Publications by authors named "Garret A FitzGerald"

238 Publications

Aspirin in hepatocellular carcinoma.

Cancer Res 2021 Apr 23. Epub 2021 Apr 23.

Medicine, University of Pennsylvania

Pre-clinical and clinical studies provide evidence for aspirin as a preventative agent for cancer. Compelling direct evidence supports a chemopreventive effect of aspirin in individuals at high risk of developing colorectal cancer (CRC) due to Lynch syndrome, while indirect evidence indicates that aspirin may reduce the risk of and mortality from sporadic CRC. There is weaker evidence for a protective effect of aspirin against all cancers taken as a group. Nevertheless, the results of recent retrospective cohort studies consistently indicate a beneficial effect of aspirin as a chemopreventive or adjuvant chemotherapeutic agent in hepatocellular carcinoma (HCC). Epidemiological studies conducted in the general population or in selected populations at higher risk for HCC reveal that regular aspirin use is associated with reduced HCC incidence. In addition, aspirin may act as an adjuvant to other therapies in reducing HCC recurrence. According to studies in animal models, the cancer-preventative effect of aspirin may be related to its antiplatelet and anti-inflammatory activities. Prospective studies are warranted to determine whether aspirin should be recommended to diverse populations of patients at risk for HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-21-0758DOI Listing
April 2021

Nanotherapeutic-Directed Approaches to Analgesia.

Trends Pharmacol Sci 2021 Apr 19. Epub 2021 Apr 19.

Center for Targeted Therapeutics and Translational Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

The ongoing opioid crisis highlighted the need for non-steroidal anti-inflammatory drugs (NSAIDs), nonaddictive analgesics against pain, fever, and inflammation. However, NSAIDs may cause gastrointestinal and cardiovascular adverse effects. To avoid systemic toxicity and deliver drugs to diseased tissues, nanotechnology methods of NSAID encapsulation have been reported and some have reached clinical development. Currently, 57 micro- and nanodrugs are approved by the US FDA. Already approved nanoanalgesics have revealed superior efficacy or reduced toxicity compared with placebo or lower doses of systemically administered active comparators. In this review, the evidence for approval of the marketed nanodrugs will be discussed, with a focus on therapies for pain and inflammation. Nanomedicine remains an attractive field for the development of targeted analgesics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tips.2021.03.007DOI Listing
April 2021

Impact of Time-Restricted Feeding to Late Night on Adaptation to a 6 h Phase Advance of the Light-Dark Cycle in Mice.

Front Physiol 2021 16;12:634187. Epub 2021 Feb 16.

School of Bioengineering, Dalian University of Technology, Dalian, China.

In modern society, more and more people suffer from circadian disruption, which in turn affects health. But until now, there are no widely accepted therapies for circadian disorders. Rhythmic feeding behavior is one of the most potent non-photic zeitgebers, thus it has been suggested that it was important to eat during specific periods of time (time-restricted feeding, TRF) so that feeding is aligned with environmental cues under normal light/dark conditions. Here, we challenged mice with a 6 h advanced shift, combined with various approaches to TRF, and found that food restricted to the second half of the nights after the shift facilitated adaptation. This coincided with improved resilience to sepsis. These results raise the possibility of reducing the adverse responses to jet lag by subsequent timing of food intake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2021.634187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920952PMC
February 2021

Loss of circadian protection against influenza infection in adult mice exposed to hyperoxia as neonates.

Elife 2021 Mar 2;10. Epub 2021 Mar 2.

The Children's Hospital of Philadelphia, Philadelphia, United States.

Adverse early-life exposures have a lasting negative impact on health. Neonatal hyperoxia that is a risk factor for bronchopulmonary dysplasia confers susceptibility to influenza A virus (IAV) infection later in life. Given our previous findings that the circadian clock protects against IAV, we asked if the long-term impact of neonatal hyperoxia vis-à-vis IAV infection includes circadian disruption. Here, we show that neonatal hyperoxia abolishes the clock-mediated time of day protection from IAV in mice, independent of viral burden through host tolerance pathways. We discovered that the lung intrinsic clock (and not the central or immune clocks) mediated this dysregulation. Loss of circadian protein, , in alveolar type 2 (AT2) cells recapitulates the increased mortality, loss of temporal gating, and other key features of hyperoxia-exposed animals. Our data suggest a novel role for the circadian clock in AT2 cells in mediating long-term effects of early-life exposures to the lungs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.61241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924938PMC
March 2021

Aspirin in the Prevention of Cardiovascular Disease and Cancer.

Annu Rev Med 2021 01;72:473-495

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; email:

More than a century after its synthesis, daily aspirin, given at a low dose, is a milestone treatment for the secondary prevention of cardiovascular disease (CVD). Its role in primary prevention of CVD is still debated. Older randomized controlled trials showed that aspirin reduced the low incidence of myocardial infarction but correspondingly increased the low incidence of serious gastrointestinal bleeds without altering mortality. More recent trials see the benefit attenuated, perhaps obscured by other cardioprotective practices, while the bleeding risk remains, especially in older patients. Indirect evidence, both preclinical and clinical, suggests that aspirin may protect against sporadic colorectal cancer and perhaps other cancers. However, further studies are still necessary to warrant the consumption of aspirin for primary prevention of CVD and cancer by apparently healthy individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1146/annurev-med-051019-102940DOI Listing
January 2021

Bioactive lipids in antiviral immunity.

Science 2021 Jan;371(6526):237-238

Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abf3192DOI Listing
January 2021

Guidelines for the design and conduct of human clinical trials on ingestion-time differences - chronopharmacology and chronotherapy - of hypertension medications.

Chronobiol Int 2021 Jan 20;38(1):1-26. Epub 2020 Dec 20.

Respiratory and Critical Care Medicine Department, Sleep Medicine Center, Tianjin Chest Hospital , Tianjin, China.

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the (not "nighttime") and , calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07420528.2020.1850468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112296PMC
January 2021

Battle for supremacy: nucleic acid interactions between viruses and cells.

J Clin Invest 2021 02;131(3)

Since the COVID-19 pandemic swept across the globe, researchers have been trying to understand its origin, life cycle, and pathogenesis. There is a striking variability in the phenotypic response to infection with SARS-CoV-2 that may reflect differences in host genetics and/or immune response. It is known that the human epigenome is influenced by ethnicity, age, lifestyle, and environmental factors, including previous viral infections. This Review examines the influence of viruses on the host epigenome. We describe general lessons and methodologies that can be used to understand how the virus evades the host immune response. We consider how variation in the epigenome may contribute to heterogeneity in the response to SARS-CoV-2 and may identify a precision medicine approach to treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI144227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843224PMC
February 2021

Steps Toward Minimal Reporting Standards for Lipidomics Mass Spectrometry in Biomedical Research Publications.

Circ Genom Precis Med 2020 12 16;13(6):e003019. Epub 2020 Nov 16.

Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom (M.J.O.W.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003019DOI Listing
December 2020

Sexual dimorphism in body clocks.

Science 2020 09;369(6508):1164-1165

Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abd4964DOI Listing
September 2020

Reopening schools during COVID-19.

Science 2020 09;369(6508):1146

Tilo Grosser is a research associate professor in the Department of Systems Pharmacology and Translational Therapeutics and at the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abe5765DOI Listing
September 2020

Accounting for Time: Circadian Rhythms in the Time of COVID-19.

J Biol Rhythms 2021 02 2;36(1):4-8. Epub 2020 Sep 2.

Institute of Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia, Pennsylvania.

The COVID-19 pandemic has necessitated novel approaches and collaborative efforts across multiple disciplines. It is known that various aspects of our physiology and response to pathogens are under tight clock control. However, the assimilation of circadian biology into our clinical and research practices is still evolving. Using a focused review of the literature and original analyses of the UK Biobank, we discuss how circadian biology may inform our diagnostic and therapeutic strategies in this pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0748730420953335DOI Listing
February 2021

COVID-19, microangiopathy, hemostatic activation, and complement.

J Clin Invest 2020 08;130(8):3950-3953

Department of Systems Pharmacology and Translational Therapeutics.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI140183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410042PMC
August 2020

Academia Europaea Position Paper on Translational Medicine: The Cycle Model for Translating Scientific Results into Community Benefits.

J Clin Med 2020 May 19;9(5). Epub 2020 May 19.

Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary.

Introduction: Translational science has gained prominence in medicine, but there is still much work to be done before scientific results are used optimally and incorporated into everyday health practice. As the main focus is still on generating new scientific data with financial resources primarily available for that purpose, other activities that are necessary in the transition from research to community benefit are considered less needy. The European Statistical Office of the European Commission has recently reported that 1.7 million people under 75 years of age died in Europe in 2016, with around 1.2 million of those deaths being avoidable through effective primary prevention and public health intervention. Therefore, Academia Europaea, one of the five Pan-European networks that form SAPEA (Science Advice for Policy by European Academies), a key element of the European Commission's Scientific Advice Mechanism (SAM), has launched a project to develop a model to facilitate and accelerate the utilisation of scientific knowledge for public and community benefit.

Methods: During the process, leaders in the field, including prominent basic and clinical researchers, editors-in-chief of high-impact journals publishing translational research articles, translational medicine (TM) centre leaders, media representatives, academics and university leaders, developed the TM cycle, a new model that we believe could significantly advance the development of TM.

Results: This model focuses equally on the acquisition of new scientific results healthcare, understandable and digestible summation of results, and their communication to all participants. We have also renewed the definition in TM, identified challenges and recommended solutions.

Conclusion: The authors, including senior officers of Academia Europaea, produced this document to serve as a basis for revising thinking on TM with the end result of enabling more efficient and cost-effective healthcare.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9051532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290380PMC
May 2020

Bmal1 Deletion in Myeloid Cells Attenuates Atherosclerotic Lesion Development and Restrains Abdominal Aortic Aneurysm Formation in Hyperlipidemic Mice.

Arterioscler Thromb Vasc Biol 2020 06 23;40(6):1523-1532. Epub 2020 Apr 23.

The Institute for Translational Medicine and Therapeutics (S.Y.T., G.A.F.), University of Pennsylvania, Philadelphia.

Objective: Although the molecular components of circadian rhythms oscillate in discrete cellular components of the vasculature and many aspects of vascular function display diurnal variation, the cellular connections between the molecular clock and inflammatory cardiovascular diseases remain to be elucidated. Previously we have shown that pre- versus postnatal deletion of Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1), the nonredundant core clock gene has contrasting effects on atherogenesis. Here we investigated the effect of myeloid cell Bmal1 deletion on atherogenesis and abdominal aortic aneurysm formation in mice. Approach and Results: Mice lacking Bmal1 in myeloid cells were generated by crossing Bmal1 flox/flox mice with lysozyme 2 promoter-driven Cre recombinase mice on a hyperlipidemic low-density lipoprotein receptor-deficient background and were fed on a high-fat diet to induce atherosclerosis. Atherogenesis was restrained, concomitant with a reduction of aortic proinflammatory gene expression in myeloid cell Bmal1 knockout mice. Body weight, blood pressure, blood glucose, triglycerides, and cholesterol were unaltered. Similarly, myeloid cell depletion of Bmal1 also restrained Ang II (angiotensin II) induced formation of abdominal aortic aneurysm in hyperlipidemic mice. In vitro, RNA-Seq analysis demonstrated a proinflammatory response in cultured macrophages in which there was overexpression of Bmal1.

Conclusions: Myeloid cell Bmal1 deletion retards atherogenesis and restrains the formation of abdominal aortic aneurysm and may represent a potential therapeutic target for inflammatory cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.120.314318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285859PMC
June 2020

Pharmacological Characterization of the Microsomal Prostaglandin E Synthase-1 Inhibitor AF3485 and .

Front Pharmacol 2020 2;11:374. Epub 2020 Apr 2.

Department of Neuroscience, Imaging and Clinical Sciences, and Center for Advanced Studies and Technology (CAST), School of Medicine, G. d'Annunzio University, Chieti, Italy.

Rationale: The development of inhibitors of microsomal prostaglandin (PG)E synthase-1 (mPGES-1) was driven by the promise of attaining antiinflammatory agents with a safe cardiovascular profile because of the possible diversion of the accumulated substrate, PGH, towards prostacyclin (PGI).

Objectives: We studied the effect of the human mPGES-1 inhibitor, AF3485 (a benzamide derivative) on prostanoid biosynthesis in human whole blood . To characterize possible off-target effects of the compound, we evaluated: i)the impact of its administration on the systemic biosynthesis of prostanoids in a model of complete Freund's adjuvant (CFA)-induced monoarthritis in rats; ii) the effects on cyclooxygenase (COX)-2 expression and the biosynthesis of prostanoids in human monocytes and human umbilical vein endothelial cells (HUVECs) .

Methods: Prostanoids were assessed in different cellular models by immunoassays. The effect of the administration of AF3485 (30 and 100 mg/kg,i.p.) or celecoxib (20mg/kg, i.p.), for 3 days, on the urinary levels of enzymatic metabolites of prostanoids, PGE-M, PGI-M, and TX-M were assessed by LC-MS.

Results: In LPS-stimulated whole blood, AF3485 inhibited PGE biosynthesis, in a concentration-dependent fashion. At 100μM, PGE levels were reduced by 66.06 ± 3.30%, associated with a lower extent of TXB inhibition (40.56 ± 5.77%). AF3485 administration to CFA-treated rats significantly reduced PGE-M (P < 0.01) and TX-M (P < 0.05) similar to the selective COX-2 inhibitor, celecoxib. In contrast, AF3485 induced a significant (P < 0.05) increase of urinary PGI-M while it was reduced by celecoxib. In LPS-stimulated human monocytes, AF3485 inhibited PGE biosynthesis with an IC value of 3.03 µM (95% CI:0.5-8.75). At 1μM, AF3485 enhanced TXB while at higher concentrations, the drug caused a concentration-dependent inhibition of TXB. At 100 μM, maximal inhibition of the two prostanoids was associated with the downregulation of COX-2 protein by 86%. These effects did not involve AMPK pathway activation, IkB stabilization, or PPARγ activation. In HUVEC, AF3485 at 100 μM caused a significant (P < 0.05) induction of COX-2 protein associated with enhanced PGI production. These effects were reversed by the PPARγ antagonist GW9662.

Conclusions: The inhibitor of human mPGES-1 AF3485 is a novel antiinflammatory compound which can also modulate COX-2 induction by inflammatory stimuli. The compound also induces endothelial COX-2-dependent PGI production PPARγ activation, both and , which might translate into a protective effect for the cardiovascular system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.00374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147323PMC
April 2020

Misguided drug advice for COVID-19.

Science 2020 03 20;367(6485):1434. Epub 2020 Mar 20.

Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-5158, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abb8034DOI Listing
March 2020

The promise and reality of therapeutic discovery from large cohorts.

J Clin Invest 2020 02;130(2):575-581

Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Technological advances in rapid data acquisition have transformed medical biology into a data mining field, where new data sets are routinely dissected and analyzed by statistical models of ever-increasing complexity. Many hypotheses can be generated and tested within a single large data set, and even small effects can be statistically discriminated from a sea of noise. On the other hand, the development of therapeutic interventions moves at a much slower pace. They are determined from carefully randomized and well-controlled experiments with explicitly stated outcomes as the principal mechanism by which a single hypothesis is tested. In this paradigm, only a small fraction of interventions can be tested, and an even smaller fraction are ultimately deemed therapeutically successful. In this Review, we propose strategies to leverage large-cohort data to inform the selection of targets and the design of randomized trials of novel therapeutics. Ultimately, the incorporation of big data and experimental medicine approaches should aim to reduce the failure rate of clinical trials as well as expedite and lower the cost of drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI129196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994121PMC
February 2020

Comparative evaluation of RNA-Seq library preparation methods for strand-specificity and low input.

Sci Rep 2019 09 17;9(1):13477. Epub 2019 Sep 17.

Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.

Library preparation is a key step in sequencing. For RNA sequencing there are advantages to both strand specificity and working with minute starting material, yet until recently there was no kit available enabling both. The Illumina TruSeq stranded mRNA Sample Preparation kit (TruSeq) requires abundant starting material while the Takara Bio SMART-Seq v4 Ultra Low Input RNA kit (V4) sacrifices strand specificity. The SMARTer Stranded Total RNA-Seq Kit v2 - Pico Input Mammalian (Pico) by Takara Bio claims to overcome these limitations. Comparative evaluation of these kits is important for selecting the appropriate protocol. We compared the three kits in a realistic differential expression analysis. We prepared and sequenced samples from two experimental conditions of biological interest with each of the three kits. We report differences between the kits at the level of differential gene expression; for example, the Pico kit results in 55% fewer differentially expressed genes than TruSeq. Nevertheless, the agreement of the observed enriched pathways suggests that comparable functional results can be obtained. In summary we conclude that the Pico kit sufficiently reproduces the results of the other kits at the level of pathway analysis while providing a combination of options that is not available in the other kits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-49889-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748930PMC
September 2019

Circadian control of lung inflammation in influenza infection.

Nat Commun 2019 09 11;10(1):4107. Epub 2019 Sep 11.

Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Influenza is a leading cause of respiratory mortality and morbidity. While inflammation is essential for fighting infection, a balance of anti-viral defense and host tolerance is necessary for recovery. Circadian rhythms have been shown to modulate inflammation. However, the importance of diurnal variability in the timing of influenza infection is not well understood. Here we demonstrate that endogenous rhythms affect survival in influenza infection. Circadian control of influenza infection is mediated by enhanced inflammation as proven by increased cellularity in bronchoalveolar lavage (BAL), pulmonary transcriptomic profile and histology and is not attributable to viral burden. Better survival is associated with a time dependent preponderance of NK and NKT cells and lower proportion of inflammatory monocytes in the lung. Further, using a series of genetic mouse mutants, we elucidate cellular mechanisms underlying circadian gating of influenza infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11400-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739310PMC
September 2019

Dosing time matters.

Science 2019 08;365(6453):547-549

Divisions of Human Genetics and Immunobiology, Center for Chronobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aax7621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011856PMC
August 2019

Platelet-Specific Deletion of Cyclooxygenase-1 Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice.

J Pharmacol Exp Ther 2019 09 27;370(3):416-426. Epub 2019 Jun 27.

Department of Neuroscience, Imaging, and Clinical Sciences and Center for Research on Aging and Translational Medicine, "G. d'Annunzio" University School of Medicine, Chieti, Italy (A.Sa., A.B., A.C., M.D., S.T., P.G.-L., T.S., L.D.F., R.F., P.B., S.A., P.P.); Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (E.R., G.A.F.); Departments of General Pathology (V.A., A.Sg.) and Pharmacology (C.P.), Catholic University School of Medicine, Rome, Italy; Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China (G.L., Y.G.); and Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (Y.Y.)

Inflammatory bowel disease (IBD) is associated with an increased risk for thromboembolism, platelet activation, and abnormalities in platelet number and size. In colitis, platelets can extravasate into the colonic interstitium. We generated a mouse with a specific deletion of cyclooxygenase (COX)-1 in megakaryocytes/platelets [(COX-1 conditional knockout (cKO)] to clarify the role of platelet activation in the development of inflammation and fibrosis in dextran sodium sulfate (DSS)-induced colitis. The disease activity index was assessed, and colonic specimens were evaluated for histologic features of epithelial barrier damage, inflammation, and fibrosis. Cocultures of platelets and myofibroblasts were performed. We found that the specific deletion of COX-1 in platelets, which recapitulated the human pharmacodynamics of low-dose aspirin, that is, suppression of platelet thromboxane (TX)A production associated with substantial sparing of the systemic production of prostacyclin, resulted in milder symptoms of colitis, in the acute phase, and almost complete recovery from the disease after DSS withdrawal. Reduced colonic accumulation of macrophages and myofibroblasts and collagen deposition was found. Platelet-derived TXA enhanced the ability of myofibroblasts to proliferate and migrate in vitro, and these effects were prevented by platelet COX-1 inhibition or antagonism of the TXA receptor. Our findings allow a significant advance in the knowledge of the role of platelet-derived TXA in the development of colitis and fibrosis in response to intestinal damage and provide the rationale to investigate the potential efficacy of the antiplatelet agent low-dose aspirin in limiting the inflammatory response and fibrosis associated with IBD. SIGNIFICANCE STATEMENT: Inflammatory bowel disease (IBD) is characterized by the development of a chronic inflammatory response, which can lead to intestinal fibrosis for which currently there is no medical treatment. Through the generation of a mouse with specific deletion of cyclooxygenase-1 in megakaryocytes/platelets, which recapitulates the human pharmacodynamics of low-dose aspirin, we demonstrate the important role of platelet-derived thromboxane A in the development of experimental colitis and fibrosis, thus providing the rationale to investigate the potential efficacy of low-dose aspirin in limiting the inflammation and tissue damage associated with IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.119.259382DOI Listing
September 2019

Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2).

J Clin Invest 2019 06 4;129(9):3594-3609. Epub 2019 Jun 4.

Department of Medicine.

Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. WhileT cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell inflamed tumor microenvironment are not fully understood. We conducted an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment(TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified EPHA2 as a candidate tumor intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that PTGS2, the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGFβ and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2-PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a novel therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2-TGFβ-PTGS2 pathway inhibitors with anti-tumor immunotherapy, and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI127755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715369PMC
June 2019

A decade of .

Sci Transl Med 2019 04;11(489)

Elazer R. Edelman is co-Chief Scientific Advisor of Science Translational Medicine. He is the Director and Edward J. Poitras Professor, Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139, Professor of Medicine at Harvard Medical School, and Senior Attending Physician in the Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Email:

In this Editorial, co-Chief Scientific Advisors of Science Translational Medicine, Elazer Edelman and Garret FitzGerald, discuss challenges and opportunities for the next decade of translational research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aax4327DOI Listing
April 2019

The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury.

Nat Commun 2019 04 23;10(1):1888. Epub 2019 Apr 23.

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.

The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk. It is unknown whether microsomal (m) prostaglandin (PG) E synthase (S)-1, a target downstream of COX, regulates myocardial (M) ischemia/reperfusion (I/R) injury, a key determinant of heart failure. Here we report that COX-1 and mPGES-1 mediate production of substantial amounts of PGE and confer cardiac protection in MI/R. Deletion of mPges-1 impairs cardiac microvascular perfusion and increases inflammatory cell infiltration in mouse MI/R. Consistently, mPges-1 deletion depresses the arteriolar dilatory response to I/R in vivo and to acetylcholine ex vivo, and enhances leukocyte-endothelial cell interaction, which is mediated via PGE receptor-4 (EP4). Furthermore, endothelium-restricted Ep4 deletion impairs microcirculation, and exacerbates MI/R injury, irrespective of EP4 agonism. Treatment with misoprostol, a clinically available PGE analogue, improves microcirculation and reduces MI/R injury. Thus, mPGES-1, a key microcirculation protector, constrains MI/R injury and this beneficial effect is partially mediated via endothelial EP4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09492-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478873PMC
April 2019

Myeloid Cell mPges-1 Deletion Attenuates Mortality Without Affecting Remodeling After Acute Myocardial Infarction in Mice.

J Pharmacol Exp Ther 2019 07 16;370(1):18-24. Epub 2019 Apr 16.

Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China (L.C., T.J.); School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China (G.Y.); Institute for Translational Medicine and Therapeutics (L.C., G.Y., S.Y.T., G.A.F.) and Cardiovascular Institute (T.W., G.A.F.), University of Pennsylvania, Philadelphia, Pennsylvania; and State Key Laboratory of Medical Molecular Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Q.W., M.W.)

Selective deletion of microsomal prostaglandin E synthase-1 (mPges-1) in myeloid cells retards atherogenesis and suppresses the vascular proliferative response to injury, while it does not predispose to thrombogenesis or hypertension. However, studies using bone marrow transplants from irradiated mice suggest that myeloid cell mPGES-1 facilitates cardiac remodeling and prolongs survival after experimental myocardial infarction (MI). Here, we addressed this question using mice lacking mPges-1 in myeloid cells, particularly macrophages [Mac-mPges-1-knockout (KO)], generated by crossing mPges-1 floxed mice with LysMCre mice and subjecting them to coronary artery ligation. Cardiac structure and function were assessed by morphometric analysis, echocardiography, and invasive hemodynamics 3, 7, and 28 days after MI. Despite a similar infarct size, in contrast to the prior report, the post-MI survival rate was markedly improved in the Mac-mPges-1-KO mice compared with wild-type controls. Left ventricular systolic (reflected by ejection fraction, fractional shortness end systolic volume, and +dP/dt) and diastolic function (reflected by end diastolic volume, -dP/dt, and Tau), cardiac hypertrophy (reflected by left ventricular dimensions), and staining for fibrosis did not differ between the groups. In conclusion, we found that Cre-loxP-mediated deletion of mPges-1 in myeloid cells has favorable effects on post-MI survival, with no detectable adverse influence on post-MI remodeling. These results add to evidence that targeting macrophage mPGES-1 may represent a safe and efficacious approach to the treatment and prevention of cardiovascular inflammatory disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.118.256057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540703PMC
July 2019

Bmal1 deletion in mice facilitates adaptation to disrupted light/dark conditions.

JCI Insight 2019 04 11;5. Epub 2019 Apr 11.

Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Recently, by utilizing conventional and tamoxifen inducible Bmal1 (Brain and muscle Arnt-like protein 1) knockout mice, we found that delaying the loss of circadian rhythms to adulthood attenuates the impact on general integrity and survival at least under 12h light/12h dark conditions (LD). To understand further the contribution of Bmal1 in post-natal life under conditions of circadian disruption, we subjected inducible knockout mice (KO) and their littermate controls (Ctrl) to forced desynchrony protocols including cycles with non-24h periods, randomized light/dark cycles, and jet lag, and monitored their locomotor activity using radiotelemetry. Under these conditions, control mice cannot be entrained, as reflected by their maintenance of circadian behavior irrespective of schedules. By contrast, KO mice displayed higher activity levels in the dark phases of most cycles. Under a 3h light/3h dark regime, Ctrls displayed higher activity levels in the dark phases of all cycles although there were still obvious circadian rhythms, suggesting that an ultradian mechanism is also involved. Insulin sensitivity was markedly reduced by disrupted light schedules as expected in Ctrls, but not in the KOs. Thus, Bmal1 deletion in adult mice facilitates adaptation to new light/dark schedules and protects from insulin resistance induced by circadian disruption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.125133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542608PMC
April 2019

Variability in the Analgesic Response to Ibuprofen Is Associated With Cyclooxygenase Activation in Inflammatory Pain.

Clin Pharmacol Ther 2019 09 29;106(3):632-641. Epub 2019 Apr 29.

Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

The mechanisms underlying interindividual variability in analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) are not well understood. Therefore, we performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars and were treated with ibuprofen (400 mg; N = 19) or placebo (N = 10). Analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, or the degree of cyclooxygenase inhibition by ibuprofen. Compared with partial responders to ibuprofen (N = 9, required rescue medication within the dosing interval), complete responders (N = 10, no rescue medication) exhibited greater induction of urinary prostaglandin metabolites and serum tumor necrosis factor-α and interleukin 8. Differentially expressed genes in peripheral blood mononuclear cells were enriched for inflammation-related pathways. These findings suggest that a less pronounced activation of the inflammatory prostanoid system is associated with insufficient pain relief on ibuprofen alone and the need for additional therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.1446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753944PMC
September 2019

Time-Dependent Hypotensive Effect of Aspirin in Mice.

Arterioscler Thromb Vasc Biol 2018 12;38(12):2819-2826

The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania (G.Y., S.T., X.L., G.A.F.).

Objective- Evening but not morning administration of low-dose aspirin has been reported to lower blood pressure in hypertensive patients. The present study was designed to determine whether this phenomenon could be replicated in mice, and if so, whether a time-dependent effect of aspirin on blood pressure was because of alteration of circadian clock function. Approach and Results- We recapitulated the protective effect of aspirin (50 μg/d for 7 days) at zeitgeber time 0 (active-to-rest transit), but not at zeitgeber time 12, on a high-salt diet-induced increase of blood pressure. However, the time of aspirin administration did not influence expression of canonical clock genes or their acetylation. We used mouse Bmal1 and Per2-luciferase reporters expressed in U2OS cells to determine the real-time effect of aspirin on circadian function but found that the oscillation of bioluminescence was unaltered. Timing of aspirin administration also failed to alter urinary prostaglandin metabolites or catecholamines, or the acetylation of its COX-1 (cyclooxygenase-1) target in platelets. Conclusions- The time-dependent hypotensive effect of aspirin in humans has been recapitulated in hypertensive mice. However, this does not seem to reflect a direct impact of aspirin on circadian clocks or on acetylation of platelet COX-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.118.311296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309345PMC
December 2018

Myeloid Cell Hypoxia-Inducible Factors Promote Resolution of Inflammation in Experimental Colitis.

Front Immunol 2018 5;9:2565. Epub 2018 Nov 5.

Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.

Colonic tissues in Inflammatory Bowel Disease (IBD) patients exhibit oxygen deprivation and activation of hypoxia-inducible factor 1α and 2α (HIF-1α and HIF-2α), which mediate cellular adaptation to hypoxic stress. Notably, macrophages and neutrophils accumulate preferentially in hypoxic regions of the inflamed colon, suggesting that myeloid cell functions in colitis are HIF-dependent. By depleting ARNT (the obligate heterodimeric binding partner for both HIFα subunits) in a murine model, we demonstrate here that myeloid HIF signaling promotes the resolution of acute colitis. Specifically, myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and Ly6C monocytic cells into diseased tissue. Myeloid HIF ablation also hinders macrophage functional conversion to a protective, pro-resolving phenotype, and elevates gut serum amyloid A levels during the resolution phase of colitis. Therefore, myeloid cell HIF signaling is required for efficient resolution of inflammatory damage in colitis, implicating serum amyloid A in this process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230677PMC
September 2019