scholarly journals Longitudinal profiling of human blood transcriptome in healthy and lupus pregnancy

2019 ◽  
Vol 216 (5) ◽  
pp. 1154-1169 ◽  
Author(s):  
Seunghee Hong ◽  
Romain Banchereau ◽  
Bat-Sheva L. Maslow ◽  
Marta M. Guerra ◽  
Jacob Cardenas ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Embryo Implantation ◽  
Adverse Outcomes ◽  
Healthy Women ◽  
Cell Counts ◽  
Increased Risk ◽  
Pregnancy And Postpartum ◽  
Blood Transcriptome

Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4+ T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes.

scholarly journals Applying a Weight-of-Evidence Approach to Evaluate Relevance of Molecular Landscapes in the Exposure-Disease Paradigm

2015 ◽  
Vol 2015 ◽  
pp. 1-11
Author(s):  
Sherilyn A. Gross ◽  
Kristen M. Fedak
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Data ◽  
Weight Of Evidence ◽  
Molecular Characteristics ◽  
Environmental Carcinogens ◽  
Environmental Carcinogen ◽  
Cell Counts ◽  
Disease Outcomes ◽  
Dna Repair Gene ◽  
Increased Risk

Information on polymorphisms, mutations, and epigenetic events has become increasingly important in our understanding of molecular mechanisms associated with exposures-disease outcomes. Molecular landscapes can be developed to illustrate the molecular characteristics for environmental carcinogens as well as associated disease outcomes, although comparison of these molecular landscapes can often be difficult to navigate. We developed a method to organize these molecular data that uses a weight-of-evidence approach to rank overlapping molecular events by relative importance for susceptibility to an exposure-disease paradigm. To illustrate the usefulness of this approach, we discuss the example of benzene as an environmental carcinogen and myelodysplastic syndrome (MDS) as a causative disease endpoint. Using this weight-of-evidence method, we found overlapping polymorphisms in the genes for the metabolic enzymesGSTandNQO1, both of which may infer risk of benzene-induced MDS. Polymorphisms in the tumor suppressor gene,TP53, and the inflammatory cytokine gene,TNF-α, were also noted, albeit inferring opposing outcomes. The alleles identified in the DNA repair geneRAD51indicated an increased risk for MDS in MDS patients and low blood cell counts in benzene-exposed workers. We propose the weight-of-evidence approach as a tool to assist in organizing the sea of emerging molecular data in exposure-disease paradigms.

scholarly journals Platelet Activation Mechanisms and Consequences of Immune Thrombocytopenia

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3386
Author(s):  
Siyu Sun ◽  
Rolf T. Urbanus ◽  
Hugo ten Cate ◽  
Philip G. de Groot ◽  
Bas de Laat ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Autoimmune Disorders ◽  
Common Mechanism ◽  
Platelet Activity ◽  
Bleeding Events ◽  
Drug Induced ◽  
Elevated Liver Enzymes ◽  
Increased Risk

Autoimmune disorders are often associated with low platelet count or thrombocytopenia. In immune-induced thrombocytopenia (IIT), a common mechanism is increased platelet activity, which can have an increased risk of thrombosis. In addition, or alternatively, auto-antibodies suppress platelet formation or augment platelet clearance. Effects of the auto-antibodies are linked to the unique structural and functional characteristics of platelets. Conversely, prior platelet activation may contribute to the innate and adaptive immune responses. Extensive interplay between platelets, coagulation and complement activation processes may aggravate the pathology. Here, we present an overview of the reported molecular causes and consequences of IIT in the most common forms of autoimmune disorders. These include idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), drug-induced thrombocytopenia (DITP), heparin-induced thrombocytopenia (HIT), COVID-19 vaccine-induced thrombosis with thrombocytopenia (VITT), thrombotic thrombocytopenia purpura (TTP), and hemolysis, the elevated liver enzymes and low platelet (HELLP) syndrome. We focus on the platelet receptors that bind auto-antibodies, the immune complexes, damage-associated molecular patterns (DAMPs) and complement factors. In addition, we review how circulating platelets serve as a reservoir of immunomodulatory molecules. By this update on the molecular mechanisms and the roles of platelets in the pathogenesis of autoimmune diseases, we highlight platelet-based pathways that can predispose for thrombocytopenia and are linked thrombotic or bleeding events.

scholarly journals Nf1 and Sh2b3 mutations cooperate in vivo in a mouse model of juvenile myelomonocytic leukemia

2021 ◽  
Author(s):  
Carolina E. Morales ◽  
Elliot Stieglitz ◽  
Scott C. Kogan ◽  
Mignon L. Loh ◽  
Benjamin S Braun
Keyword(s):  
Adverse Outcomes ◽  
Juvenile Myelomonocytic Leukemia ◽  
Ras Signaling ◽  
Hemoglobin F ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Increased Risk ◽  
Genetically Engineered Mice ◽  
The Impact ◽  
Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is initiated in early childhood by somatic mutations that activate Ras signaling. While some patients have only a single identifiable oncogenic mutation, others have one or more additional alterations. Such secondary mutations, as a group, are associated with an increased risk of relapse after hematopoietic stem cell transplantation, or transformation to acute myeloid leukemia. These clinical observations suggest a cooperative effect between initiating and secondary mutations. However, the roles of specific genes in the prognosis or clinical presentation of JMML have not been described. In this study, we investigate the impact of secondary SH2B3 mutations in JMML. We find that patients with SH2B3 mutations have adverse outcomes, as well as higher white blood cell counts and hemoglobin F levels in the peripheral blood. We further demonstrate this interaction in genetically engineered mice. Deletion of Sh2b3 cooperates with conditional Nf1 deletion in a dose-dependent fashion. These studies illustrate that haploinsufficiency for Sh2b3 contributes to the severity of myeloproliferative disease and provide an experimental system for testing treatments for a high-risk cohort of JMML patients.

scholarly journals Diabetes and coronavirus (SARS-CoV-2): Molecular mechanism of Metformin intervention and the scientific basis of drug repurposing

2021 ◽  
Vol 17 (6) ◽  
pp. e1009634
Author(s):  
Elizabeth Varghese ◽  
Samson Mathews Samuel ◽  
Alena Liskova ◽  
Peter Kubatka ◽  
Dietrich Büsselberg
Keyword(s):  
Molecular Mechanisms ◽  
Drug Repurposing ◽  
Scientific Basis ◽  
Adverse Outcomes ◽  
Oral Antidiabetic Drugs ◽  
Vascular Protection ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Increased Risk

Coronavirus Disease 2019 (COVID-19), caused by a new strain of coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was declared a pandemic by WHO on March 11, 2020. Soon after its emergence in late December 2019, it was noticed that diabetic individuals were at an increased risk of COVID-19–associated complications, ICU admissions, and mortality. Maintaining proper blood glucose levels using insulin and/or other oral antidiabetic drugs (such as Metformin) reduced the detrimental effects of COVID-19. Interestingly, in diabetic COVID-19 patients, while insulin administration was associated with adverse outcomes, Metformin treatment was correlated with a significant reduction in disease severity and mortality rates among affected individuals. Metformin was extensively studied for its antioxidant, anti-inflammatory, immunomodulatory, and antiviral capabilities that would explain its ability to confer cardiopulmonary and vascular protection in COVID-19. Here, we describe the various possible molecular mechanisms that contribute to Metformin therapy’s beneficial effects and lay out the scientific basis of repurposing Metformin for use in COVID-19 patients.

scholarly journals Effects of Thyroid Peroxidase Antibody on Maternal and Neonatal Outcomes in Pregnant Women in an Iodine-Sufficient Area in China

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Xi Chen ◽  
Bai Jin ◽  
Jun Xia ◽  
Xincheng Tao ◽  
Xiaoping Huang ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Thyroid Function ◽  
Placenta Previa ◽  
Adverse Outcomes ◽  
Thyroid Peroxidase ◽  
Negative Group ◽  
Thyroid Peroxidase Antibody ◽  
Increased Risk ◽  
Pregnancy And Postpartum ◽  
Underlying Mechanisms

Purposes.To evaluate the effects of thyroid peroxidase antibodies (TPOAb) on maternal and neonatal adverse outcomes in pregnant women.Methods.208 pregnant women at 24–28 weeks were divided into two groups, TPOAb-positive and TPOAb-negative groups. Thyroid function and TPOAb were determined in all subjects until 12 months postpartum. Levothyroxine was supplemented to maintain euthyroid with periodical checking of thyroid functions. The prevalence of postpartum thyroiditis (PPT), placenta previa, placental abruption, premature rupture of membrane, postpartum haemorrhage, polyhydramnios, oligohydramnios, preterm birth, low birth weight, congenital hypothyroidism, and neonatal diseases were observed in two groups.Results.Of all women, 11.54% had a PPT. The prevalence of PPT was significantly higher in TPOAb-positive than TPOAb-negative group (42.31% versus 7.14%,P<0.001), with 45.46% and 53.85% of PPT happening at 6 weeks postpartum in TPOAb-positive and TPOAb-negative groups. The incidence of polyhydramnios was significantly higher in TPOAb-positive than TPOAb-negative group (15.38% versus 2.74%,P=0.02).Conclusion.Pregnant women with TPOAb-positive had increased risk of PPT, predominantly happening at 6 weeks postpartum. TPOAb was associated with increased incidence of polyhydramnios and the underlying mechanisms required further investigation. Earlier screening of thyroid function during pregnancy and postpartum was warranted in our region.

Thrombin Generation Measured Ex Vivo Following Microvasculor Injury Is Increased in SLE Patients with Antiphospholipid-protein Antibodies

1997 ◽  
Vol 78 (04) ◽  
pp. 1173-1177 ◽  
Author(s):  
Jacek Musiał ◽  
Jakub Swadźba ◽  
Miłosz Jankowski ◽  
Marek Grzywacz ◽  
Stanisława Bazan-Socha ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Skin Incision ◽  
Anticardiolipin Antibodies ◽  
Small Blood Vessel ◽  
Anionic Phospholipids ◽  
Increased Risk ◽  
High Concentrations

SummaryAntiphospholipid-protein antibodies (APA) include lupus-type anticoagulant (LA) and antibodies recognizing complexes of anionic phospholipids (e.g. cardiolipin) and proteins (e.g. prothrombin and (β2-glycoprotein I). The presence of APA is associated with an increased risk of both arterial and venous thrombosis. However, the pathogenic mechanism leading to thrombosis in patients with APA remains unclear. We studied 32 patients with systemic lupus erythematosus (SLE) who were divided into two groups depending on the presence (n = 19) or absence (n = 13) of APA. Healthy volunteers (n = 12) matched by age and sex served as controls. In all subjects LA and IgG class anticardiolipin antibodies (ACA) were determined. Thrombin generation was monitored ex vivo measuring fibrinopeptide A (FPA) and prothrombin fragment F1 + 2 (F1 + 2) in blood emerging from a skin microvasculature injury, collected at 30 second intervals. In subjects with antiphospholipid antibodies mean FPA and F1 + 2 concentrations were signiF1cantly higher at most blood sampling times than in controls. In some SLE patients with APA the process of thrombin generation was clearly disturbed and very high concentrations of F1brinopeptide A were detected already in the F1rst samples collected. Two minutes after skin incision SLE patients without APA produced slightly more FPA, but not F1 + 2, as compared to healthy subjects. Mathematical model applied to analyze the thrombin generation kinetics revealed that APA patients generated signiF1cantly greater amounts of thrombin than healthy controls (p = 0.02 for either marker). In contrast, in the same patients generation of thrombin in recalciF1ed plasma in vitro was delayed pointing to the role of endothelium in the phenomenon studied. In summary, these data show for the F1rst time that in SLE patients with antiphospholipid-protein antibodies thrombin generation after small blood vessel injury is markedly increased. Enhanced thrombin generation might explain thrombotic tendency observed in these patients.

Impact of Natural Dietary Agents on Multiple Myeloma Prevention and Treatment: Molecular Insights and Potential for Clinical Translation

2020 ◽  
Vol 27 (2) ◽  
pp. 187-215 ◽  
Author(s):  
Lavinia Raimondi ◽  
Angela De Luca ◽  
Gianluca Giavaresi ◽  
Agnese Barone ◽  
Pierosandro Tagliaferri ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Natural Products ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Signal Transduction Pathways ◽  
Pharmacologically Active ◽  
Dietary Agents

: Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. : Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. : In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

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