Recombinant hirudin attenuates pulmonary hypertension and thrombosis in acute pulmonary embolism rat model.

Background: Acute pulmonary embolism (APE) is classified as a subset of diseases that are characterized by lung obstruction due to various types of emboli. Current clinical APE treatment using anticoagulants is frequently accompanied by high risk of bleeding complications. Recombinant hirudin (R-hirudin) has been found to have antithrombotic properties. However, the specific impact of R-hirudin on APE remains unknown. Methods: Sprague-Dawley (SD) rats were randomly assigned to five groups, with thrombi injections to establish APE models. Control and APE group rats were subcutaneously injected with equal amounts of dimethyl sulfoxide (DMSO). The APE+R-hirudin low-dose, middle-dose, and high-dose groups received subcutaneous injections of hirudin at doses of 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg, respectively. Each group was subdivided into time points of 2 h, 6 h, 1 d, and 4 d, with five animals per point. Subsequently, all rats were euthanized, and serum and lung tissues were collected. Following the assessment of right ventricular pressure (RVP) and mean pulmonary artery pressure (mPAP), blood gas analysis, enzyme-linked immunosorbnent assay (ELISA), pulmonary artery vascular testing, hematoxylin-eosin (HE) staining, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, immunohistochemistry, and Western blot experiments were conducted. Results: R-hirudin treatment caused a significant reduction of mPAP, RVP, and Malondialdehyde (MDA) content, as well as H2O2 and myeloperoxidase (MPO) activity, while increasing pressure of oxygen (PaO2) and Superoxide Dismutase (SOD) activity. R-hirudin also decreased wall area ratio and wall thickness to diameter ratio in APE rat pulmonary arteries. Serum levels of endothelin-1 (ET-1) and thromboxaneB2 (TXB2) decreased, while prostaglandin (6-K-PGF1α) and NO levels increased. Moreover, R-hirudin ameliorated histopathological injuries and reduced apoptotic cells and Matrix metalloproteinase-9 (MMP9), vascular cell adhesion molecule-1 (VCAM-1), p-Extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P65/P65 expression in lung tissues. Conclusion: R-hirudin attenuated pulmonary hypertension and thrombosis in APE rats, suggesting its potential as a novel treatment strategy for APE.

Therapeutic potential of natural flavonoids in pulmonary arterial hypertension: A review.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease caused by pulmonary vascular remodeling, with a high incidence and mortality. At present, many clinical drugs for treating PAH mainly exert effects by relaxing the pulmonary artery, with limited therapeutic effects, so the search for viable therapeutic agents continues uninterrupted. In recent years, natural flavonoids have shown promising potential in the treatment of cardiovascular diseases. It is necessary to comprehensively elucidate the potential of natural flavonoids to combat PAH. PURPOSE: To evaluate the potential of natural flavonoids to hinder or slow down the occurrence and development of PAH, and to identify promising drug discovery candidates. METHODS: Literature was collected from PubMed, Science Direct, Web of science, CNKI databases and Google scholar. The search terms used included "pulmonary arterial hypertension", "pulmonary hypertension", "natural products", "natural flavonoids", "traditional chinese medicine", etc., and several combinations of these keywords. RESULTS: The resources, structural characteristics, mechanisms, potential and prospect strategies of natural flavonoids for treating PAH were summarized. Natural flavonoids offer different solutions as possible treatments for PAH. These mechanisms may involve various pathways and molecular targets related to the pathogenesis of PAH, such as inflammation, oxidative stress, vascular remodeling, genetic, ion channels, cell proliferation and autophagy. In addition, prospect strategies of natural flavonoids for anti-PAH including structural modification and nanomaterial delivery systems have been explored. This review suggests that the potential of natural flavonoids as alternative therapeutic agents in the prevention and treatment of PAH holds promise for future research and clinical applications. CONCLUSION: Despite displaying the enormous potential of flavonoids in PAH, some limitations need to be further explored. Firstly, using advanced drug discovery tools, including computer-aided design and high-throughput screening, to further investigate the safety, biological activity, and precise mechanism of action of flavonoids. Secondly, exploring the structural modifications of these compounds is expected to optimize their efficacy. Lastly, it is necessary to conduct well controlled clinical trials and a comprehensive evaluation of potential side effects to determine their effectiveness and safety.

Salidroside protects pulmonary artery endothelial cells against hypoxia-induced apoptosis via the AhR/NF-κB and Nrf2/HO-1 pathways.

BACKGROUND: The apoptosis of pulmonary artery endothelial cells (PAECs) is an important factor contributing to the development of pulmonary hypertension (PH), a serious cardio-pulmonary vascular disorder. Salidroside (SAL) is a bioactive compound derived from an herb Rhodiola, but the potential protective effects of SAL on PAECs and the underlying mechanisms remain elusive. PURPOSE: The objective of this study was to determine the role of SAL in the hypoxia-induced apoptosis of PAECs and to dissect the underlying mechanisms. STUDY DESIGN: Male Sprague-Dawley (SD) rats were subjected to hypoxia (10% O2) for 4 weeks to establish a model of PH. Rats were intraperitoneally injected daily with SAL (2, 8, and 32 mg/kg/d) or vehicle. To define the molecular mechanisms of SAL in PAECs, an in vitro model of hypoxic cell injury was also generated by exposed PAECs to 1% O2 for 48 h. METHODS: Various techniques including hematoxylin and eosin (HE) staining, immunofluorescence, flow cytometry, CCK-8, Western blot, qPCR, molecular docking, and surface plasmon resonance (SPR) were used to determine the role of SAL in rats and in PAECs in vitro. RESULTS: Hypoxia stimulation increases AhR nuclear translocation and activates the NF-κB signaling pathway, as evidenced by upregulated expression of CYP1A1, CYP1B1, IL-1ß, and IL-6, resulting in oxidative stress and inflammatory response and ultimately apoptosis of PAECs. SAL inhibited the activation of AhR and NF-κB, while promoted the nuclear translocation of Nrf2 and increased the expression of its downstream antioxidant proteins HO-1 and NQO1 in PAECs, ameliorating the hypoxia-induced oxidative stress in PAECs. Furthermore, SAL lowered right ventricular systolic pressure, and decreased pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-exposed rats. CONCLUSIONS: SAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.

Analyzing the molecular mechanism of xuefuzhuyu decoction in the treatment of pulmonary hypertension with network pharmacology and bioinformatics and verifying molecular docking.

BACKGROUND: XueFuZhuYu (XFZY), a typical Chinese herbal formula, has remarkable clinical effects for treating Pulmonary Hypertension (PH) with unclear mechanisms. Our research involved the utilization of network pharmacology to explore the traditional Chinese herbal monomers and their related targets within XFZY for PH treatment. Furthermore, molecular docking verification was performed. METHODS: The XFZY's primary active compounds, along with their corresponding targets, were both obtained from the TCMSP, ChEMBL, and UniProt databases. The target proteins relevant to PH were sifted through OMIM, GeneCards and TTD databases. The common "XFZY-PH" targets were evaluated with Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses with the assistance of R software. The Protein-Protein Interaction (PPI) network and compound-target-pathway network were constructed and a systematic analysis of network parameters was performed by the powerful software Cytoscape. Molecular docking was employed for assessing and verifying the interactions between the core targets and the top Chinese herbal monomer. RESULTS: The screening included 297 targets of active compounds in XFZY and 8400 PH-related targets. DO analysis of the above common 268 targets indicated that the treatment of the diseases by XFZY is mediated by genes related to Chronic Obstructive Pulmonary Disease (COPD), Obstructive Lung Disease (OLD), ischemia, and myocardial infarction. The findings from molecular docking indicated that the binding energies of 57 ligand-receptor pairs in PH and 20 ligand-receptor pairs in COPD-PH were lower than -7kJ•mol-1. CONCLUSIONS: This study indicates that XFZY is a promising option within traditional Chinese medicine compound preparation for combating PH, particularly in cases associated with COPD. Our demonstration of the specific molecular mechanism of XFZY anti-PH and its effective active ingredients provides a theoretical basis for better clinical application of the compound.

Descriptive spectrum of thiamine deficiency in pregnancy: A potentially preventable condition.

OBJECTIVE: Pregnancy, a nutritionally demanding situation in terms of macro- and micronutrient supply owing to heightened maternal, placental, and fetal needs, significantly affects thiamine reserves. Thiamine deficiency during pregnancy and the postpartum period, presenting with varied manifestations and outcomes, is a relatively common condition in our population. The study aimed to understand the various manifestations and outcomes of acute thiamine deficiency in pregnant and postpartum women, emphasizing the significance of early recognition and thiamine therapy to prevent serious complications during pregnancy and after childbirth. METHODS: This prospective study conducted in a tertiary care center in North India enrolled consecutive pregnant and postpartum women presenting with clinical features consistent with thiamine deficiency disorders, such as thiamine deficiency-related neuropathy, high-output heart failure, heart failure with reduced ejection fraction, Wernicke's encephalopathy, gastric beriberi, and thiamine-responsive acute pulmonary hypertension. In addition to capturing medical history including drug intake, dietary consumption, and comorbidities, women underwent brief relevant clinical examinations and laboratory assessments, including whole-blood thiamine levels. Response to intravenous thiamine supplementation was also monitored. RESULTS: Data of 31 women (12 pregnant, 19 postpartum) with a diagnosis of acute thiamine deficiency and a mean age of 28.88 ± 2.69 years were analyzed. The mean thiamine level was 1.28 ± 0.44 µg/dL with mean blood lactate of 3.46 ± 3.33. The most common presentation was gastric beriberi (n = 10), followed by paraparesis (n = 6), high-output heart failure (n = 6), acute pulmonary hypertension, heart failure with reduced ejection fraction (n = 3 each), and an acute confusional state (n = 2). All patients responded to thiamine challenge. CONCLUSION: In the context of borderline thiamine status, particularly in our population with endemic thiamine deficiency and heightened demand for thiamine during pregnancy and the peripartum period, the deficiency can have varied and serious manifestations of dry and wet beriberi. Early recognition of the clinical features and thiamine therapy can be life-saving. There is a need for validated clinical criteria owing to the non-availability of thiamine testing in resource-limited settings.

Rieske Iron-Sulfur Protein Mediates Pulmonary Hypertension Following Nicotine/Hypoxia Coexposure.

The high mortality rate in patients with chronic obstructive pulmonary disease (COPD) may be due to pulmonary hypertension (PH). These diseases are highly associated with cigarette smoke and its key component nicotine. Here, we created a novel animal model of PH using coexposure to nicotine (or cigarette smoke) and hypoxia. This heretofore unreported model showed significant early-onset pulmonary vasoremodeling and PH. Using newly generated mice with complementary smooth muscle-specific Rieske iron-sulfur protein (RISP) gene knockout and overexpression, we demonstrate that RISP is critically involved in promoting pulmonary vasoremodeling and PH, which are implemented by oxidative ataxia telangiectasia-mutated-mediated DNA damage and NF-κB-dependent inflammation in a reciprocal positive mechanism. Together, our findings establish for the first time an animal model of hypoxia-induced early-onset PH in which mitochondrial RISP-dependent DNA damage and NF-κB inflammation play critical roles in vasoremodeling. Specific therapeutic targets for RISP and related oxidative stress-associated signaling pathways may create unique and effective treatments for PH, chronic obstructive pulmonary disease, and their complications.

Astragaloside IV restrains pyroptosis and fibrotic development of pulmonary artery smooth muscle cells to ameliorate pulmonary artery hypertension through the PHD2/HIF1α signaling pathway.

BACKGROUND: Astragaloside (AS)-IV, extracted from traditional Chinese medicine Astragalus mongholicus, has been widely used in the anti-inflammatory treatment for cardiovascular disease. However, the mechanism by which AS-IV affects pulmonary artery hypertension (PAH) development remains largely unknown. METHODS: Monocrotaline (MCT)-induced PAH model rats were administered with AS-IV, and hematoxylin-eosin staining and Masson staining were performed to evaluate the histological change in pulmonary tissues of rats. Pulmonary artery smooth muscle cells (PASMCs) were treated by hypoxia and AS-IV. Pyroptosis and fibrosis were assessed by immunofluorescence, western blot and enzyme-linked immunosorbent assay. RESULTS: AS-IV treatment alleviated pulmonary artery structural remodeling and pulmonary hypertension progression induced by MCT in rats. AS-IV suppressed the expression of pyroptosis-related markers, the release of pro-inflammatory cytokine interleukin (IL)-1ß and IL-18 and fibrosis development in pulmonary tissues of PAH rats and in hypoxic PAMSCs. Interestingly, the expression of prolyl-4-hydroxylase 2 (PHD2) was restored by AS-IV administration in PAH model in vivo and in vitro, while hypoxia inducible factor 1α (HIF1α) was restrained by AS-IV. Mechanistically, silencing PHD2 reversed the inhibitory effect of AS-IV on pyroptosis, fibrosis trend and pyroptotic necrosis in hypoxia-cultured PASMCs, while the HIF1α inhibitor could prevent these PAH-like phenomena. CONCLUSION: Collectively, AS-IV elevates PHD2 expression to alleviate pyroptosis and fibrosis development during PAH through downregulating HIF1α. These findings may provide a better understanding of AS-IV preventing PAH, and the PHD2/HIF1α axis may be a potential anti-pyroptosis target during PAH.

Research Progress of Inflammatory Factors in Chronic Obstructive Pulmonary Disease with Pulmonary Hypertension at High Altitude.

Chronic obstructive pulmonary disease (COPD) is currently one of the highest morbidity and mortality worldwide, a serious public health problem. Pulmonary hypertension is a common complication of COPD. At present, the pathogenesis of pulmonary hypertension is not clear. A concise overview of the known factors contributing to pulmonary hypertension in COPD includes hypoxia and inflammation. Hypoxia, resulting from lung damage and inadequate oxygen supply, can lead to pulmonary vasoconstriction and increased vascular resistance, thus contributing to the development of pulmonary hypertension in COPD patients. Inflammation also plays a significant role in the progression of pulmonary hypertension. COPD patients exhibit inflammatory responses in their lung tissues, with the release of various inflammatory mediators. These mediators can stimulate abnormal proliferation of endothelial cells and smooth muscle cells within the pulmonary arteries, leading to vascular wall thickening and restricted blood flow. This paper focuses on the pathogenesis of four inflammatory factors, namely interleukin (IL-1ß), IL-6, IL-8, and tumor necrosis factor (TNF)-α, in pulmonary hypertension. IL-1ß, IL-6, IL-8, and TNF-α are known as pro-inflammatory cytokines that play crucial roles in the inflammatory response. In the context of pulmonary hypertension, these inflammatory factors have been implicated in the remodeling of the pulmonary vasculature, leading to increased vascular resistance and impaired blood flow. The research presented in this paper will delve into the current scientific knowledge surrounding IL-1ß, IL-6, IL-8, and TNF-α, and their roles in pulmonary vascular remodeling, endothelial dysfunction, smooth muscle cell proliferation, and inflammation. The goal is to provide a comprehensive overview of their involvement in pulmonary hypertension and how these factors may be influenced by the hypoxic environment prevalent in high-altitude regions. By focusing on the relevance of these inflammatory factors in high-altitude areas, we hope to contribute valuable insights that can inform clinical management strategies, prevention approaches, and potential therapeutic interventions for individuals residing in such regions who are at an increased risk of developing pulmonary hypertension.

An optimized machine learning method for predicting wogonin therapy for the treatment of pulmonary hypertension.

Human health is at risk from pulmonary hypertension (PH), characterized by decreased pulmonary vascular resistance and constriction of the pulmonary vessels, resulting in right heart failure and dysfunction. Thus, preventing PH and monitoring its progression before treating it is vital. Wogonin, derived from the leaves of Scutellaria baicalensis Georgi, exhibits remarkable pharmacological activity. In this study, we examined the effectiveness of wogonin in mitigating the progression of PH in mice using right heart catheterization and hematoxylin-eosin (HE) staining. As an alternative to minimize the possibility of harming small animals, we present a scientifically effective feature selection method (BSCDWOA-KELM) that will allow us to develop a novel simpler noninvasive prediction method for wogonin in treating PH. In this method, we use the proposed enhanced whale optimizer (SCDWOA) in conjunction with the kernel extreme learning machine (KELM). Initially, we let SCDWOA perform global optimization experiments on the IEEE CEC2014 benchmark function set to verify its core advantages. Lastly, 12 public and PH datasets are examined for feature selection experiments using BSCDWOA-KELM. As shown in the experimental results for global optimization, the proposed SCDWOA has better convergence performance. Meanwhile, the proposed binary SCDWOA (BSCDWOA) significantly improves the ability of KELM to classify data. By utilizing the BSCDWOA-KELM, key indicators such as the Red blood cell (RBC), the Haemoglobin (HGB), the Lymphocyte percentage (LYM%), the Hematocrit (HCT), and the Red blood cell distribution width-size distribution (RDW-SD) can be efficiently screened in the Pulmonary hypertension dataset, and one of its most essential points is its accuracy of greater than 0.98. Consequently, the BSCDWOA-KELM introduced in this study can be used to predict wogonin therapy for treating pulmonary hypertension in a simple and noninvasive manner.

Effects of Inspiratory Muscle Training in Patients With Pulmonary Hypertension.

The study aimed to examine the effects of inspiratory muscle training (IMT) in patients with pulmonary hypertension (PH). A total of 24 patients with PH were included in the randomized controlled evaluator-blind study. IMT was performed at 40% to 60% of the maximal inspiratory pressure for 30 min/d, 7 d/wk (1 day supervised) for 8 weeks. Respiratory muscle strength, dyspnea, diaphragm thickness (DT), pulmonary functions, 24-hour ambulatory blood pressure (BP), arterial stiffness, exercise capacity, upper extremity functional exercise capacity, physical activity levels, fatigue, anxiety-depression levels, activities of daily living (ADL), and quality of life were evaluated. A total of 24 patients (treatment = 12, control = 12) completed the 8-week follow-up. There was no significant difference between the patient groups in terms of demographic and clinical characteristics (p >0.05). Considering the change between the groups in the treatment and control groups, brachial and central BP, dyspnea, respiratory muscle strength, DT in total lung capacity, knee extension muscle strength, functional exercise capacity, upper extremity functional exercise capacity, physical activity, ADL, fatigue, anxiety, and quality of life improved in favor of the IMT group (p <0.05). In conclusion, IMT has improved brachial and central BP, dyspnea, respiratory muscle strength, DT in total lung capacity, knee extension muscle strength, functional exercise capacity, upper extremity functional exercise capacity, physical activity, ADL, fatigue, anxiety, and quality of life compared with the control group. IMT is an effective method in cardiopulmonary rehabilitation for patients with PH.

[Compound Tinglizi Decoction intervenes COPD-associated pulmonary hypertension through regulation of HMGB1-mediated pyroptosis and immune imbalance].

This paper aimed to investigate the effects of high mobility group box 1(HMGB1)-mediated pulmonary artery smooth muscle cell pyroptosis and immune imbalance on chronic obstructive pulmonary disease-associated pulmonary hypertension(COPD-PH) in rats and the intervening mechanism of Compound Tinglizi Decoction. Ninety rats were randomly divided into a normal group, a model group, low-dose, medium-dose, and high-dose Compound Tinglizi Decoction groups, and a simvastatin group. The rat model of COPD-PH was established by fumigation combined with lipopolysaccharide(LPS) intravascular infusion, which lasted 60 days. Rats in the low, medium, and high-dose Compound Tinglizi Decoction groups were given 4.93, 9.87, and 19.74 g·kg~(-1) Compound Tinglizi Decoction by gavage, respectively. Rats in the simvastatin group were given 1.50 mg·kg~(-1) simvastatin by gavage. After 14 days, the lung function, mean pulmonary artery pressure, and arterial blood gas of rats were analyzed. Lung tissues of rats were collected for hematoxylin-eosin(HE) staining to observe the pathological changes. Real-time fluorescent quantitative polymerase chain reaction(qRT-PCR) was used to determine the expression of related mRNA in lung tissues, Western blot(WB) was used to determine the expression of related proteins in lung tissues, and enzyme linked immunosorbent assay(ELISA) was used to determine the levels of inflammatory factors in the lung tissues of rats. The ultrastructure of lung cells was observed by transmission electron microscope. The forced vital capacity(FVC), forced expiratory volume in 0.3 second(FEV_(0.3)), FEV_(0.3)/FVC, peek expiratory flow(PEF), respiratory dynamic compliance(Cdyn), arterial partial pressure of oxygen(PaO_2), and arterial oxygen saturation(SaO_2) were increased, and resistance of expiration(Re), mean pulmonary arterial pressure(mPAP), right ventricular hypertrophy index(RVHI), and arterial partial pressure of carbon dioxide(PaCO_2) were decreased by Compound Tinglizi Decoction in rats with COPD-PH. Compound Tinglizi Decoction inhibited the protein expression of HMGB1, receptor for advanced glycation end products(RAGE), pro caspase-8, cleaved caspase-8, and gasdermin D(GSDMD) in lung tissues of rats with COPD-PH, as well as the mRNA expression of HMGB1, RAGE, and caspase-8. Pulmonary artery smooth muscle cell pyroptosis was inhibited by Compound Tinglizi Decoction. Interferon-γ(IFN-γ) and interleukin-17(IL-17) were reduced, and interleukin-4(IL-4) and interleukin-10(IL-10) were incresead by Compound Tinglizi Decoction in lung tissues of rats with COPD-PH. In addition, the lesion degree of trachea, alveoli, and pulmonary artery in lung tissues of rats with COPD-PH was improved by Compound Tinglizi Decoction. Compound Tinglizi Decoction had dose-dependent effects. The lung function, pulmonary artery pressure, arterial blood gas, inflammation, trachea, alveoli, and pulmonary artery disease have been improved by Compound Tinglizi Decoction, and its mechanism is related to HMGB1-mediated pulmonary artery smooth muscle cell pyroptosis and helper T cell 1(Th1)/helper T cell 2(Th2), helper T cell 17(Th17)/regulatory T cell(Treg) imbalance.

A Meta-analysis Assessing the Efficacy of Balloon Pulmonary Angioplasty in Resolving Chronic Thromboembolic Pulmonary Hypertension.

Background and Purpose: Chronic thromboembolic pulmonary hypertension (CTEPH) is the fourth most common form of pulmonary hypertension (PH), representing a pre-capillary manifestation of the disorder. This meta-analysis aims to evaluate the role of balloon pulmonary angioplasty (BPA) in the treatment of CTEPH. Methods: Our investigation was conducted using PubMed, Embase, Cochrane Library, and Web of Science platforms. Results: This meta-analysis includes the analysis of seven studies. BPA demonstrated a significant reduction in pulmonary arterial pressure in CTEPH patients (Mean difference (MD) = -9.80, 95% CI: -1.10 to -8.59, P < .00001). BPA also resulted in a decrease in pulmonary vascular resistance in CTEPH patients (MD = -4.70, 95% CI: -7.17 to -2.22, P = .0002). Moreover, BPA was associated with improved 6-minute walk distance of CTEPH patients (MD = 43.86, 95% CI: 26.19 to 61.53, P < .00001). Additionally, BPA led to a reduction in NT-proBNP levels in CTEPH patients (MD = -3.46, 95% CI: -10.63 to 3.71, p-value = 0.34). BPA also resulted in an improvement in the WHO functional class of CTEPH patients, with an increase in class I-II (MD = 0.28, 95% CI: 0.22 to 0.35, P < .00001) and a decrease in class III-IV (MD = 0.16, 95% CI: 0.10 to 0.26, P < .00001). Conclusion: These findings support the effectiveness of BPA as an alternative treatment option for CTEPH patients, leading to improvements in prognostic factors such as hemodynamics, functional ability, and biomarkers. BPA may offer enhanced therapeutic benefits and potentially serve as an alternative treatment for select CTEPH patients.

Severe Pulmonary Arterial Hypertension in Healthy Young Infants: Single Center Experience.

OBJECTIVE: We studied the clinical presentation and management of acute pulmonary arterial hypertension (PAH) in healthy young infants, and the effect of thiamine therapy. METHODS: Review of hospital records was conducted for 56 healthy infants (aged below 6 month) who developed sudden onset of pulmonary arterial hypertension as diagnosed on 2D echocardiography, and were admitted at our institution. RESULTS: All patients received supportive care and pulmonary vasodilator therapy, whereas those admitted after Sep-tember, 2019 (n=28) received thiamine in addition, as per the institute's protocol. Overall, complete recovery was seen in 80% (n=45). Infants who died had significantly lower mean pH (7.05 vs 7.27; P=0.001) and serum bicarbonate (9.1 vs 14.9; P=0.007), higher arterial lactate (72.7 vs 61.5; P=0.92), ventricular dysfunction (16 vs 10; P=0.01) and shock (7 vs 9; P=0.008) when compared to those who survived. Baseline characteristics, severity of acidosis and pulmonary hypertension, time taken to recover from PAH, presence of ventricular dysfunction were comparable among those who received thiamine and those who did not receive it. Similarly, recovery (89% vs 71%; P=0.17) and mortality (11% vs 29%) were also comparable between the two groups. CONCLUSIONS: A significant proportion of infants with PAH improve with supportive treatment and pulmonary vasodilator therapy. Thiamine supplementation may not give any additional benefit in these patients.

HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo.

BACKGROUND: HMGB1 and ER stress have been considered to participate in the progression of pulmonary artery hypertension (PAH). However, the molecular mechanism underlying HMGB1 and ER stress in PAH remains unclear. This study aims to explore whether HMGB1 induces pulmonary artery smooth muscle cells (PASMCs) functions and pulmonary artery remodeling through ER stress activation. METHODS: Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. Cell proliferation and migration were determined by CCK-8, EdU and transwell assay. Western blotting was conducted to detect the protein levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor-4 (ATF4), seven in absentia homolog 2 (SIAH2) and homeodomain interacting protein kinase 2 (HIPK2). Hemodynamic measurements, immunohistochemistry staining, hematoxylin and eosin staining were used to evaluate the development of PAH. The ultrastructure of ER was observed by transmission electron microscopy. RESULTS: In primary cultured PASMCs, HMGB1 reduced HIPK2 expression through upregulation of ER stress-related proteins (PERK and ATF4) and subsequently increased SIAH2 expression, which ultimately led to PASMC proliferation and migration. In MCT-induced PAH rats, interfering with HMGB1 by glycyrrhizin, suppression of ER stress by 4-phenylbutyric acid or targeting SIAH2 by vitamin K3 attenuated the development of PAH. Additionally, tetramethylpyrazine (TMP), as a component of traditional Chinese herbal medicine, reversed hemodynamic deterioration and vascular remodeling by targeting PERK/ATF4/SIAH2/HIPK2 axis. CONCLUSIONS: The present study provides a novel insight to understand the pathogenesis of PAH and suggests that targeting HMGB1/PERK/ATF4/SIAH2/HIPK2 cascade might have potential therapeutic value for the prevention and treatment of PAH.

Identification and characterization of the new generation soluble guanylate cyclase stimulator BAY-747 designed for the treatment of resistant hypertension.

BACKGROUND AND PURPOSE: First-generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat). However, given the broad therapeutic opportunities for sGC stimulators, tailored molecules for distinct indications are required. EXPERIMENTAL APPROACH: We report the high-throughput screening (HTS)-based discovery of a second generation of sGC stimulators from a novel imidazo[1,2-a]pyridine lead series. An intense medicinal chemistry programme resulted in the discovery of the sGC stimulator BAY 1165747 (BAY-747). The pharmacokinetic profile of BAY-747 was determined in different species, and it was broadly characterized in pharmacological model systems relevant for vasodilatation and hypertension. KEY RESULTS: BAY-747 is a highly potent sGC stimulator in vitro. In addition, BAY-747 showed an excellent pharmacokinetic profile with long half-life and low peak-to-trough ratio. BAY-747 was investigated in experimental in vivo models of malignant and resistant hypertension (rHT). In spontaneously hypertensive (SH) rats, BAY-747 caused a dose-related and long-lasting decrease in mean arterial blood pressure (MAP). Oral treatment over 12 days resulted in a persistent decrease. BAY-747 provided additional benefit when dosed on top of losartan, amlodipine or spironolactone and even on top of triple combinations of frequently used antihypertensive drugs. In a new canine model of rHT, BAY-747 caused a dose-related and long-lasting (>6 h) MAP decrease. CONCLUSION AND IMPLICATIONS: BAY-747 is a potent, orally available sGC stimulator. BAY-747 shows long-acting pharmacodynamic effects with a very low peak-to-trough ratio. BAY-747 could be a treatment alternative for patients with hypertension, especially those not responding to standard-of-care therapy.

Jiedu Quyu Decoction mitigates monocrotaline-induced right-sided heart failure associated with pulmonary artery hypertension by inhibiting NLRP3 inflammasome in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Right-side heart failure could accelerate mortality in patients of pulmonary hypertension, Jiedu Quyu Decoction (JDQYF) was used to manage pulmonary hypertension, but its right-sided heart protective effect associated with pulmonary artery hypertension is still unclear. AIM OF THE STUDY: Here, we evaluated the therapeutic effect of JDQYF on monocrotaline-induced right-sided heart failure associated with pulmonary arterial hypertension in Sprague-Dawley (SD) rats and investigated the potential mechanism of action. MATERIALS AND METHODS: The main chemical components of JDQYF were detected and analyzed using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. The effects of JDQYF were investigated using a rat model of monocrotaline-induced right-sided heart failure associated with pulmonary arterial hypertension. We assessed the morphology of cardiac tissue using histopathology and the structure and function of the right heart using echocardiography. The biomarkers of heart failure, atrial natriuretic peptide and B-type natriuretic peptide, as well as serum pro-inflammatory markers, interleukin (IL)-1ß, and IL-18, were measured by enzyme-linked immunosorbent assay (ELISA). Furthermore, the mRNA and protein expression levels of NLRP3 (NOD-, LRR-, and pyrin domain-containing 3), capase-1, IL-1ß, and IL-18 in the right heart tissue were examined by real-time quantitative reverse transcription PCR and western blotting. RESULTS: JDQYF improved ventricular function, alleviated pathological lesions in the right cardiac tissue, reduced the expression levels of biomarkers of heart failure and serum pro-inflammatory factors (IL-1ß and IL-18), and downregulated the mRNA and protein expression levels of NLRP3, caspase-1, IL-1ß, and IL-18 in the right cardiac tissue. CONCLUSIONS: JDQYF possesses cardioprotective effect against right heart failure induced by pulmonary arterial hypertension, possibly owing to reduction of cardiac inflammation through the inhibition of NLRP3 inflammasome activation.

THROMBOLYSIS IN PULMONARY EMBOLISM TREATMENT.

OBJECTIVE: The aim: To assess the effectiveness of thrombolytic therapy in treatment pulmonary embolism. PATIENTS AND METHODS: Materials and methods: The work analyzed the results of the survey and conservative treatment of 284 patients with pulmonary embolism treated in cardiological department in «Uzhgorod Central City Clinical Hospital¼ during 2019-2022. Patients were divided into two groups: group I - 250 (88%) patients received anticoagulant therapy; group II - 34 (12%) patients received thrombolytic therapy that was then switched to new oral anticoagulants. RESULTS: Results: In I group, the first three days were carried out continuously intravenous infusion of heparin in a dose of 25-30 thousand units per day, on the fourth day switched to subcutaneous injection for 10-14 days with subsequent switching to rivaroxaban. 34 (12.0%) patients of the II group, was started with thrombolytic therapy. 32 (94.1%) patients were prescribed alteplase 100 mg/day, and 2 (5.9%) patients - streptokinase 1.5 million units/day. After thrombolysis, patients were prescribed rivaroxaban for prolonged period. Thrombolytic therapy made it possible to prevent fatal cases, and in monotherapy with anticoagulants - mortality was 4.8%. Minor hemorrhagic complications like hematuria, local hematomas at the injection site, bleeding gums were observed in 7.6% of patients during thrombolytic therapy. No cases of large hemorrhages were observed. Manifestations of chronic postembolic pulmonary hypertension in the distant period were found in 97.1% and 6.9% of patients of the I and II groups, respectively. Lethality in the remote period was 5.3% - all in the 1st group of patients due to PE recurrence and acute myocardial infarction. CONCLUSION: Conclusions: Implementation of thrombolytic therapy in patients with thromboembolism of the pulmonary artery allows effectively prevent recurrence with a fatal outcome, restore the lumen of the pulmonary arteries and prevent the development of chronic postembolic pulmonary hypertension in the immediate and remote period of observation compared to isolated anticoagulant therapy.