Potential therapeutic targets to prevent organ damage in chronic pulmonary sarcoidosis

Systemic sclerosis (SSc) is a complex rheumatologic autoimmune disease in which inflammation, fibrosis, and vasculopathy share several pathogenic pathways that lead to skin and internal organ damage. Recent findings regarding the participation and interaction of the innate and acquired immune system have led to a better understanding of the pathogenesis of the disease and to the identification of new therapeutic targets, many of which have been tested in preclinical and clinical trials with varying results. In this manuscript, we review the state of the art of the pathogenesis of this disease and discuss the main therapeutic targets related to each pathogenic mechanism that have been discovered so far.

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Single-Cell and Bulk RNASeq Profiling of COVID-19 Patients Reveal Immune and Inflammatory Mechanisms of Infection-Induced Organ Damage

Viruses ◽

10.3390/v13122418 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2418

Author(s):

Alexandrea Bass ◽

Yiran Liu ◽

Sivanesan Dakshanamurthy

Keyword(s):

Immune Response ◽

Single Cell ◽

Innate Immune Response ◽

Therapeutic Targets ◽

Organ Damage ◽

Multiple Organ ◽

Innate Immune ◽

Host Protein ◽

Organ Injury ◽

Initiation Factor

The SARS-CoV-2 virus’s ability to induce hypercytokinemia and cause multiple organ failure makes it imperative to find effective treatments. To understand the mechanism of viral infection and its effects on organ tissues, we analyzed multiple single-cell and bulk RNAseq data from COVID-19 patients’ organ samples. Various levels of severity of infection were accounted for, with comparative analyses between mild, moderate, and severely infected patients. Our analysis uncovered an upregulation of the innate immune response via several inflammatory genes, IL-2, IL-6, IL-8, IL-17A, and NF-κB. Consequently, we found that the upregulation of these downstream effects can lead to organ injury. The downregulated pathways such as eukaryotic initiation factor 2 (eIF2) and eIF4-mediated host translation, were found to lead to an increased viral translation. We also found that the loss of inhibitory peptides can suppress an overactive innate immune response via NF-κB and interleukin-mediated pathways. Investigation of viral-host protein mapping showed that the interaction of viral proteins with host proteins correlated with the down- and upregulation of host pathways such as decreased eIF2-mediated host translation and increased hypertrophy and fibrosis. Inflammation was increased via the stimulation of pro-inflammatory cytokines and suppression of host translation pathways that led to reduced inflammatory inhibitors. Cardiac hypertrophy and organ fibrosis were the results of increased inflammation in organs of severe and critical patients. Finally, we identified potential therapeutic targets for the treatment of COVID-19 and its deleterious effects on organs. Further experimental investigation would conclusively determine the effects of COVID-19 infection on organs other than the lungs and the effectiveness of the proposed therapeutic targets.

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Ferroptosis in Myocardial Infarction:An Epiphenomenon or Not (Preprint)

10.2196/preprints.24953 ◽

2020 ◽

Author(s):

Sheng Kang

Keyword(s):

Neurological Diseases ◽

Therapeutic Targets ◽

Iron Chelator ◽

Organ Damage ◽

Vital Role ◽

Pathological Process ◽

Cardiac Biomarkers ◽

Death Process ◽

Voltage Dependent ◽

Cell Death Process

UNSTRUCTURED Identification of effective cardiac biomarkers and therapeutic targets for myocardial infarction (MI) will play an important role in early diagnosis and the improving prognosis. Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage, cancer, and neurological diseases. Its modulators were involved in transferrin receptor, iron chelator, and clock protein ARNTL, etc. Its mechanisms included the inhibition of the system XC-, the diminished GPX4 activity, the change of mitochondrial voltage-dependent anion channels, and the rising intracellular ROS level, etc. Further, the inhibitors of apoptosis, pyroptosis and autophagy did not prevent the occurrence of ferroptosis, but iron chelating agents and antioxidants could inhibit it. Noticeably, ferroptosis is an important pattern of cardiomyocyte death in the infarcted area, which may play a vital role in support of myocardial pathological process of heart disease. However, the molecular mechanism of ferroptosis in the pathogenesis and development of MI is not clear. Therefore, a greater depth of exploration of the mechanism of ferroptosis in MI and ferroptosis inhibitors will undoubtedly improve the pathological process of MI, which is expected to identify ferroptosis as novel diagnostic and therapeutic targets of MI.

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Ferroptosis in myocardial infarction: not a marker but a maker

Open Biology ◽

10.1098/rsob.200367 ◽

2021 ◽

Vol 11 (4) ◽

Author(s):

Xiao-dong Wang ◽

Sheng Kang

Keyword(s):

Myocardial Infarction ◽

Neurological Diseases ◽

Therapeutic Targets ◽

Iron Chelator ◽

Organ Damage ◽

Vital Role ◽

Pathological Process ◽

Cardiac Biomarkers ◽

Death Process ◽

Voltage Dependent

Identification of effective cardiac biomarkers and therapeutic targets for myocardial infarction (MI) will play an important role in early diagnosis and improving prognosis. Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage, cancer and neurological diseases. Its modulators were involved in transferrin receptor, iron chelator, clock protein ARNTL, etc. Its mechanisms included the inhibition of system X C − , diminished GPX4 activity, change of mitochondrial voltage-dependent anion channels and rising intracellular reactive oxygen species level. Further, the inhibitors of apoptosis, pyroptosis and autophagy did not prevent the occurrence of ferroptosis, but iron chelating agents and antioxidants could inhibit it. Noticeably, ferroptosis is an important pattern of cardiomyocyte death in the infarcted area, which may play a vital role in support of the myocardial pathological process of heart disease. However, the molecular mechanism of ferroptosis in the pathogenesis and the development of MI is not clear. Therefore, a greater depth of exploration of the mechanism of ferroptosis and its inhibitors will undoubtedly improve the pathological process of MI, which may be expected to identify ferroptosis as novel diagnostic and therapeutic targets of MI.

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Inflammation, Infection and Venous Thromboembolism

Circulation Research ◽

10.1161/circresaha.121.318225 ◽

2021 ◽

Vol 128 (12) ◽

pp. 2017-2036

Author(s):

Meaghan E. Colling ◽

Benjamin E. Tourdot ◽

Yogendra Kanthi

Keyword(s):

Human Physiology ◽

Venous Thromboembolism ◽

Venous Thrombosis ◽

Host Defense ◽

Therapeutic Targets ◽

Organ Damage ◽

Effective Response ◽

Pathogen Invasion ◽

Prevention And Treatment ◽

Novel Therapeutic

The association between inflammation, infection, and venous thrombosis has long been recognized; yet, only in the last decades have we begun to understand the mechanisms through which the immune and coagulation systems interact and reciprocally regulate one another. These interconnected networks mount an effective response to injury and pathogen invasion, but if unregulated can result in pathological thrombosis and organ damage. Neutrophils, monocytes, and platelets interact with each other and the endothelium in host defense and also play critical roles in the formation of venous thromboembolism. This knowledge has advanced our understanding of both human physiology and pathophysiology, as well as identified mechanisms of anticoagulant resistance and novel therapeutic targets for the prevention and treatment of thrombosis. In this review, we discuss the contributions of inflammation and infection to venous thromboembolism.

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