The renin-angiotensin system (RAS) conceived as a coordinated hormonal cascade plays an important role in controlling multiple functions in many organs and is much more complex than previously thought. The RAS has continued to expand, with the identification of new components, functions and subsystems. Angiotensin-converting enzyme (ACE) and its novel homolog angiotensin converting enzyme 2 (ACE2) are two key enzymes involved in the synthesis of bioactive components of the RAS. The main active peptides of the RAS include angiotensin II (Ang II), Ang III, Ang IV, and angiotensin-(1-7) [Ang-(1-7)] among which Ang II and Ang-(1-7) are much more important in health and disease. The axis formed by ACE2 represents an endogenous counter-regulatory pathway within the RAS, and its actions are opposite to those of the ACE axis. Conventionally the RAS has been considered to be important in the cardiovascular system, metabolism, cell growth and homeostasis. In recent years, a key role of ACE and ACE2 and their peptides has been recognized in the inflammatory process in conditions such as cardiac hypertrophy, pulmonary hypertension, glomerulonephritis, lung injury, sepsis, and acute pancreatitis. Investigations are ongoing to better understand the role of the RAS in inflammation. A comprehensive understanding of the RAS components in inflammation can provide new possibilities for therapeutic approaches against inflammatory diseases. In this review, we discuss our current understanding of the subject, based on recent findings, on the role of ACE and ACE2 in inflammation.

MicroRNAs (miRs) are emerging as attractive therapeutic targets because of their small size, specific targetability, and critical role in disease pathogenesis. However, <20 miR targeting molecules have entered clinical trials, and none progressed to phase III. The difficulties in miR target identification, the moderate efficacy of miR inhibitors, cell type-specific delivery, and adverse outcomes have impeded the development of miR therapeutics. These hurdles are rooted in the functional complexity of miR’s role in disease and sequence complementarity-dependent/-independent effects in nontarget tissues. The advances in understanding miR’s role in disease, the development of efficient miR inhibitors, and innovative delivery approaches have helped resolve some of these hurdles. In this review, we provide a multidisciplinary viewpoint on the challenges and opportunities in the development of miR therapeutics.

Significance: Inflammation is a normal response to injury, but uncontrolled inflammation can lead to several diseases. In recent years, research has shown endogenously synthesized hydrogen sulfide (H₂S) to be a novel mediator of inflammation. This review summarizes the current understanding and recent advances of H₂S role with respect to inflammation in different diseases. Recent Advances: Promising early results from clinical studies suggest an important role of H₂S in human inflammatory disease. Critical Issues: Defining the precise mechanism by which H₂S contributes to inflammation is a complex challenge, and there is active ongoing research that is focused on addressing this question. Most of this work has been conducted on animal models of human disease and isolated/cultured cells, and its translation to the clinic is another challenge in the area of H₂S research. Future Directions: Defining the mechanism by which H₂S acts as an inflammatory mediator will help us better understand different inflammatory diseases and help develop novel therapeutic approaches for these diseases.

MiRNA-155 (miR-155) is overexpressed in various types of lymphomas and leukemias, suggesting that targeting miR-155 could be a potential platform for the development of precision medicine. Here, we tested the anticancer activity of novel, chemically modified, triplex peptide nucleic acid (PNA)–based antimiRs compared with the current state-of-the-art conventional full-length antimiRs. Next-generation modified PNAs that bound miR-155 by Watson–Crick and Hoogsteen domains possessed superior therapeutic efficacy in vivo and ex vivo compared with conventional full-length anti–miR-155. The efficacy of anti–miR-155 targeting in multiple lymphoma cell lines was comprehensively corroborated by gene expression, Western blot analysis, and cell viability–based functional studies. Finally, preclinical testing in vivo in xenograft mouse models containing lymphoma cell lines demonstrated that treatment with the miR-155-targeting next-generation antimiR resulted in a significant decrease in miR-155 expression, followed by reduced tumor growth. These findings support the effective therapeutic application of chemically modified triplex PNAs to target miR-155 to treat lymphoma. Overall, the present proof-of-concept study further implicates the potential for next-generation triplex gamma PNAs to target other miRNAs for treating cancer.Significance: This study demonstrates the utility of novel oncomiR inhibitors as cancer therapeutics, providing a new approach for targeting miRNAs and other noncoding RNAs.

Hydrogen sulfide (H₂S), produced by the activity of cystathionine-gamma-lyase (CSE), is a key mediator of inflammation in sepsis. The liver sinusoidal endothelial cells (LSECs) are important target and mediator of sepsis. The aim of this study was to investigate the role of CSE-derived H₂S on inflammation and LSECs fenestrae in caecal-ligation and puncture (CLP)-induced sepsis using CSE KO mice. Sepsis was induced by CLP, and mice (C57BL/6J, male) were sacrificed after 8 hours. Liver, lung, and blood were collected and processed to measure CSE expression, H₂S synthesis, MPO activity, NF-κB p65, ERK1/2, and cytokines/chemokines levels. Diameter, frequency, porosity and gap area of the liver sieve were calculated from scanning electron micrographs of the LSECs. An increased CSE expression and H₂S synthesizing activity in the liver and lung of wild-type mice following CLP-induced sepsis. This was associated with an increased liver and lung MPO activity, and increased liver and lung and plasma levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and the chemokines MCP-1 and MIP-2α. Conversely, CSE KO mice had less liver and lung injury and reduced inflammation following CLP-induced sepsis as evidenced by decreased levels of H₂S synthesizing activity, MPO activity, and pro-inflammatory cytokines/chemokines production. Extracellular-regulated kinase (ERK1/2) and nuclear factor-κB p65 (NF-κB) became significantly activated after the CLP in WT mice but not in CSE KO mice. In addition, CLP-induced damage to the LSECs, as indicated by increased defenestration and gaps formation in the LSECs compared to WT sham control. CSE KO mice showed decreased defenestration and gaps formation following sepsis. Mice with CSE (an H₂S synthesising enzyme) gene deletion are less susceptible to CLP-induced sepsis and associated inflammatory response through ERK1/2-NF-κB p65 pathway as evidenced by reduced inflammation, tissue damage, and LSECs defenestration and gaps formation.