Bioactivities and mechanisms of natural medicines in the management of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and rare disease without obvious clinical symptoms that shares characteristics with pulmonary vascular remodeling. Right heart failure in the terminal phase of PAH seriously threatens the lives of patients. This review attempts to comprehensively outline the current state of knowledge on PAH its pathology, pathogenesis, natural medicines therapy, mechanisms and clinical studies to provide potential treatment strategies. Although PAH and pulmonary hypertension have similar pathological features, PAH exhibits significantly elevated pulmonary vascular resistance caused by vascular stenosis and occlusion. Currently, the pathogenesis of PAH is thought to involve multiple factors, primarily including genetic/epigenetic factors, vascular cellular dysregulation, metabolic dysfunction, even inflammation and immunization. Yet many issues regarding PAH need to be clarified, such as the “oestrogen paradox”. About 25 kinds monomers derived from natural medicine have been verified to protect against to PAH via modulating BMPR2/Smad, HIF-1α, PI3K/Akt/mTOR and eNOS/NO/cGMP signalling pathways. Yet limited and single PAH animal models may not corroborate the efficacy of natural medicines, and those natural compounds how to regulate crucial genes, proteins and even microRNA and lncRNA still need to put great attention. Additionally, pharmacokinetic studies and safety evaluation of natural medicines for the treatment of PAH should be undertaken in future studies. Meanwhile, methods for validating the efficacy of natural drugs in multiple PAH animal models and precise clinical design are also urgently needed to promote advances in PAH. Graphical Abstract

Efficacy and safety of fenfluramine in the treatment of Dravet syndrome - literature review

Dravet Syndrome is a severe, drug-resistant, and rare epileptiform disorder that is typically presented in the first year of life in an otherwise healthy child. It is characterized by prolonged seizures that are often resistant to current anti-epileptic drug regimens, which made them poorly controlled, and almost 50% of patients experience at least four tonic-clonic seizures per month. There are three new medicines: stiripentol, cannabidiol, and fenfluramine, with documented efficacy and safety as adjunctive therapies in pharmacoresistant Dravet syndrome treatment. This study aimed to assess the efficacy and safety of fenfluramine in the treatment of Dravet syndrome. Our study material consisted of publications, which were found in PubMed, Google Scholar, and Embase databases. In order to find the proper publications, the search has been conducted with the use of a combination of keywords like: “fenfluramine”, “Dravet syndrome”, “epilepsy treatment”, “Dravet syndrome pediatric patients”. The first step was to find proper publications from the last 10 years. The second step was to carry out an overview of the found publications. Results of mentioned studies proved that in Dravet syndrome, fenfluramine provided a significantly greater reduction in convulsive seizure frequency compared with placebo. No patient developed valvular heart disease or pulmonary arterial hypertension, the side effects that occurred during its use were mild and the drug was generally well-tolerated. The bioequivalence and tolerability of single oral doses of fenfluramine hydrochloride oral solution in the fed and fasted states support drug administration without regard to meals. Fenfluramine may represent a new important treatment option for Dravet syndrome.

Epigenetic Mechanisms as Emerging Therapeutic Targets and Microfluidic Chips Application in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a disease that progress over time and is defined as an increase in pulmonary arterial pressure and pulmonary vascular resistance that frequently leads to right-ventricular (RV) failure and death. Epigenetic modifications comprising DNA methylation, histone remodeling, and noncoding RNAs (ncRNAs) have been established to govern chromatin structure and transcriptional responses in various cell types during disease development. However, dysregulation of these epigenetic mechanisms has not yet been explored in detail in the pathology of pulmonary arterial hypertension and its progression with vascular remodeling and right-heart failure (RHF). Targeting epigenetic regulators including histone methylation, acetylation, or miRNAs offers many possible candidates for drug discovery and will no doubt be a tempting area to explore for PAH therapies. This review focuses on studies in epigenetic mechanisms including the writers, the readers, and the erasers of epigenetic marks and targeting epigenetic regulators or modifiers for treatment of PAH and its complications described as RHF. Data analyses from experimental cell models and animal induced PAH models have demonstrated that significant changes in the expression levels of multiple epigenetics modifiers such as HDMs, HDACs, sirtuins (Sirt1 and Sirt3), and BRD4 correlate strongly with proliferation, apoptosis, inflammation, and fibrosis linked to the pathological vascular remodeling during PAH development. The reversible characteristics of protein methylation and acetylation can be applied for exploring small-molecule modulators such as valproic acid (HDAC inhibitor) or resveratrol (Sirt1 activator) in different preclinical models for treatment of diseases including PAH and RHF. This review also presents to the readers the application of microfluidic devices to study sex differences in PAH pathophysiology, as well as for epigenetic analysis.

Inflammasome Activation in Pulmonary Arterial Hypertension

Inflammasomes are multi-protein complexes that sense both infectious and sterile inflammatory stimuli, launching a cascade of responses to propagate danger signaling throughout an affected tissue. Recent studies have implicated inflammasome activation in a variety of pulmonary diseases, including pulmonary arterial hypertension (PAH). Indeed, the end-products of inflammasome activation, including interleukin (IL)-1β, IL-18, and lytic cell death (“pyroptosis”) are all key biomarkers of PAH, and are potentially therapeutic targets for human disease. This review summarizes current knowledge of inflammasome activation in immune and vascular cells of the lung, with a focus on the role of these pathways in the pathogenesis of PAH. Special emphasis is placed on areas of potential drug development focused on inhibition of inflammasomes and their downstream effectors.

Computed tomography lung parenchymal descriptions in routine radiological reporting have diagnostic and prognostic utility in patients with idiopathic pulmonary arterial hypertension and pulmonary hypertension associated with lung disease

BackgroundPatients with pulmonary hypertension (PH) and lung disease may pose a diagnostic dilemma between idiopathic pulmonary arterial hypertension (IPAH) and PH associated with lung disease (PH-CLD). The prognostic impact of common CT parenchymal features is unknown.Methods660 IPAH and PH-CLD patients assessed between 2001–19 were included. Reports for all CT scans one year prior to diagnosis were analysed for common lung parenchymal patterns. Cox regression and Kaplan-Meier analysis was performed.ResultsAt univariate analysis of the whole cohort, centrilobular ground glass (CGG) changes (Hazard Ratio, HR 0.29) and ground glass opacification (GGO, HR 0.53) predicted improved survival while honeycombing (HR 2.79), emphysema (HR 2.09) and fibrosis (HR 2.38) predicted worse survival (p all <0.001). Fibrosis was an independent predictor after adjusting for baseline demographics, PH severity and DLco (HR 1.37, p<0.05). Patients with a clinical diagnosis of IPAH who had an absence of reported parenchymal lung disease (IPAH-noLD) demonstrated superior survival to patients diagnosed with either IPAH who had coexistent CT lung disease or PH-CLD (2-year survival of 85%, 60% and 46% respectively, p<0.05). CGG changes were present in 23.3% of IPAH-noLD and 5.8% of PH-CLD patients. There was no significant difference in survival between IPAH-noLD patients with or without CGG changes. PH-CLD patients with fibrosis had worse survival than those with emphysema.InterpretationRoutine clinical reports of CT lung parenchymal disease identify groups of patients IPAH and CLD-PH with significantly different prognoses. Isolated CGG changes are not uncommon in IPAH but are not associated with worse survival.

The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy

Pulmonary hypertension (PH) is characterized by increased pulmonary arterial pressure caused by the accumulation of mesenchymal-like cells in the pulmonary vasculature. PH can lead to right ventricular hypertrophy (RVH) and, ultimately, heart failure and death. In PH etiology, endothelial-to-mesenchymal transition (EndMT) has emerged as a critical process governing the conversion of endothelial cells into mesenchymal cells, and S100A4, EGF, and EGFR are implicated in EndMT. However, a potential role of S100A4, EGF, and EGFR in PH has to date not been elucidated. We therefore quantified S100A4, EGF, and EGFR in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH). To determine specificity for unilateral heart disease, the EndMT biomarker signature was further compared between PH patients presenting with RVH and patients suffering from aortic valve stenosis (AVS) with left ventricular hypertrophy. Reduced S100A4 concentrations were found in CTEPH and iPAH patients with RVH. Systemic EGF was increased in CTEPH but not in iPAH, while AVS patients displayed slightly diminished EGF levels. EGFR was downregulated in all patient groups when compared to healthy controls. Longitudinal data analysis revealed no effect of surgical therapies on EndMT markers. Pulmonary thrombo-endarterectomized samples were devoid of S100A4, while S100A4 tissue expression positively correlated with higher grades of Heath–Edwards histopathological lesions of iPAH-derived lung tissue. Histologically, EGFR was not detectable in CTEPH lungs or in iPAH lesions. Together, our data suggest an intricate role for S100A4 and EGF/EGFR in PH with right heart pathology.