patients on extracorporeal membrane oxygenation. High levels of free acellular adult hemoglobin (free HbA) are associated with clotting in this mechanical device that can result in thrombotic complications. Adsorption of fibrinogen onto the surface of biomaterial correlates with platelet adhesion, which is mediated by von Willebrand factor (VWF). Because free Hb interacts with VWF, we studied the effect of hemoglobin (Hb) on platelet adhesion to fibrin(ogen) under conditions of different hydrodynamic forces. This effect was investigated using purified human HbA and fibrinogen, extracellular matrix, collagen, or purified plasma VWF as surface-coated substrates to examine flow-dependent platelet adhesion. Antibodies and VWF-deficient plasma were also used. Free Hb(≥50 mg/dL) effectively augmented platelet adhesion, and microthrombi formation on fibrin(ogen), extracellular matrix, and collagen at high shear stress. The effect of free Hb was effectively blocked by anti-glycoprotein Iba (GPIbα) antibodies or depletion of VWF. Unexpectedly, free Hb also promoted firm platelet adhesion and stable microthrombi on VWF. Lastly, we determined that Hb interacts directly with the A1 domain. This study is the first to demonstrate that extracellular Hb directly affects the GPIbα-VWF interaction in thrombosis, and describes another mechanism by which hemolysis is connected to thrombotic events. Copyright 2011 by The American Society of Hematology; all rights reserved.
News Article | February 9, 2017
Studies abound that point to a role for plain old aspirin in keeping deadly cancers at bay. While aspirin is not yet part of mainstream treatment for any cancer, it is recommended by the U.S. Preventive Services Task Force for certain adults to help prevent colorectal cancer. But researchers have puzzled over how exactly the "wonder drug" works to ward off cancer. Most think it has to do with the drug's inflammation-lowering effects. Now Veterans Affairs (VA) scientists and colleagues in Texas have a new theory, tested successfully in mice and cell cultures. It has to do with aspirin's effects on platelets--blood cells that form clots to stop bleeding. The findings appear in the February 2017 issue of Cancer Prevention Research. Along with clotting, platelets also play a role in forming new blood vessels. That action is normally beneficial, such as when a new clot forms after a wound, and new vessels are needed to redirect blood flow. But the same action can help tumors grow. It's this process that aspirin can interrupt, say the researchers. Their lab tests showed how aspirin blocked the interaction between platelets and cancer cells by shutting down the enzyme COX-1, thereby curbing the number of circulating platelets and their level of activity. Some of the experiments used regular aspirin from a local drug store. In another phase, the researchers used a special preparation of aspirin combined with phosphatidylcholine, a type of lipid, or fat molecule. The molecule is a main ingredient in soy lecithin. The product, known as Aspirin-PC/PL2200, now in development by Houston-based PLx Pharma, Inc., is designed to ease the gastrointestinal risk associated with standard aspirin. The enhanced aspirin complex was even stronger against cancer than the regular aspirin. Summarizing their findings, the researchers wrote: "These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic [supporting new, abnormal growth, as in cancer] action of platelets and [they support] the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers." Dr. Lenard Lichtenberger, who led the research, has a financial stake in PLx Pharma, the company developing the new lipid-based aspirin under the brand name Aspertec. None of the other authors reported potential conflicts of interest. Lichtenberger is a professor of integrative biology and pharmacology at the University of Texas Health Sciences Center. The VA leader in the group was Dr. Vinod Vijayan, a research health scientist at the DeBakey VAMC and an expert in platelet biology. He is with the site's Center for Translational Research on Inflammatory Diseases. Vijayan is also an associate professor at Baylor College of Medicine. The group says they plan to test the lipid-aspirin complex for safety and efficacy in people at high risk for colorectal cancer in a collaboration with researchers at MD Anderson Cancer Center in Houston. Meanwhile, they say their results so far "support the use of low-dose aspirin for chemoprevention." They add that Aspirin-PC/PL2200 has "similar chemopreventive actions to low-dose aspirin and may be more effective."
Sever S.,Baylor College of Medicine |
White D.L.,Baylor College of Medicine |
White D.L.,Section of Health Services Research IQuESt |
White D.L.,Center for Translational Research on Inflammatory Diseases |
And 3 more authors.
Endocrine-Related Cancer | Year: 2016
Ghrelin is a hormone with multiple physiologic functions, including promotion of growth hormone release, stimulation of appetite and regulation of energy homeostasis. Treatment with ghrelin/ghrelin-receptor agonists is a prospective therapy for diseaserelated cachexia and malnutrition. In vitro studies have shown high expression of ghrelin in cancer tissue, although its role including its impact in cancer risk and progression has not been established. We performed a systematic literature review to identify peer-reviewed human or animal in vivo original research studies of ghrelin, ghrelinreceptor agonists, or ghrelin genetic variants and the risk, presence, or growth of cancer using structured searches in PubMed database as well as secondary searches of article reference lists, additional reviews and meta-analyses. Overall, 45 (73.8%) of the 61 studies reviewed, including all 11 involving exogenous ghrelin/ghrelin-receptor agonist treatment, reported either a null (no statistically significant difference) or inverse association of ghrelin/ghrelin-receptor agonists or ghrelin genetic variants with cancer risk, presence or growth; 10 (16.7%) studies reported positive associations; and 6 (10.0%) reported both negative or null and positive associations. Differences in serum ghrelin levels in cancer cases vs controls (typically lower) were reported for some but not all cancers. The majority of in vivo studies showed a null or inverse association of ghrelin with risk and progression of most cancers, suggesting that ghrelin/ghrelin-receptor agonist treatment may have a favorable safety profile to use for cancer cachexia. Additional large-scale prospective clinical trials as well as basic bioscientific research are warranted to further evaluate the safety and benefits of ghrelin treatment in patients with cancer. © 2016 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain.
Lerner L.,AVEO Pharmaceuticals |
Hayes T.G.,Center for Translational Research on Inflammatory Diseases |
Hayes T.G.,Baylor College of Medicine |
Tao N.,AVEO Pharmaceuticals |
And 8 more authors.
Journal of Cachexia, Sarcopenia and Muscle | Year: 2015
Background Cancer-related weight loss is associated with increased inflammation and decreased survival. The novel inflammatory mediator growth differentiation factor (GDF)15 is associated with poor prognosis in cancer but its role in cancer-related weight loss (C-WL) remains unclear. Our objective was to measure GDF15 in plasma samples of cancer subjects and controls and establish its association with other inflammatory markers and clinical outcomes. Methods We measured body weight, appetite, plasma GDF15, and other inflammatory markers in men with cancer-related weight loss (C-WL, n = 58), weight stable patients with cancer (C-WS, n = 72), and non-cancer controls (Co, n = 59) matched by age and pre-illness body mass index. In a subset of patients we also measured handgrip strength, appendicular lean body mass (aLBM), Eastern Cooperative Oncology Group (ECOG), and Karnofsky performance scores. Results GDF15, interleukin (IL)-6 and IL-8 were increased in C-WL versus other groups. IL-1 receptor antagonist, IL-4, interferon–gamma, tumour necrosis factor alpha, and vascular endothelial growth factor A were increased in C-WL versus C-WS, and Activin A was significantly downregulated in Co versus other groups. C-WL patients had lower handgrip strength, aLBM, and fat mass, and Eastern Cooperative Oncology Group and Karnofsky performance scores were lower in both cancer groups. GDF15, IL-6, and IL-8 significantly correlated with weight loss; GDF15 negatively correlated with aLBM, handgrip strength, and fat mass. IL-8 and Activin A negatively correlated with aLBM and fat mass. GDF15 and IL-8 predicted survival adjusting for stage and weight change (Cox regression P<0.001 for both). Conclusion GDF15 and other inflammatory markers are associated with weight loss, decreased aLBM and strength, and poor survival in patients with cancer. GDF15 may serve as a prognostic indicator in cancer patients and is being evaluated as a potential therapeutic target for cancer-related weight loss. © 2015 The Authors.
PubMed | Center for Translational Research on Inflammatory Diseases, Michael bakey Va Medical Center and Baylor College of Medicine
Type: Journal Article | Journal: Thrombosis research | Year: 2015
Disseminated fibrin deposition in the microvasculature such as in disseminated intravascular coagulation (DIC) arises from uninhibited activated coagulation secondary to sustained systemic inflammation. Currently there is no treatment for DIC. Treating the underlying trigger and supportive care are the current recommendations to manage DIC. This study aims at using recombinant von Willebrand factor (VWF) A2 domain polypeptide to inhibit VWF-mediated platelet adhesion to fibrin and prevent DIC.We use flow chamber assay to test the capacity of purified A2 protein to inhibit platelet adhesion to immobilized fibrin(ogen) and platelet-fibrin clot formation. We use a murine model of lipopolysaccharide-induced DIC to examine the effect of A2 protein on DIC.The A2 protein blocked flow-dependent platelet adhesion to fibrin, delayed fibrin polymerization, and inhibited platelet-fibrin clot formation in vitro. The infusion of the purified A2 protein to the endotoxin-treated mice prevented fibrin-rich microthrombi formation in brain, lung, kidney, and liver. It also attenuated levels of inflammatory mediators, and markedly reduced mortality rates at 96hours.The A2 protein inhibited platelet interaction with fibrin(ogen). Furthermore, A2 prevented disseminated fibrin-rich microthrombi and decrease mortality in a lipopolysaccharide-induced DIC murine model. A2 could provide a novel therapeutic approach in critically ill patients with uninhibited activated coagulation and disseminated fibrin deposition such as DIC.
Chen C.J.,Baylor College of Medicine |
Lu J.-M.,Baylor College of Medicine |
Yao Q.,Baylor College of Medicine |
Yao Q.,Center for Translational Research on Inflammatory Diseases
Medical Science Monitor | Year: 2016
Uric acid is the final oxidation product of purine metabolism in humans. Xanthine oxidoreductase (XOR) catalyzes oxidative hydroxylation of hypoxanthine to xanthine to uric acid, accompanying the production of reactive oxygen species (ROS). Uric acid usually forms ions and salts known as urates and acid urates in serum. Clinically, overproduction or under-excretion of uric acid results in the elevated level of serum uric acid (SUA), termed hyperuricemia, which has long been established as the major etiologic factor in gout. Accordingly, urate-lowering drugs such as allopurinol, an XOR-inhibitor, are extensively used for the treatment of gout. In recent years, the prevalence of hyperuricemia has significantly increased and more clinical investigations have confirmed that hyperuricemia is an independent risk factor for cardiovascular disease, hypertension, diabetes, and many other diseases. Urate-lowering therapy may also play a critical role in the management of these diseases. However, current XOR-inhibitor drugs such as allopurinol and febuxostat may have significant adverse effects. Therefore, there has been great effort to develop new XOR-inhibitor drugs with less or no toxicity for the long-term treatment or prevention of these hyperuricemia-related diseases. In this review, we discuss the mechanism of uric acid homeostasis and alterations, updated prevalence, therapeutic outcomes, and molecular pathophysiology of hyperuricemia-related diseases. We also summarize current discoveries in the development of new XOR inhibitors. © Med Sci Monit.
Lam F.W.,Center for Translational Research on Inflammatory Diseases |
Lam F.W.,Baylor College of Medicine |
Vijayan K.V.,Center for Translational Research on Inflammatory Diseases |
Vijayan K.V.,Baylor College of Medicine |
And 2 more authors.
Comprehensive Physiology | Year: 2015
Platelets are anucleate blood cells, long known to be critically involved in hemostasis and thrombosis. In addition to their role in blood clots, increasing evidence reveals significant roles for platelets in inflammation and immunity. However, the notion that platelets represent immune cells is not broadly recognized in the field of Physiology. This article reviews the role of platelets in inflammation and immune responses, and highlights their interactions with other immune cells, including examples of major functional consequences of these interactions. © 2015 American Physiological Society.
Lam F.W.,Baylor College of Medicine |
Cruz M.A.,Baylor College of Medicine |
Leung H.-C.E.,Baylor College of Medicine |
Parikh K.S.,Baylor College of Medicine |
And 3 more authors.
Thrombosis Research | Year: 2013
Introduction Histones are small, nuclear proteins that serve to package DNA. Recent reports suggest that extracellular histones, including histone H4, may contribute to the pathogenesis of sepsis; they promote platelet aggregation and thrombosis when released into the circulation during inflammation or cell death. The mechanisms by which the body minimizes the deleterious effects of circulating histones are unclear. Because histones can bind to plasma proteins, including albumin, we hypothesized that normal albumin can prevent histones from activating platelets. Materials and Methods Platelets and platelet-free plasma were obtained from healthy, adult subjects. The dose-dependent effects of histone H4 on platelet aggregation were studied by optical aggregometry. The effects of native and albumin-depleted plasma (prepared by affinity chromatography) on histone-induced platelet aggregation were also assessed. The effects of normal and surface-neutralized albumin (through modification of carboxyl groups) on histone-induced platelet activation and aggregation were evaluated using flow cytometry and aggregometry. Results Histone H4 induced platelet aggregation in a dose-dependent manner. This histone-induced platelet aggregation was inhibited by both plasma and human serum albumin in a dose-dependent fashion. Furthermore, depletion of albumin from plasma reduced its ability to inhibit aggregation. Finally, surface neutralization of albumin decreased its ability to inhibit histone-induced activation and aggregation. Discussion These data suggest that normal albumin serves a role in preventing histone-induced platelet aggregation in a charge-dependent manner. © 2013 Elsevier Ltd. All rights reserved.
Agrawal V.,Center for Translational Research on Inflammatory Diseases |
Garcia J.M.,Center for Translational Research on Inflammatory Diseases |
Garcia J.M.,Baylor College of Medicine
Expert Review of Molecular Diagnostics | Year: 2014
Adult growth hormone deficiency (AGHD) causes a reduction in lean body mass, bone mineral density, exercise tolerance and overall quality of life and treatment with growth hormone (GH) improves some of these outcomes. Because symptoms are non-specific and random GH levels are not useful in establishing its diagnosis, provocative tests are often necessary. The insulin tolerance test is the 'gold standard' test for diagnosis of AGHD but it is often cumbersome to perform and is contraindicated in certain patients due to the risk of hypoglycemia. Administration of the orally available ghrelin mimetic and GH secretagogue macimorelin increases GH levels acutely via the ghrelin receptor GHSR1-a and it has been shown to have good sensitivity and specificity for diagnosing AGHD. Here we review the evidence of the potential use of macimorelin for this indication. © 2014 Informa UK, Ltd.