scholarly journals Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1398 ◽  
Author(s):  
Manuel Janeiro ◽  
María Ramírez ◽  
Fermin Milagro ◽  
J. Martínez ◽  
Maite Solas
Keyword(s):  
Therapeutic Target ◽  
Neurological Disorders ◽  
Disease Process ◽  
Major Adverse Cardiovascular Events ◽  
Monooxygenase Activity ◽  
Potential Biomarker ◽  
Increased Risk ◽  
Inflammatory Processes ◽  
Health And Disease

Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.

Role of Microglia in Neurological Disorders and Their Potentials as a Therapeutic Target

2016 ◽  
Vol 54 (10) ◽  
pp. 7567-7584 ◽  
Author(s):  
Li Du ◽  
Ying Zhang ◽  
Yang Chen ◽  
Jie Zhu ◽  
Yi Yang ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Neurological Disorders

scholarly journals Alzheimer’s-Like Pathology at the Crossroads of HIV-Associated Neurological Disorders

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 930
Author(s):  
Divya T. Chemparthy ◽  
Muthukumar Kannan ◽  
Lila Gordon ◽  
Shilpa Buch ◽  
Susmita Sil
Keyword(s):  
Neurological Disorders ◽  
Disease Process ◽  
Amyloid Β ◽  
Viral Proteins ◽  
Epidemiological Studies ◽  
Model Systems ◽  
People Living With Hiv ◽  
Living With Hiv ◽  
The Brain

Despite the widespread success of combined antiretroviral therapy (cART) in suppressing viremia, the prevalence of human immunodeficiency virus (HIV)-associated neurological disorders (HAND) and associated comorbidities such as Alzheimer’s disease (AD)-like symptomatology is higher among people living with HIV. The pathophysiology of observed deficits in HAND is well understood. However, it has been suggested that it is exacerbated by aging. Epidemiological studies have suggested comparable concentrations of the toxic amyloid protein, amyloid-β42 (Aβ42), in the cerebrospinal fluid (CSF) of HAND patients and in the brains of patients with dementia of the Alzheimer’s type. Apart from abnormal amyloid-β (Aβ) metabolism in AD, a better understanding of the role of similar pathophysiologic processes in HAND could be of substantial value. The pathogenesis of HAND involves either the direct effects of the virus or the effect of viral proteins, such as Tat, Gp120, or Nef, as well as the effects of antiretrovirals on amyloid metabolism and tauopathy, leading, in turn, to synaptodendritic alterations and neuroinflammatory milieu in the brain. Additionally, there is a lack of knowledge regarding the causative or bystander role of Alzheimer’s-like pathology in HAND, which is a barrier to the development of therapeutics for HAND. This review attempts to highlight the cause–effect relationship of Alzheimer’s-like pathology with HAND, attempting to dissect the role of HIV-1, HIV viral proteins, and antiretrovirals in patient samples, animal models, and cell culture model systems. Biomarkers associated with Alzheimer’s-like pathology can serve as a tool to assess the neuronal injury in the brain and the associated cognitive deficits. Understanding the factors contributing to the AD-like pathology associated with HAND could set the stage for the future development of therapeutics aimed at abrogating the disease process.

scholarly journals Diet in Brain Health and Neurological Disorders: Risk Factors and Treatments

2019 ◽  
Vol 9 (9) ◽  
pp. 234 ◽  
Author(s):  
Jason Brandt
Keyword(s):  
Risk Factors ◽  
Neurological Disorders ◽  
Brain Health ◽  
Health And Disease

The role of nutrition in health and disease has been appreciated from time immemorial [...]

The C1542G and G505A Polymorphisms of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) in Patients with Thrombotic Microangiopathies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2141-2141
Author(s):  
Christoph Sucker ◽  
Firuseh Farokhzad ◽  
Fieras Dahhan ◽  
Michael Schmitz ◽  
Gerd R. Hetzel ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Arterial Thrombosis ◽  
Case Control ◽  
Thrombotic Microangiopathies ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Increased Risk ◽  
Fibrinolysis Inhibitor ◽  
Inflammatory Processes ◽  
History Of

Abstract Background Thrombotic microangiopathies are characterized by vascular microthromboses, microangiopathic hemolytic anemia, and thrombocytopenia. Although recent research has elucidated the pathogenesis of these rare thrombotic disorders to some extent, the determinants contributing to the onset and modulating the severity are largely unknown. It is likely that risk factors of venous and arterial thrombosis also play a role in this clinical setting. Patients and Methods In the present study, we used a case-control and a case-only design, enrolling 23 patients (mean age [± SD] 35 ± 11 years) with a history of thrombotic microangiopathy and 689 control subjects to assess the role of gene polymorphisms of the thrombin-activatable fibrinolysis inhibitor (TAFI). Results The prevalence of the TAFI decreasing G/G genotype of the C1542G polymorphism was significantly higher in patients compared to controls (odds ratio 3.88; 95 % CI 1.07 – 11.47; p=0.02). In addition, in a case-only design the TAFI 1542 G allele was more prevalent in patients suffering from a severe course compared to those with a mild or moderate course (odds ratio 20; 95 % CI 1.85 – 216.17; p=0.009). By contrast, no such association was found for the TAFI G505A polymorphism. Conclusions Our study shows an association of the TAFI decreasing 1542 G/G genotype with an increased risk for thrombotic microangiopathies and a more severe course. This finding might be explained by the role of TAFI as an inhibitor of local inflammatory processes.

scholarly journals The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

2021 ◽  
Vol 22 (4) ◽  
pp. 1693
Author(s):  
Alison Domingues ◽  
Julia Jolibois ◽  
Perrine Marquet de Rougé ◽  
Valérie Nivet-Antoine
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Diseases ◽  
Therapeutic Target ◽  
Redox Status ◽  
Interacting Protein ◽  
Cellular Redox ◽  
Thioredoxin Interacting Protein ◽  
Potential Biomarker ◽  
Ischemic Diseases

Thioredoxin interacting protein (TXNIP) is a metabolism- oxidative- and inflammation-related marker induced in cardiovascular diseases and is believed to represent a possible link between metabolism and cellular redox status. TXNIP is a potential biomarker in cardiovascular and ischemic diseases but also a novel identified target for preventive and curative medicine. The goal of this review is to focus on the novelties concerning TXNIP. After an overview in TXNIP involvement in oxidative stress, inflammation and metabolism, the remainder of this review presents the clues used to define TXNIP as a new marker at the genetic, blood, or ischemic site level in the context of cardiovascular and ischemic diseases.

scholarly journals Virome in the Lungs: The Role of Anelloviruses in Childhood Respiratory Diseases

2021 ◽  
Vol 9 (7) ◽  
pp. 1357
Author(s):  
Giulia Dodi ◽  
Marina Attanasi ◽  
Paola Di Filippo ◽  
Sabrina Di Pillo ◽  
Francesco Chiarelli
Keyword(s):  
Immune System ◽  
Respiratory Diseases ◽  
Epidemiological Data ◽  
Chronic Inflammatory Disease ◽  
Molecular Techniques ◽  
Chronic Respiratory Diseases ◽  
Constant Change ◽  
Inflammatory Processes ◽  
Health And Disease

More recently, increasing attention has been directed to exploring the function of the global virome in health and disease. Currently, by new molecular techniques, such as metagenomic DNA sequencing, the virome has been better unveiled. By investigating the human lung virome, we could provide novel insights into respiratory diseases. The virome, as a part of the microbiome, is characterized by a constant change in composition related to the type of diet, environment, and our genetic code, and other incalculable factors. The virome plays a substantial role in modulating human immune defenses and contributing to the inflammatory processes. Anelloviruses (AVs) are new components of the virome. AVs are already present during early life and reproduce without apparently causing harm to the host. The role of AVs is still unknown, but several reports have shown that AVs could activate the inflammasomes, intracellular multiprotein oligomers of the innate immune system, which show a crucial role in the host defense to several pathogens. In this narrative revision, we summarize the epidemiological data related to the possible link between microbial alterations and chronic respiratory diseases in children. Briefly, we also describe the characteristics of the most frequent viral family present in the lung virome, Anelloviridae. Furthermore, we discuss how AVs could modulate the immune system in children, affecting the development of chronic respiratory diseases, particularly asthma, the most common chronic inflammatory disease in childhood.

scholarly journals Pericytes for Therapeutic Approaches to Ischemic Stroke

2021 ◽  
Vol 15 ◽  
Author(s):  
Lu Cao ◽  
Yanbo Zhou ◽  
Mengguang Chen ◽  
Li Li ◽  
Wei Zhang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ischemic Stroke ◽  
Therapeutic Target ◽  
Neurological Disorders ◽  
Neurovascular Unit ◽  
Therapeutic Approaches ◽  
Multipotent Cells ◽  
The Central Nervous System

Pericytes are perivascular multipotent cells located on capillaries. Although pericytes are discovered in the nineteenth century, recent studies have found that pericytes play an important role in maintaining the blood—brain barrier (BBB) and regulating the neurovascular system. In the neurovascular unit, pericytes perform their functions by coordinating the crosstalk between endothelial, glial, and neuronal cells. Dysfunction of pericytes can lead to a variety of diseases, including stroke and other neurological disorders. Recent studies have suggested that pericytes can serve as a therapeutic target in ischemic stroke. In this review, we first summarize the biology and functions of pericytes in the central nervous system. Then, we focus on the role of dysfunctional pericytes in the pathogenesis of ischemic stroke. Finally, we discuss new therapies for ischemic stroke based on targeting pericytes.

scholarly journals Scarless genome editing reveals risk SNP rs6983267-G and lncRNA CCAT2 dictate targetable PI3K signaling dependence in WNT-dysregulated CRC

2021 ◽  
Author(s):  
Nicole B. Coggins ◽  
Henriette O’Geen ◽  
Paul C. Lott ◽  
David J. Segal ◽  
Luis Carvajal Carmona
Keyword(s):  
Risk Allele ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Growth Factor Signaling ◽  
Cellular Models ◽  
Genome Wide ◽  
Potential Biomarker ◽  
Increased Risk ◽  
Hct 116

Abstract Genome-wide association studies have identified numerous loci associated with increased risk for colorectal cancer (CRC), including 8q24.21 which contains a known enhancer of proto-oncogene MYC . However, the role of candidate functional SNP rs6983267 within this locus remains unclear. Here, we generate isogenic cellular models of risk SNP rs6983267 in human CRC line, HCT-116. Comprehensive molecular characterization reveals risk allele-G drives enhancer DNA contacts with downstream regions that include MYC . Absence of risk allele leads to activation of lncRNA CCAT2 . Rather than changes in MYC expression, we observe activation of alternative growth factor signaling pathways with loss of both risk allele and CCAT2 expression. Analysis of TCGA CRC cases demonstrates low CCAT2 expression combined with non-risk rs6983267 genotype correlate with higher frequency of PI3K mutations in CRC patients displaying WNT dysregulation. Together, these provide a potential biomarker for therapeutically targetable PI3K dysregulation in CRC and application in cancer precision medicine.

Lipoprotein-associated Phospholipase A2 and Coronary Heart Disease

2018 ◽  
Vol 24 (3) ◽  
pp. 291-296 ◽  
Author(s):  
Areti Sofogianni ◽  
Stelina Alkagiet ◽  
Konstantinos Tziomalos
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Phospholipase A2 ◽  
Therapeutic Target ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Markers Of Inflammation ◽  
Chd Risk ◽  
Increased Risk

In the last decades, the role of inflammation in the pathogenesis of atherosclerosis has been the topic of intense research. Several markers of inflammation have shown predictive value for first and recurrent coronary events in patients without and with established Coronary Heart Disease (CHD). Among these markers, lipoprotein- associated phospholipase A2 (Lp-PLA2) has recently received considerable attention. In the present review, the potential role of Lp-PLA2 as a marker of CHD risk and as a therapeutic target is discussed. Elevated Lp- PLA2 mass and activity appears to be associated with increased risk for CHD, both in the general population and in patients with established CHD. However, it is unclear whether the measurement of Lp-PLA2 improves risk discrimination when incorporated in models that include traditional cardiovascular risk factors. Moreover, the lack of effect on CHD events of darapladib, a potent, selective Lp-PLA2 inhibitor, in two large, randomized, placebo-controlled trials and the mostly negative findings of genetic association studies suggest that Lp-PLA2 is unlikely to represent a causal factor in atherogenesis. Therefore, it is doubtful whether Lp-PLA2 will constitute a therapeutic target for the prevention of CHD.

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