Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

Sleep-disordered breathing and nocturnal hypoxemia in chronic thromboembolic pulmonary disease.

BACKGROUND AND AIMS: Sleep-disordered breathing (SDB) and nocturnal hypoxemia were known to be present in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the difference between SDB and nocturnal hypoxemia in patients who have chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) at rest remains unknown. METHODS: Patients who had CTEPH (n = 80) or CTEPD without PH (n = 40) and who had undergone sleep studies from July 2020 to October 2022 at Shanghai Pulmonary Hospital were enrolled. Nocturnal mean SpO2 (Mean SpO2) <90% was defined as nocturnal hypoxemia, and the percentage of time with a saturation below 90% (T90%) exceeding 10% was used to evaluate the severity of nocturnal hypoxemia. Logistic and linear regression analyses were performed to investigate the difference and potential predictor of SDB or nocturnal hypoxemia between CTEPH and CTEPD without PH. RESULTS: SDB was similarly prevalent in CTEPH and CTEPD without PH (P = 0.104), both characterised by obstructive sleep apnoea (OSA). Twenty-two patients with CTEPH were diagnosed with nocturnal hypoxemia, whereas only three were diagnosed with CTEPD without PH (P = 0.021). T90% was positively associated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance in patients with CTEPH and CTEPD without PH (P < 0.001); T90% was also negatively related to cardiac output in these patients. Single-breath carbon monoxide diffusing capacity, sex and mPAP were all correlated with nocturnal hypoxemia in CTEPH and CTEPD without PH (all P < 0.05). CONCLUSION: Nocturnal hypoxemia was worse in CTEPD with PH; T90%, but not SDB, was independently correlated with the hemodynamics in CTEPD with or without PH.

Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH. METHODS AND RESULTS: Increased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH. CONCLUSION: This study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.

Dihydroartemisinin suppresses renal fibrosis in mice by inhibiting DNA-methyltransferase 1 and increasing Klotho.

Renal fibrosis is an unavoidable end result of all forms of progressive chronic kidney diseases (CKD). Discovery of efficacious drugs against renal fibrosis is in crucial need. In a preliminary study we found that a derivative of artemisinin, dihydroartemisinin (DHA), exerted strong renoprotection, and reversed renal fibrosis in adenine-induced CKD mouse model. In this study we investigated the anti-fibrotic mechanisms of DHA, particularly its specific target in renal cells. Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) or oral administration of adenine (80 mg · kg-1), the mice received DHA (30 mg · kg-1 · d-1, i.g.) for 14 or 21 days, respectively. We showed that DHA administration markedly attenuated the inflammation and fibrotic responses in the kidneys and significantly improved the renal function in both the renal fibrosis mouse models. In adenine-treated mice, DHA was more effective than 5-azacytidine against renal fibrosis. The anti-fibrotic effects of DHA were also observed in TGF-ß1-treated HK-2 cells. In order to determine the target protein of DHA, we conducted pull-down technology coupled with shotgun proteomics using a small-molecule probe based on the structure of DHA (biotin-DHA). As a results, DNA methyltransferase 1 (DNMT1) was identified as the anti-fibrotic target of DHA in 3 different types of renal cell lines (HK-2, HEK293 and 3T3). We demonstrated that DHA directly bound to Asn 1529 and Thr 1528 of DNMT1 with a Kd value of 8.18 µM. In primary mouse renal tubular cells, we showed that DHA (10 µM) promoted DNMT1 degradation via the ubiquitin-proteasome pathway. DHA-reduced DNMT1 expression effectively reversed Klotho promoter hypermethylation, which led to the reversal of Klotho protein loss in the kidney of UUO mice. This subsequently resulted in inhibition of the Wnt/ß-catenin and TGF-ß/Smad signaling pathways and consequently conferred renoprotection in the animals. Knockdown of Klotho abolished the renoprotective effect of DHA in UUO mice. Our study reveals a novel pharmacological activity for DHA, i.e., renoprotection. DHA exhibits this effect by targeting DNMT1 to reverse Klotho repression. This study provides an evidence for the possible clinical application of DHA in the treatment of renal fibrosis.

[Toxicity mechanism of Rhododendri Mollis Flos: based on serum metabolomics and network toxicology].

This study aims to explore the toxicity mechanism of Rhododendri Mollis Flos(RMF) based on serum metabolomics and network toxicology. The toxic effect of RMF on normal rats was evaluated according to the symptoms, serum biochemical indexes, and histopathology. Serum metabolomics was combined with multivariate statistical analysis to search endogenous differential metabolites and related metabolic pathways. The toxic components, targets, and signaling pathways of RMF were screened by network toxicology technique, and the component-target-metabolite-metabolic pathway network was established with the help of serum metabolomics. The result suggested the neurotoxicity, hepatotoxicity, and cardiotoxicity of RMF. A total of 31 differential metabolites and 10 main metabolic pathways were identified by serum metabolomics, and 11 toxic components, 332 related target genes and 141 main signaling pathways were screened out by network toxicology. Further analysis yielded 7 key toxic components: grayanotoxin Ⅲ,grayanotoxinⅠ, rhodojaponin Ⅱ, rhodojaponin Ⅴ, rhodojaponin Ⅵ, rhodojaponin Ⅶ, and kalmanol, which acted on the following 12 key targets: androgen receptor(AR), albumin(ALB), estrogen receptor ß(ESR2), sex-hormone binding globulin(SHBG), type 11 hydroxysteroid(17-beta) dehydrogenase(HSD17 B11), estrogen receptor α(ESR1), retinoic X receptor-gamma(RXRG), lactate dehydrogenase type C(LDHC), Aldo-keto reductase(AKR) 1 C family member 3(AKR1 C3), ATP binding cassette subfamily B member 1(ABCB1), UDP-glucuronosyltransferase 2 B7(UGT2 B7), and glutamate-ammonia ligase(GLUL). These targets interfered with the metabolism of gamma-aminobutyric acid, estriol, testosterone, retinoic acid, 2-oxobutyric acid, and affected 4 key metabolic pathways of alanine, aspartate and glutamate metabolism, cysteine and methionine metabolism, steroid hormone biosynthesis, and retinol metabolism. RMF exerts toxic effect on multiple systems through multiple components, targets, and pathways. Through the analysis of key toxic components, target genes, metabolites, and metabolic pathways, this study unveiled the mechanism of potential neurotoxicity, cardiotoxicity, and hepatotoxicity of RMF, which is expected to provide a clue for the basic research on toxic Chinese medicinals.

Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension.

BACKGROUND: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown. METHODS: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes. RESULTS: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines. CONCLUSIONS: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.

Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease with high heritability. Although several predisposing genes have been linked to IPAH, the genetic aetiology remains unknown for a large number of IPAH cases. METHODS: We conducted an exome-wide gene-based burden analysis on two independent case-control studies, including a total of 331 IPAH cases and 10 508 controls. Functional assessments were conducted to analyse the effects of genetic mutations on protein biosynthesis and function. RESULTS: The gene encoding human bone morphogenetic protein 9 (BMP9) was identified as a novel genetic locus displaying exome-wide association with IPAH in the discovery cohort (OR 18.8; p=1.9×10-11). This association was authenticated in the independent replication cohort (p=1.0×10-5). Collectively, the rare coding mutations in BMP9 occurred in 6.7% of cases, ranking this gene second to BMPR2, comprising a combined significance of 2.7×10-19 (OR 21.2). Intriguingly, the patients with BMP9 mutations had lower plasma levels of BMP9 than those without. Functional studies showed that the BMP9 mutations led to reduced BMP9 secretion and impaired anti-apoptosis ability in pulmonary arterial endothelial cells. CONCLUSION: We identify BMP9 as an IPAH culprit gene.

Natural Occurrence, Bioactivity and Biosynthesis of Elaiophylin Analogues.

Elaiophylins belong to a special family of 16-membered macrodiolides with C2-symmetry. They have exhibited remarkable biological activities, such as antimicrobial, anthelmintic, anticancer, immunosuppressive, anti-inflammatory, antiviral, and α-glucosidase inhibitory activities. A member of elaiophylins, efomycin M, is as a specific small molecule inhibitor of selectin in preclinical trial for the treatment of psoriasis, ischemia-reperfusion, and allergy. The biosynthetic investigation of elaiophylins has uncovered a unique thioesterase, which is responsible for the formation of C2-symmetric diolide. We herein summarize the natural occurrence, bioactivity, and biosynthesis of elaiophylins covering the literatures from 1959 to 2019. Hopefully, this review will inspire further research interests of these compounds and encourage the discovery of new analogues by metabolic engineering or genome mining.

Is ERAS effective and safe in laparoscopic gastrectomy for gastric carcinoma? A meta-analysis.

BACKGROUND: It is still unclear whether enhanced recovery after surgery is effective and safe in laparoscopic gastrectomy for gastric carcinoma. METHODS: Cochrane library databases, Medline, Embase, and Pubmed were searched from January 1, 1986, to December 31, 2016. Randomized controlled trials (RCTs) comparing fast-track recovery with conventional recovery strategies in laparoscopic radical gastrectomy for gastric carcinoma were included. The main outcomes measured were postoperative hospital stay, time to first flatus, hospital charge, and overall complication rate. RESULTS: Six RCTs with 400 patients were included in this study. Fast-track surgery has shorter postoperative hospital stays (weighted mean difference (WMD) - 2.65; 95% CI, - 4.01 to - 1.29, z = 3.82, P < 0.01) and less hospitalization expenditure (WMD - 523.43; 95% CI, - 799.79 to - 247.06, z = 3.71, P < 0.01) than conventional recovery strategies. There was no significant difference with respect to duration to first flatus (WMD - 17.72; 95% CI, - 39.46-4.02, z = 1.60, P = 0.11) and complication rate (OR 1.57; 95% CI, 0.82-2.98, z = 1.37, P = 0.17). CONCLUSIONS: Enhanced recovery after surgery is effective and safe and is thus recommended in laparoscopic radical gastrectomy for gastric carcinoma.

Lower socioeconomic status is associated with worse outcomes in pulmonary arterial hypertension.

RATIONALE: Lower socioeconomic status (SES) confers a heightened risk of common cardiovascular and pulmonary diseases and increased mortality. The association of SES with outcomes in patients with pulmonary arterial hypertension (PAH) is less clear. OBJECTIVES: To determine the association between SES and outcomes in patients with PAH. METHODS: We performed a prospective cohort study at a national referral center for patients with PAH in China. Two hundred sixty-two consecutive incident patients aged 18 to 65 years with a diagnosis of idiopathic PAH were recruited between January 2007 and June 2011 and followed up until November 2011. The primary endpoint was all-cause mortality. An SES score for each patient was derived from their educational level, annual household income, occupation, and medical reimbursement rate. MEASUREMENTS AND MAIN RESULTS: Patients with a lower SES had higher unadjusted mortality rates, with 3-year survival estimates of 50.1, 70.8, and 86.0% in increasing tertiles of SES (P for trend < 0.001). After adjustment for clinical features, hemodynamics, and type of PAH treatment, the hazard ratios for death were 2.98 (95% confidence interval, 1.51-5.89) in the lowest tertile of SES and 1.80 (95% confidence interval, 0.89-3.63) in the middle tertile of SES compared with the upper tertile (P for trend = 0.006). CONCLUSIONS: A lower SES is strongly associated with a higher risk of death in idiopathic PAH. This association was independent of clinical characteristics, hemodynamics, and treatment. Addressing the health disparities associated with a lower SES may improve the outcomes of patients with PAH.

[Research on building method of spleen kidney Yang deficiency diarrhea rats model].

Spleen kidney Yang deficiency (SKYD) diarrhea is a common syndrome in tranditional Chinese medicine (TCM). Until now, there is not an ideal SKYD diarrhea rat model for the research. In this study, we compared single factor way (method I, injecting hydrocortisone and gavaging Sennae Folium) with compound factors way(method II, gavaging adenine, improper diet, exhaustion, and gavaging Sennae Folium) on establishing SKYD diarrhea rat model. After modelling, diarrhea index, D-xylose excretory rate, NOS/cGMP signal transduction system, organ index and histopathology examination were used to evaluate the two ways. The results showed that, compared with health group, all the assessment criterias of method I and method II had significant differences (P < 0.01, 0.05). In addition, the index such as diarrhea index, NOS/cGMP signal transduction system, organ index (kidney, testis and thymus) and histopathology examination had significant differences (P < 0.01, 0.05) between method I and method II. In conclusion, the compound factors modelling method better conforms to the symptom of diarrhoea model caused by SKYD. This new modelling method provides a basis for studying on TCM astringents warming and tonifying the spleen and kidney, relieving diarrhea.

Enhancing Bioactivity and Mechanical Properties of Nano-Hydroxyapatite Derived from Oyster Shells through Hydrothermal Synthesis.

Nano-hydroxyapatite (nHA) demonstrates favorable biological activity, cell adhesion, cell proliferation, and osteoconductivity, making it highly valuable in biomedicine. It is extensively used as a bone substitute and in bone transplantation within the dental and orthopedic fields. This study employed oyster shells as a calcium source to synthesize nHA at 150 °C with various hydrothermal reaction durations (10 min, 1 h, 6 h, and 12 h). As a control, HA synthesized via a wet precipitation method for 1 h at room temperature was utilized. Subsequent material analyses, including XRD, FE-SEM, FTIR, and ICP-MS, were conducted, followed by comprehensive evaluations of the bioactivity, cell attachment, cell proliferation, and sintering properties of the synthesized nHA. The results indicated that nHA synthesized through the hydrothermal reaction produced nanoscale crystals, with the aspect ratio of nHA particles increasing with the duration of hydrothermal treatment. Notably, rod-like nHA particles became prominent with hydrothermal durations exceeding 6 h. nHA particles derived from oyster shells contained carbonate and trace elements (Na, Mg, K, and Sr), similar to constituents found in human hard tissue such as bone and teeth. The immersion of nHA synthesized at 150 °C for 1 h (HT2) in simulated body fluid (SBF) for 28 d led to the formation of a bone-like apatite layer on the surface, indicating the excellent bioactivity of the synthesized nHA. The cell culture results revealed superior cell attachment and proliferation for nHA (HT2). Following the sequential formation and sintering at 1200 °C for 4 h, HT2 ceramics exhibited enhanced microhardness (5.65 GPa) and fracture toughness (1.23 MPa·m0.5), surpassing those of human tooth enamel.

Operation Procedure and Precautions of Lingnan Fire-Needle Therapy in Osteoporosis Model Rats.

Compared to filiform needle therapy, fire-needle therapy has both the stimulation of needles and the warming effect of heat, making it have unexpected effects on some chronic diseases and incurable diseases. Osteoporosis (OP) has a high incidence in postmenopausal women and middle-aged and elderly men, and the treatment cycle is long. According to Traditional Chinese Medicine (TCM), Lingnan fire-needle therapy has shown potential in treating osteoporosis. However, there is still a long way to go before it can be widely used. This article focuses on the application of Lingnan fire-needle therapy in the intervention of OP in rats. It covers the selection of needle tools, acupuncture point selection, positioning of rats' bodies, and fixation methods. We also outline the steps and precautions to be taken during and after needling with fire needles. The experiment was done with three groups: a normal group, a model group, and a fire-needle group, each containing 10 rats. The rats in the fire-needle group were treated with fire-needle intervention for six sessions. After the intervention period, we collected femoral specimens and performed micro-CT scans. The results suggest that fire needling can enhance bone morphology and mineral density in OP rats. This information can serve as a methodological basis for conducting basic research on fire-needle therapy.

CPS1 augments hepatic glucagon response through CaMKII/FOXO1 pathway.

Introduction: Elevated glucagon levels are a characteristic feature of type 2 diabetes. This abnormal increase in glucagon can lead to an accelerated rate of gluconeogenesis. Glucagon also stimulates hepatic metabolism of amino acids, particularly promoting the formation of urea. The specific role of carbamoyl phosphate synthetase 1 (CPS1), a rate-limiting enzyme in the urea cycle, in the development versus the persistence of glucagon-induced hyperglycemia has not been previously established. Methods: The study employed both in vivo and in vitro approaches to assess the impact of CPS1 modulation on glucagon response. CPS1 was knockdown or overexpression to evaluate its influence on hepatic gluconeogenesis. In addition, an in-silico strategy was employed to identify a potential CPS1 inhibitor. Results: Knockdown of CPS1 significantly reduced the glucagon response both in vivo and in vitro. Conversely, overexpression of CPS1 resulted in an overactive hepatic gluconeogenic response. Mechanistically, CPS1 induced the release of calcium ions from the endoplasmic reticulum, which in turn triggered the phosphorylation of CaMKII. The activation of CaMKII then facilitated the dephosphorylation and nuclear translocation of FOXO1, culminating in the enhancement of hepatic gluconeogenesis. Furthermore, cynarin, a natural CPS1 inhibitor derived from the artichoke plant, had the capacity to attenuate the hepatic glucagon response in a CPS1-dependent manner. Discussion: CPS1 played a pivotal role in mediating glucagon-induced hepatic gluconeogenesis. The discovery of cynarin as a natural inhibitor of CPS1 suggested its potential as a therapeutic agent for diabetes treatment.

Pulmonary vascular resistance predicts the mortality in patients with bronchiectasis-associated pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension is a severe complication of bronchiectasis, characterized by elevated pulmonary vascular resistance (PVR) and subsequent right heart failure. The association between PVR and mortality in bronchiectasis-associated pulmonary hypertension has not been investigated previously. METHODS: In the present study, a retrospective analysis was conducted on 139 consecutive patients diagnosed with bronchiectasis-associated pulmonary hypertension based on right heart catheterization, enrolled between January 2010 and June 2023. Baseline clinical characteristics and hemodynamic assessment were analyzed. The survival time for each patient was calculated in months from the date of diagnosis until the date of death or, if the patient was still alive, until their last visit. RESULTS: Patients with bronchiectasis-associated pulmonary hypertension exhibited estimated survival rates of 89.5, 70, and 52.9 at 1-year, 3-year, and 5-year intervals respectively, with a median survival time of 67 months. Multivariable Cox regression analysis revealed that increased age [(adjusted hazard ratio per year 1.042, 95% confidence interval (CI) 1.008-1.076, P  = 0.015] and elevated PVR (adjusted HR per 1 Wood Units 1.115, 95% CI 1.015-1.224, P  = 0.023) were associated with an increased risk of all-cause mortality. In contrast, higher BMI was associated with a decreased risk of all-cause death (adjusted hazard ratio per 1 kg/m 2 0.915, 95% CI 0.856-0.979, P  = 0.009). Receiver-operating characteristic analyses identified a cutoff value for PVR at 4 Wood Units as predictive for all-cause death within 3 years [area under the curve (AUC) = 0.624; specificity= 87.5%; sensitivity= 35.8%; P  < 0.05]. Patients with a PVR greater than 4 Wood Units had a significantly higher risk of all-cause death compared with those with 4 Wood Units or less (adjusted hazard ratio 2.392; 95% CI 1.316-4.349; P  = 0.019). Notably, there were no significant differences in age, sex, BMI, WHO functional class, 6-min walk distance, and NT-proBNP levels at baseline between patients categorized as having 4 Wood Units or less or greater than 4 Wood Units for PVR. CONCLUSION: Based on these data, PVR could serve as a discriminative marker for distinguishing between nonsevere pulmonary hypertension (PVR ≤ 4 Wood Units) and severe pulmonary hypertension (PVR > 4 Wood Units). The utilization of a PVR cutoff value of 4.0 Wood Units provides enhanced prognostic capabilities for predicting mortality.

Prognostic Value of Plasma Immunoglobulin G N-Glycome Traits in Pulmonary Arterial Hypertension.

BACKGROUND: B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide is the only blood biomarker in established risk calculators for pulmonary arterial hypertension (PAH). Profiling systemic-originated plasma immunoglobulin G (IgG) N-glycans, which reflect different components of the pathophysiology of PAH including immune dysregulation and inflammation, may improve PAH risk assessment. OBJECTIVES: This study sought to identify plasma IgG N-glycan biomarkers that predict survival in PAH to improve risk assessment. METHODS: This cohort study examined 622 PAH patients from 2 national centers (Beijing [discovery] cohort: n = 273; Shanghai [validation] cohort: n = 349). Plasma IgG N-glycomes were profiled by a robust mass spectrometry-based method. Prognostic IgG N-glycan traits were identified and validated in the 2 cohorts using Cox regression and Kaplan-Meier survival analyses. The added value of IgG N-glycan traits to previously established risk models was assessed using Harrell C-indexes and survival analysis. RESULTS: Plasma IgG fucosylation was found to predict survival independent of age and sex in the discovery cohort (HR: 0.377; 95% CI: 0.168-0.845; P = 0.018) with confirmation in the validation cohort (HR: 0.445; 95% CI: 0.264-0.751; P = 0.005). IgG fucosylation remained a robust predictor of mortality in combined cohorts after full adjustment and in subgroup analyses. Integrating IgG fucosylation into previously established risk models improved their predictive capacity, marked by an overall elevation in Harrell C-indexes. IgG fucosylation was useful in further stratifying the intermediate-risk patients classified by a previously established model. CONCLUSIONS: Plasma IgG fucosylation informs PAH prognosis independent of established factors, offering additional value for predicting PAH outcomes.

Oestradiol ameliorates monocrotaline pulmonary hypertension via NO, prostacyclin and endothelin-1 pathways.

Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17ß-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension. Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg·kg(-1)) and were treated with 17ß-oestradiol (1 mg·kg(-1) per day) for either 5 weeks or only from week 4 to week 5. Plasma 17ß-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7 ± 4.7 versus 50.3 ± 15.4 pg·mL(-1); p=0.029). The 17ß-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17ß-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I2) levels and reducing endothelin (ET)-1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17ß-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17ß-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI2 and ET-1 expression.