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.

An Unusual Etiology of Severe Right Heart Failure Deserving of Wider Recognition.

A previously healthy 31-year-old man presented with worsening shortness of breath and a petechial rash. Echocardiography showed severe right-sided heart failure with midsystolic notching of the antegrade right ventricular outflow Doppler envelope suggesting pulmonary hypertension. An extensive work-up revealed scurvy, with a dramatic resolution of symptoms shortly after vitamin C supplementation.

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.

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.

Aureane-type sesquiterpene tetraketides as a novel class of immunomodulators with interleukin-17A inhibitory activity.

Interleukin (IL)-17A, a pro-inflammatory cytokine, is a fundamental function in the onset and advancement of multiple immune diseases. To uncover the primary compounds with IL-17A inhibitory activity, a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions. Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus, Myrothecium gramineum, showed remarkable IL-17A inhibitory activity. Nine new aureane-type sesquiterpene tetraketides, myrogramins A-I (1, 4-11), and two known ones (2 and 3) were isolated and identified from the strain. Compounds 1, 3, 4, 10, and 11 exhibited significant IL-17A inhibitory activity. Among them, compound 3, with a high fermentation yield dose-dependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions. Strikingly, compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension. Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity, and hold great promise applications in treating IL-17A-mediated immune diseases.

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.

Inhaled iloprost is an effective alternative therapy for persistent pulmonary hypertension in newborns.

Persistent pulmonary hypertension of the newborn (PPHN) is one of the diseases of the neonate with severe potential morbidity and mortality. Inhaled iloprost, a stable prostacyclin analog, has been suggested as an alternative treatment for inhaled nitric oxide (iNO). However, more data on neonates' dosing, setting, and effectiveness still needs to be solved. This study suggests using inhaled iloprost as rescue therapy for PPHN based on our experience. This was a retrospective study. The data from medical records of six newborns diagnosed with PPHN and had received inhaled iloprost from December 2019 to April 2022 were collected. Demographic and clinical features, dosing regimen, changes in oxygenation index, echocardiographic findings, and mortality were evaluated. The inhalation dose was 2-4 mcg/dose, and 3-48 inhalations per day were applied over 2-7 days. Inhaled iloprost was effective in all patients. No side effects were attributable to inhaled iloprost, and no mortality was recorded. Our experience suggests that inhaled iloprost can be used as a first-line therapy in newborn infants with PPHN when iNO is unavailable. However, there are large fluctuations in the oxygenation index due to the setting.

Future Comorbidities in an Aging Cystic Fibrosis Population.

Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. With the advent of highly effective modulator therapy targeting the abnormal CFTR protein, people with CF (PwCF) are living more than 40 years longer than the pre-modulator therapy era. As a result, PwCF are facing new challenges of managing similar comorbidities affecting the average aging population. While CF is notoriously identified as a chronic respiratory disease, the multisystem presence of the CFTR gene can contribute to other organ-related complications acutely, but also heighten the likelihood of chronic conditions not routinely encountered in this cohort. In this overview, we will focus on risk factors and epidemiology for PwCF as they relate to cardiovascular disease, dyslipidemia, CF-related diabetes, pulmonary hypertension, obstructive sleep apnea, CF-liver disease, bone health and malignancy. With increased awareness of diseases affecting a newly aging CF population, a focus on primary and secondary prevention will be imperative to implementing a comprehensive care plan to improve long-term morbidity and mortality.

[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.

Impact of l-citrulline on nitric oxide signaling and arginase activity in hypoxic human pulmonary artery endothelial cells.

Impaired nitric oxide (NO) signaling contributes to the development of pulmonary hypertension (PH). The l-arginine precursor, l-citrulline, improves NO signaling and has therapeutic potential in PH. However, there is evidence that l-citrulline might increase arginase activity, which in turn, has been shown to contribute to PH. Our major purpose was to determine if l-citrulline increases arginase activity in hypoxic human pulmonary artery endothelial cells (PAECs). In addition, to avoid potential adverse effects from high dose l-citrulline monotherapy, we evaluated whether the effect on NO signaling is greater using co-treatment with l-citrulline and another agent that improves NO signaling, folic acid, than either alone. Arginase activity was measured in human PAECs cultured under hypoxic conditions in the presence of l-citrulline (0-1 mM). NO production and endothelial nitric oxide synthase (eNOS) coupling, as assessed by eNOS dimer-to-monomer ratios, were measured in PAECs treated with l-citrulline and/or folic acid (0.2 µM). Arginase activity increased in hypoxic PAECs treated with 1 mM but not with either 0.05 or 0.1 mM l-citrulline. Co-treatment with folic acid and 0.1 mM l-citrulline increased NO production and eNOS dimer-to-monomer ratios more than treatment with either alone. The potential to increase arginase activity suggests that there might be plasma l-citrulline concentrations that should not be exceeded when using l-citrulline to treat PH. Rather than progressively increasing the dose of l-citrulline as a monotherapy, co-therapy with l-citrulline and folic acid merits consideration, due to the possibility of achieving efficacy at lower doses and minimizing side effects.

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.

Management of neonatal pulmonary hypertension-a survey of neonatal intensive care units in India.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition associated with significant morbidity and mortality. First-line diagnostic and treatment options such as echocardiography and inhaled nitric oxide (iNO) are not routinely available in resource limited settings and alternative treatment modalities need to be utilized. This study was conducted to assess current diagnostic and management strategies used for PPHN in Indian neonatal intensive care units (NICUs). METHODS: A questionnaire in multiple choice question format was sent to practising neonatologists in India via an online survey tool between July to August 2021. Information pertaining to demographic data, diagnostic criteria and management strategies of PPHN was requested. The responses were collated and information processed. RESULTS: There were 118 respondent NICUs (response rate 74%). The majority of neonatal units (65%) admitted an average of 1-3 patients of PPHN per month. Targeted neonatal echocardiography (TnECHO) was practised in 80% of the units. Most common management strategies being followed were pulmonary vasodilators (88.1%), inotropes (85.6%), conventional ventilation (68.6%) and high frequency ventilation (59.3%). The most preferred pulmonary vasodilator was sildenafil (79%) and inotropic agent was milrinone (32%). Only 25% of respondents reported use of iNO. None of the participating units used extracorporeal membrane oxygenation. CONCLUSION: We found wide variability in management practices of PPHN across Indian NICUs. Non-selective pulmonary vasodilators are more widely used than iNO. There is an urgent need for structured TnECHO training programs and evidence based national guidelines for standardized management of PPHN as per availability of resources in India. Additional research on low cost alternative therapies to iNO in Indian settings might be helpful.

Dramatically Improved Severe Pulmonary Arterial Hypertension Caused by Qing-Dai (Chinese Herbal Drug) for Ulcerative Colitis.

Pulmonary arterial hypertension (PAH) is a rare and fatal disease for which some causative drugs have been developed. Qing-Dai is a Chinese herbal drug that is sometimes used as a specific treatment for ulcerative colitis in Asia, including Japan. Here, we report a case of severe Qing-Dai-induced PAH. A 19-year-old woman who has been taking Qing-Dai for 8 months was admitted for exertional dyspnea. Her mean pulmonary artery pressure dramatically improved from 72 to 18 mmHg with Qing-Dai discontinuation and PAH-specific therapy. After 6 years of onset, she had not relapsed with PAH with PAH-specific therapy.

Scurvy-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that results in precapillary pulmonary hypertension. PAH is caused by a group of clinical conditions involving multiple organ systems. Several cases have been reported in the literature demonstrating an association between vitamin C deficiency and PAH. Low endothelial nitric oxide levels in the pulmonary vasculature, combined with the inappropriate activation of hypoxia-inducible transcription factors, seen in patients with ascorbic acid deficiency, are believed to be the main contributors to the pathogenesis of pulmonary vasculopathy and the exaggerated pulmonary vasoconstrictive response seen in patients with scurvy-induced PAH. Vitamin C supplementation is considered the definitive treatment.

Kaempferol ameliorates pulmonary vascular remodeling in chronic hypoxia-induced pulmonary hypertension rats via regulating Akt-GSK3ß-cyclin axis.

Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is considered a major contributor to elevated pulmonary vascular resistance and a key mechanism of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Kaempferol is a natural flavonoid compound and can be derived from numerous common medicinal herbs and vegetables, which exhibit antiproliferative and proapoptotic properties, however, the effects of kaempferol on vascular remodeling in HPH remain unexplored. In this study, SD rats were placed in a hypobaric hypoxia chamber for four weeks to establish a pulmonary hypertension model and given either kaempferol or sildenafil (an inhibitor of PDE-5) during days 1-28, after which the hemodynamic parameter and pulmonary vascular morphometry were assessed. Furthermore, primary rat PASMCs were exposed to hypoxic conditions to generate a cell proliferation model, then incubated with either kaempferol or LY294002 (an inhibitor of PI3K). Immunoblotting and real-time quantitative PCR assessed the protein and mRNA expression levels in HPH rat lungs and PASMCs. We found that kaempferol reduced pulmonary artery pressure and pulmonary vascular remodeling, and alleviated right ventricular hypertrophy in HPH rats. The mechanistic analysis demonstrated that kaempferol reduced the protein levels of phosphorylation of Akt and GSK3ß, leading to decreased expression of pro-proliferation (CDK2, CDK4, Cyclin D1, and PCNA) and anti-apoptotic related proteins (Bcl-2) and increased expression of pro-apoptosis proteins (Bax and cleaved caspase 3). These results collectively demonstrate that kaempferol ameliorates HPH in rats by inhibiting PASMC proliferation and pro-apoptosis via modulation of the Akt/GSK3ß/CyclinD axis.

Natural Products for the Treatment of Pulmonary Hypertension: Mechanism, Progress, and Future Opportunities.

Pulmonary hypertension (PH) is a lethal disease due to the remodeling of pulmonary vessels. Its pathophysiological characteristics include increased pulmonary arterial pressure and pulmonary vascular resistance, leading to right heart failure and death. The pathological mechanism of PH is complex and includes inflammation, oxidative stress, vasoconstriction/diastolic imbalance, genetic factors, and ion channel abnormalities. Currently, many clinical drugs for the treatment of PH mainly play their role by relaxing pulmonary arteries, and the treatment effect is limited. Recent studies have shown that various natural products have unique therapeutic advantages for PH with complex pathological mechanisms owing to their multitarget characteristics and low toxicity. This review summarizes the main natural products and their pharmacological mechanisms in PH treatment to provide a useful reference for future research and development of new anti-PH drugs and their mechanisms.

Metallomics in pulmonary arterial hypertension patients.

Pulmonary arterial hypertension (PAH) prevalence is increasing worldwide, and the prognosis is poor with 5-year survival < 50% in high risk patients. The relationship between metal exposure/essential metal dyshomeostasis and PAH/right ventricular dysfunction is less investigated. The aim of this study is to investigate vegetable consumptions and metal levels between PAH patients and controls. This was a prospective, single center pilot study. Questionnaires were completed by all study subjects (20 PAH patients and 10 healthy controls) on smoking, metal exposure risks, metal supplements, and vegetable consumptions. Blood and urine samples were collected to measure 25 metal levels in blood, plasma, and urine using an X Series II quadrupole inductively coupled plasma mass spectrometry. Statistical analysis was conducted using SAS 9.5 and results with p value < 0.05 were considered significant. Vegetables consumptions (broccoli risk ratio [RR] = 0.4, CI = (0.2, 0.9)], cabbage [RR = 0.2, CI = (0.1, 0.8)], and brussel sprouts [RR = 0.2, CI = (0.1, 0.5)]) are associated with less risks of PAH. In the plasma samples, silver (p < 0.001), and copper (p = 0.002) levels were significantly higher in PAH patients. There was significant positive correlation between cardiac output and cardiac index with plasma levels of silver (r = 0.665, p = 0.001 and r = 0.678 p = 0.001), respectively. There was significant correlation between mixed venous saturation, 6-min walk distance, and last BNP with plasma levels of chromium (r = -0.520, p = 0.022; r = -0.55, p = 0.014; r = 0.463, p = 0.039), respectively. In conclusion, there are significant differences between PAH and control groups in terms of vegetable consumptions and metal concentrations. Silver and chromium levels are correlated with clinical indicators of PAH severities.

Antemortem diagnosis of pulmonary tumor thrombotic microangiopathy associated with gastric cancer and response to immediate chemotherapy.

Pulmonary tumor thrombotic microangiopathy is a rare and fatal complication of cancer that features widespread tumor cell-derived embolisms in the small arteries and arterioles of the lung and is often associated with thrombus formation. We describe the case of a 43-year-old woman who was hospitalized with cough and respiratory distress that lasted for 2 months. Computed tomography findings demonstrated multiple areas of interlobular septal thickening and ground-glass opacities in both lungs. Transthoracic echocardiography demonstrated a D-shaped left ventricle suggesting right heart overload, and pulmonary blood flow scintigraphy revealed multiple small, peripheral, and patchy areas of reduced blood flow. Upper gastrointestinal endoscopy revealed a signet-ring carcinoma. The patient was diagnosed with pulmonary tumor thrombotic microangiopathy based on her clinical presentation and treatment with tegafur, gimeracil oteracil potassium, oxaliplatin, and an anticoagulant was initiated on the 3rd day after admission. The symptoms improved rapidly after treatment initiation. The patient was discharged 28 days after initiation of chemotherapy without the need for supplemental oxygen. This case suggests that the immediate use of chemotherapy and anticoagulants for treating pulmonary tumor thrombotic microangiopathy may improve patient survival.

Effectiveness of Respiratory Muscle Training in Adults With Pulmonary Hypertension. A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with pulmonary hypertension (PH) may have impaired exercise capacity and quality of life; this may possibly be due to the early onset of dyspnoea associated with respiratory muscle weakness. Respiratory muscle training could improve the condition of these patients, so this study aimed to determine, through a systematic review and meta-analysis, the effectiveness of respiratory muscle training in adult patients with PH. METHODS: Medline, Embase, CENTRAL, clinical trial registries databases, and grey literature and reference lists of reviews related to the objective were searched up to March 2022. Controlled clinical trials comparing the effectiveness of respiratory muscle training with sham or no intervention in adults with PH were included. Records were independently screened by two authors. The primary outcomes were maximal and functional exercise capacity, quality of life, and dyspnoea. The secondary outcomes were respiratory muscle strength, physical activity, lung function, and adverse events. Two authors independently extracted data and the study quality was assessed using the Cochrane risk-of-bias tool 2 (RoB 2). The certainty of the evidence was assessed according to the GRADE approach. RESULTS: A total of 5,524 records were screened, and seven randomised clinical trials (RCTs) (257 participants) were included. It was uncertain whether inspiratory muscle training (IMT), compared with sham IMT or no intervention, increased the distance walked in the 6-minute walk test (6MWT) (MD, 39 m; 95% CI, 20.72-57.39; I2=27%; four RCTs; very low certainty of evidence) and slightly decreased the perceived sensation of dyspnoea (MD, 0.5 points on the mMRC scale; 95% CI, -0.87 to -0.13; I2=0%; two RCTs; very low certainty of evidence). In addition, it was uncertain whether IMT had no effect on the emotional (SMD, -0.34; 95% CI, -1.06 to 0.38; I2=64%; three RCTs; very low certainty of evidence) and physical (SMD, 0.06; 95% CI, -0.41 to 0.52; I2=16%; three RCTs; very low certainty of evidence) component of quality of life. CONCLUSIONS: It is uncertain whether IMT increases functional exercise capacity and slightly decreases the sensation of dyspnoea. In addition, it is uncertain whether IMT does not affect the quality of life. More RCTs and with a better methodological design are needed to increase the certainty of the evidence and determine the real effect of this intervention.