Approaching Sex Differences in Cardiovascular Non-Coding RNA Research

Cardiovascular disease (CVD) is the biggest cause of sickness and mortality worldwide in both males and females. Clinical statistics demonstrate clear sex differences in risk, prevalence, mortality rates, and response to treatment for different entities of CVD. The reason for this remains poorly understood. Non-coding RNAs (ncRNAs) are emerging as key mediators and biomarkers of CVD. Similarly, current knowledge on differential regulation, expression, and pathology-associated function of ncRNAs between sexes is minimal. Here, we provide a state-of-the-art overview of what is known on sex differences in ncRNA research in CVD as well as discussing the contributing biological factors to this sex dimorphism including genetic and epigenetic factors and sex hormone regulation of transcription. We then focus on the experimental models of CVD and their use in translational ncRNA research in the cardiovascular field. In particular, we want to highlight the importance of considering sex of the cellular and pre-clinical models in clinical studies in ncRNA research and to carefully consider the appropriate experimental models most applicable to human patient populations. Moreover, we aim to identify sex-specific targets for treatment and diagnosis for the biggest socioeconomic health problem globally.

Download Full-text

Experimental Rodent Models of Vascular Dementia: A Systematic Review

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666210108123438 ◽

2021 ◽

Vol 19 ◽

Author(s):

Nidhi Tiwari ◽

Jyoti Upadhyay ◽

Mohd Nazam Ansari ◽

Syed Shadab Raza ◽

Wasim Ahmad ◽

...

Keyword(s):

Vascular Dementia ◽

Small Vessel Disease ◽

Current Knowledge ◽

Vascular Cognitive Impairment ◽

Experimental Models ◽

New Drugs ◽

Amyloid Angiopathy ◽

Vessel Disease ◽

The Brain ◽

Large Vessel Disease

: Vascular dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of vascular cognitive impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small vessel disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and cerebral amyloid angiopathy (CAA),which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

Download Full-text

Thyroid Hormone Regulation of Transcription Factors Involved in Malic Enzyme Gene Expression

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)60489-2 ◽

1989 ◽

Vol 264 (19) ◽

pp. 11483-11490 ◽

Cited By ~ 6

Author(s):

K J Petty ◽

H Morioka ◽

T Mitsuhashi ◽

V M Nikodem

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Thyroid Hormone ◽

Malic Enzyme ◽

Regulation Of Transcription ◽

Hormone Regulation ◽

Enzyme Gene ◽

Malic Enzyme Gene

Download Full-text

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Cells ◽

10.3390/cells10030506 ◽

2021 ◽

Vol 10 (3) ◽

pp. 506

Author(s):

Loris Zamai

Keyword(s):

Chelating Agents ◽

Ethylenediaminetetraacetic Acid ◽

Current Knowledge ◽

Clinical Manifestations ◽

Renin Angiotensin System ◽

Experimental Models ◽

Zinc Metalloprotease ◽

Previous Hypothesis ◽

Zinc Metalloproteases

The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

Download Full-text

6S RNA regulation of relA alters ppGpp levels in early stationary phase

Microbiology ◽

10.1099/mic.0.043992-0 ◽

2010 ◽

Vol 156 (12) ◽

pp. 3791-3800 ◽

Cited By ~ 21

Author(s):

Amy T. Cavanagh ◽

Pete Chandrangsu ◽

Karen M. Wassarman

Keyword(s):

Amino Acid ◽

Stationary Phase ◽

Regulation Of Transcription ◽

Early Stationary Phase ◽

Rna Regulation ◽

Global Regulators ◽

Expression Of Genes ◽

Non Coding Rna ◽

6S Rna ◽

Altered Regulation

6S RNA is a small, non-coding RNA that interacts directly with σ 70-RNA polymerase and regulates transcription at many σ 70-dependent promoters. Here, we demonstrate that 6S RNA regulates transcription of relA, which encodes a ppGpp synthase. The 6S RNA-dependent regulation of relA expression results in increased ppGpp levels during early stationary phase in cells lacking 6S RNA. These changes in ppGpp levels, although modest, are sufficient to result in altered regulation of transcription from σ 70-dependent promoters sensitive to ppGpp, including those promoting expression of genes involved in amino acid biosynthesis and rRNA. These data place 6S RNA as another player in maintaining appropriate gene expression as cells transition into stationary phase. Independent of this ppGpp-mediated 6S RNA-dependent regulation, we also demonstrate that in later stationary phase, 6S RNA continues to downregulate transcription in general, and specifically at a subset of the amino acid promoters, but through a mechanism that is independent of ppGpp and which we hypothesize is through direct regulation. In addition, 6S RNA-dependent regulation of σ S activity is not mediated through observed changes in ppGpp levels. We suggest a role for 6S RNA in modulating transcription of several global regulators directly, including relA, to downregulate expression of key pathways in response to changing environmental conditions.

Download Full-text

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Cells ◽

10.3390/cells10081844 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1844

Author(s):

Maria Luísa da Silveira Hahmeyer ◽

José Eduardo da Silva-Santos

Keyword(s):

Septic Shock ◽

Actin Polymerization ◽

Current Knowledge ◽

Cecal Ligation ◽

Experimental Models ◽

Rho Proteins ◽

Growing Cell ◽

Sepsis And Septic Shock

Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models.

Download Full-text

Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

Download Full-text

Sex Differences in Cancer Genomes: Much Learned, More Unknown

Endocrinology ◽

10.1210/endocr/bqab170 ◽

2021 ◽

Author(s):

Chenghao Zhu ◽

Paul C Boutros

Keyword(s):

Sex Differences ◽

Precision Medicine ◽

Cause Of Death ◽

Clinical Presentation ◽

Response To Treatment ◽

Critical Gap ◽

Cancer Genomes ◽

Cancer Initiation ◽

Cancer Types ◽

Key Resources

Abstract Cancer is a leading cause of death worldwide. Sex influences cancer in a bewildering variety of ways. In some cancer types it affects prevalence, in others genomic profiles, or response to treatment, or mortality. In some sex seems to have little or no influence. How and when sex influences cancer initiation and progression remain a critical gap in our understanding of cancer, with direct relevance to precision medicine. Here, we note several factors that complicate our understanding of sex differences: representativeness of large cohorts, confounding with features like ancestry, age and obesity, and variability in clinical presentation. We summarize the key resources available to study molecular sex differences, and suggest some likely directions for improving our understanding of how patient sex influences cancer behaviour.

Download Full-text

Emerging role of a novel small non-coding regulatory RNA: tRNA-derived small RNA

ExRNA ◽

10.1186/s41544-019-0036-7 ◽

2019 ◽

Vol 1 (1) ◽

Author(s):

Fangfang Jin ◽

Zhigang Guo

Keyword(s):

Small Rna ◽

Current Knowledge ◽

Future Research ◽

Regulatory Rna ◽

Biological Functions ◽

Research Directions ◽

Non Coding Rna ◽

Future Research Directions ◽

Non Coding Rnas

Abstract The discovery of small non-coding RNAs, such as miRNA and piRNA, has dramatically changed our understanding of the role RNA plays in organisms. Recent studies show that a novel small non-coding RNA generated from cleavage of tRNA or pre-tRNA, called tRNA-derived small RNA (tsRNA), serves as a new regulator of gene expression. tsRNA has been determined participate in regulating some specific physiological and pathological processes. Although knowledge regarding the biological roles of miRNA and piRNA is expanding, whether tsRNAs play similar roles remains poorly understood. Here, we review the current knowledge regarding the mechanisms of action and biological functions of tsRNAs in intracellular, extracellular and intergenerational inheritance, and highlight the potential application of tsRNAs in human diseases, and present the current problems and future research directions.

Download Full-text

Pharmacological Rationale for Targeting IL-17 in Asthma

Frontiers in Allergy ◽

10.3389/falgy.2021.694514 ◽

2021 ◽

Vol 2 ◽

Author(s):

Siti Farah Rahmawati ◽

Maurice te Velde ◽

Huib A. M. Kerstjens ◽

Alexander S. S. Dömling ◽

Matthew Robert Groves ◽

...

Keyword(s):

Severe Asthma ◽

Inhaled Corticosteroids ◽

Current Knowledge ◽

Experimental Models ◽

Airflow Limitation ◽

Interleukin 17 ◽

Asthma Phenotype ◽

T Helper 2 ◽

Bronchial Biopsies

Asthma is a respiratory disease that currently affects around 300 million people worldwide and is defined by coughing, shortness of breath, wheezing, mucus overproduction, chest tightness, and expiratory airflow limitation. Increased levels of interleukin 17 (IL-17) have been observed in sputum, nasal and bronchial biopsies, and serum of patients with asthma compared to healthy controls. Patients with higher levels of IL-17 have a more severe asthma phenotype. Biologics are available for T helper 2 (Th2)-high asthmatics, but the Th17-high subpopulation has a relatively low response to these treatments, rendering it a rather severe asthma phenotype to treat. Several experimental models suggest that targeting the IL-17 pathway may be beneficial in asthma. Moreover, as increased activation of the Th17/IL-17 axis is correlated with reduced inhaled corticosteroids (ICS) sensitivity, targeting the IL-17 pathway might reverse ICS unresponsiveness. In this review, we present and discuss the current knowledge on the role of IL-17 in asthma and its interaction with the Th2 pathway, focusing on the rationale for therapeutic targeting of the IL-17 pathway.

Download Full-text