Rationally designed nanotrap structures for efficient separation of rare earth elements over a single step.

Extracting rare earth elements (REEs) from wastewater is essential for the growth and an eco-friendly sustainable economy. However, it is a daunting challenge to separate individual rare earth elements by their subtle differences. To overcome this difficulty, we report a unique REE nanotrap that features dense uncoordinated carboxyl groups and triazole N atoms in a two-fold interpenetrated metal-organic framework (named NCU-1). Notably, the synergistic effect of suitable pore sizes and REE nanotraps in NCU-1 is highly responsive to the size variation of rare-earth ions and shows high selectivity toward light REE. As a proof of concept, Pr/Lu and Nd/Er are used as binary models, which give a high separation factor of SFPr/Lu = 796 and SFNd/Er = 273, demonstrating highly efficient separation over a single step. This ability achieves efficient and selective extraction and separation of REEs from mine tailings, establishing this platform as an important advance for sustainable obtaining high-purity REEs.

Identification of potential pathogenic targets and survival strategies of Vibrio vulnificus through population genomics.

Vibrio vulnificus, a foodborne pathogen, has a high mortality rate. Despite its relevance to public health, the identification of virulence genes associated with the pathogenicity of currently known clinical isolates of V. vulnificus is incomplete and its synergistic pathogenesis remains unclear. Here, we integrate whole genome sequencing (WGS), genome-wide association studies (GWAS), and genome-wide epistasis studies (GWES), along with phenotype characterization to investigate the pathogenesis and survival strategies of V. vulnificus. GWAS and GWES identified a total of six genes (purH, gmr, yiaV, dsbD, ramA, and wbpA) associated with the pathogenicity of clinical isolates related to nucleotide/amino acid transport and metabolism, cell membrane biogenesis, signal transduction mechanisms, and protein turnover. Of these, five were newly discovered potential specific virulence genes of V. vulnificus in this study. Furthermore, GWES combined with phenotype experiments indicated that V. vulnificus isolates were clustered into two ecological groups (EGs) that shared distinct biotic and abiotic factors, and ecological strategies. Our study reveals pathogenic mechanisms and their evolution in V. vulnificus to provide a solid foundation for designing new vaccines and therapeutic targets.

Retrospective on global pulmonary hypertension clinical trials: 1999-2021.

Background: Data are quite sparse on the comprehensive analyses of pulmonary hypertension (PH) clinical trials worldwide. Methods: Information including participating countries (developed or developing), intervention type, trial size, PH categories, sponsorship, study phase, design strategies, and participants' demographic characteristics was extracted from PH trials registered on ClinicalTrials.gov from 1999 to 2021. Results: A total of 203 eligible clinical PH trials were screened, involving 23,402 participants, 67.8% of whom were females. Major clinical trials were designed to test drug interventions (95.6%), sponsored solely by industries in 59.5%, and targeting Group 1 PH patients in 76.3%. A large number of countries participated in PH clinical trials; however, most clinical trials were conducted in developed countries (84.2%). Developing countries were involved in clinical trials with larger sample sizes (P<0.01). Additionally, the differences between developed and developing countries centered on interventions, sponsors, PH groups, and design strategies. Furthermore, developing countries participated in multinational clinical trials with good quality, homogeneity, reliability, and data authenticity. All pediatric participants were diagnosed with Group 1 PH and were only involved in drug intervention trials. Children participated in far fewer clinical trials than adults (P<0.01), and most were enrolled in PH clinical trials in developed countries. Among the entire clinical trial population, younger patients with Group 1 PH had a much higher participation to prevalence ratio (PPR). There was no difference in women's PPRs between developed and developing countries. However, developing countries had higher PPRs for PH Groups I and IV (1.28 vs. 1.22, P<0.01), while developed countries had a lower PPR for Group III (P=0.02). Conclusions: PH is attracting increasing global attention, which is not at the same level of progress in developed and developing countries. Women and children with this disease have unique characteristics and require more attention.

Relationship between ambulatory arterial stiffness index and the severity of angiographic atherosclerosis in patients with H-type hypertension and coronary artery disease.

OBJECTIVE: To investigate coronary artery disease (CAD) and its correlation with the ambulatory arterial stiffness index (AASI) in patients with H-type hypertension (essential hypertension combined with hyper-homocysteinemia) and coronary heart disease (CHD). METHODS: Patients with essential hypertension and CHD who were undergoing coronary angiography were enrolled. The general clinical data, biochemical indicators, ambulatory blood pressure monitoring results and coronary angiography results of the selected patients were collected, and the AASI and Gensini scores were calculated. According to homocysteine (Hcy) levels, the patients were divided into two groups: a study group and a control group. The differences in general clinical data, biochemical indexes, AASI scores and degree of coronary artery lesions between the two groups were compared. The correlation between the AASI and the Gensini score and the relationship between the AASI and the Gensini score of CAD and various factors were analyzed. RESULTS: Compared with the control group, the Hcy level in the study group was significantly increased (8.16 ± 2.33 vs 19.20 ± 2.36, P = .001). The 24-h diastolic blood pressure (DBP) in the study group was significantly lower than that in the control group (76.38 ± 9.33 vs 79.91 ± 9.25, P = .002), and the AASI was significantly higher than in the control group (0.62 ± 0.81 vs 0.420 ± 0.70, P = .001). The number of patients having coronary stenoses with a Gensini score of ≤ 38 was significantly lower in the study group than in the control group (21.3% vs 49.4%, P < .001). The number of patients with a Gensini score of ≥ 51 in the study group was significantly higher than in the control group (22.0% vs 18.8%, P < .001). There was a significant positive correlation between the AASI and the Gensini score in the study group (R = 0.732, P < .001). Hypertension duration (ß = 0.168), diabetes history (ß = 0.236), 24-h SBP (ß = 0.122), 24-h DBP (ß = -0.131), low-density lipoprotein cholesterol (ß = 0.134) and Hcy (ß = 0.233) were the influencing factors for AASI (P < .05). Both Hcy * AASI (ß = 0.356) and Hcy × 24-h HR (ß = 0.331) had a synergistic effect on the Gensini score (P = .017), with Hcy * AASI having a more significant effect on the Gensini score (P < .001). CONCLUSION: The AASI was significantly increased in patients with H-type hypertension and CHD, which was associated with the severity of CAD. Therefore, Hcy levels and the AASI have a synergistic effect when evaluating the severity of CAD in patients with hypertensive CHD.

Mitochondrial stress induces hepatic stellate cell activation in response to the ATF4/TRIB3 pathway stimulation.

BACKGROUND: The activation of hepatic stellate cells (HSCs) is the key step in the pathogenesis of liver fibrosis, which directly leads to fibrotic pathological changes in the hepatic tissue. Mitochondrial stress exacerbates inflammatory diseases by inducing pathogenic shifts in normal cells. However, the role of mitochondrial stress in HSC activation remains to be elucidated.  METHODS: We analyzed the effect of mitochondrial stress on HSC activation. An in vivo hepatic fibrosis model was established by intraperitoneal injection of 40% carbon tetrachloride (CCl4) for 12 weeks. Additionally, using in vitro approach, HSC-T6 cells were treated with 10 ng/mL platelet-derived growth factor-BB (PDGF-BB) for 24 h. RESULTS: Transcriptional activator 4 (ATF4) is highly expressed in fibrotic liver tissue samples and activated HSCs. We found that AAV8-shRNA-Atf4 alleviated liver fibrosis in rats. ATF4 promoted the activation of HSCs, which was induced by mitochondrial stress. The mechanisms involved ATF4 binding to a specific region of the tribble homologue 3 (TRIB3) promoter. Further, TRIB3 promoted HSCs activation mediated by mitochondrial stress. CONCLUSIONS: ATF4 induces mitochondrial stress by upregulating TRIB3, leading to the activation of HSCs. Therefore, the inhibition of ATF4 during mitochondrial stress may be a promising therapeutic target for liver fibrosis.

Halogen microregulation in metal-organic frameworks for enhanced adsorption performance of ReO4-/TcO4.

Effective and selective removal of 99TcO4-, one of the most nuisance radionuclides in nuclear waste, is highly desirable but remains a significant challenge. Herein, two isostructural MOFs, NCU-3-X (X = Cl, Br) were constructed by ZnX2 coordinated to nitrogen-containing neutral ligand tri(4-(1H-imidazole-1-l) phenyl) amine for efficient adsorption ReO4-/TcO4-. Owning to the twofold interpenetrating structure, both of them exhibit strong alkaline resistance. Consequently, NCU-3-Br exhibited superior adsorption performances with a maximum capacity as high as 483 mg/g, which is 2.23 times larger than that of NCU-3-Cl. The primary reasons accounting for the enhanced adsorption performances of NCU-3-Br are that compared to chlorine atoms, the smaller electronegativity of bromine atoms as halogen bonds donor can facilitate the formation of σ-holes, enhance positively charged skeleton, and reduce the adsorption energy associated with ReO4-/TcO4-. In addition, the one-dimensional hydrophobic channels in the NCU-3-Br framework enable NCU-3-Br to have highly selective toward ReO4-, which has a low relative charge density against interfering ions. The SRS simulation removal experiment further confirmed the excellent adsorption capacity of NCU-3-Br to ReO4-/TcO4-. This work illustrated that the halogenated new strategy incorporated different halogen atoms into MOF skeletons can dramatically modulate the adsorption performances for ReO4-/TcO4-.

Synthesis of cationic polymer decorated with halogen for highly efficient trapping 99TcO4-/ReO4.

The elimination of anion is of great importance from radioactive nuclear waste containing 99TcO4- by rationally designing anion-scavenging materials with high density of charge and more accessible adsorption sites. Herein, a tailor-made cationic organic polymer with donor-acceptor (D-A) structure, namely TrDCPN, was successfully synthesized by rationally modifying the benzimidazole unit for efficient trapping the perrhenate (ReO4-) as a 99Tc surrogate. Systematic control of the skeleton affect enables the material to integrate a variety of features, surmounting the long-term challenge of 99TcO4-/ReO4- remediation under extreme conditions of high acid/base and high ionic strength. Furthermore, the TrDCPN shows excellent affinity toward ReO4- in the existence of large excess of competitive anions (SO42-, NO3- and PO43-etc.) as well as promising reusability for trapping ReO4-. The excellent stability and separation were derived from the introduction of large conjugated modules, triazine core and hydrophobic. More importantly, the synthetic cationic organic polymer with D-A feature was first proved that the introduction of halogen can effectively enhance the backbone charge, and increase the adsorption capacity by synergy of ion exchange, electrostatic interaction and δ hole-anion interaction. The adsorption capacity of TrDCPN can be up to 420.3 mg/g and reach equilibrium within 20 min. It is noteworthy that TrDCPN successfully immobilizes ReO4- from simulated Hanford waste with a high separation efficiency of 93 %, providing a new paradigm for material design to dispose of the problem of radioactive pollutants in the environment.

Tailor-Made Multiple Interpenetrated Metal-Organic Framework for Selective Detection and Adsorption of ReO4.

Rationally designed new materials for the selective detection and adsorption of 99Tc, a problematic element in nuclear waste, are important and challenging in environmental monitoring. Here, we utilize an interpenetration approach to develop a cationic fluorescent metal-organic framework (NCU-2), which was constructed by a flexible tridentate nitrogen-containing ligand and Ag+ metal ions. The NCU-2 is a scarce case of 14-fold interpenetrated with excellent chemical stability even under 0.5 M HNO3, which is helpful for the detection and removal of ReO4-/TcO4- from nuclear waste. Excitingly, the fluorescence signal of NCU-2 was obviously quenched in the presence of ReO4- (a nonradioactive surrogate of TcO4-) due to the robust interaction between ReO4- and the host for the formation of a non-fluorescent complex. Furthermore, the NCU-2 exhibits a high selectivity sensing of ReO4- in the presence of excess competitive ions. The superior response of NCU-2 toward ReO4- is ascribed to the high-fold structure and the luxuriant unsaturated Ag metal sites on the wall of 1D pore channels, which can enhance the framework positive charge and accelerate the transport of guest molecules to strengthen the interaction between them. Notably, NCU-2 successfully quantified trace levels of ReO4- in simulated Hanford waste with a broad linear range (0.2-200 µM) and a low detection limit of 66.7 nM. Moreover, NCU-2 also shows a high adsorption capacity to ReO4- (541 mg/g) and rapid sorption kinetics, making it extremely attractive for waste monitoring and emergency remediation.

Discovery of a Series of 5-Amide-1H-pyrazole-3-carboxyl Derivatives as Potent P2Y14R Antagonists with Anti-Inflammatory Characters.

UDPG/P2Y14R signaling pathway has been considered as a potential therapeutic target for innate immune system diseases. Based on the scaffold hopping strategy, a series of pyrazole analogues were designed and synthesized as novel P2Y14R antagonists with improved physicochemical properties, together with potential anti-inflammatory activities. Additionally, we designed and synthesized a fluorescent probe based on highly selective and potent PPTN to study the affinity of synthesized compounds. The optimized compound 16 (1-(4-fluorobenzyl)-5-(4-methylbenzamido)-1H-pyrazole-3-carboxylic acid, P2Y14R IC50 = 1.93 nM) showed strong binding ability to P2Y14R, high selectivity, notably improved solubility, and more favorable pharmacokinetic profiles. Moreover, compound 16 possessed extremely low cytotoxicity and anti-inflammatory effect in vitro. In an acute peritonitis model, compound 16 could effectively reduce the levels of inflammatory factor IL-6, IL-1ß, and TNF-α of mice induced by LPS. Compound 16, with potent in vitro and in vivo efficacy and favorable druggability, can be a promising candidate for further research.

An alkali-resistant metal-organic framework as halogen bond donor for efficient and selective removing of ReO4-/TcO4.

99Tc is one of the most problematic nuclear fuel products due to its long half-life and high environmental mobility. Direct removal of TcO4- from the highly alkaline solution of nuclear fuel is a serious and challenging environmental issue. In this work, the first efficient synthetic approach introducing halogens into a two-dimensional metal-organic framework, named Mn-MOF, is established using MnCl2·4H2O coordinating with neutral nitrogen-donor ligand, showing ultrahigh stability in alkaline aqueous even under 1 M NaOH. The luxuriant Mn-Cl bonds and ordered hydrophobic pore channels enable the Mn-MOF to have an efficient adsorption capacity for ReO4- with a large capacity (403 mg g-1), which is higher than most MOF adsorbents. More importantly, the Mn-MOF shows an excellent selectivity toward ReO4- in high-density competitive anions, such as NO3- and SO42-. Moreover, the outstanding performance of Mn-MOF in removing ReO4- endowed it successfully separated ReO4- from the simulated Savannah River Site (SRS) high-level waste (HLW) stream with high removal of 66.84% at the phase ratio of 10. The adsorption mechanism is further demonstrated by FT-IR, XPS analysis, and DFT calculation, showing that the ReO4- can selectively interact with Mn-Cl bonds and imidazole groups, forming unique halogen bonds Cl-O-Re, and a series of hydrogen bonds, respectively. This work suggests a new approach to the removal of TcO4- from nuclear fuel.

CaM/CaMKII mediates activation and proliferation of hepatic stellate cells regulated by ASIC1a.

The activation of hepatic stellate cells (HSCs) is closely related to hepatic fibrosis and plays a key role in its occurrence and development. In the damaged liver, inhibition of the activation, proliferation, and clearance of HSCs is an important therapeutic strategy. However, the mechanism underlying the activation of HSCs is not completely clear. Acid-sensitive ion channel 1a (ASIC1a) is a cation channel activated by extracellular acid, which is responsible for the transport of Ca2+ and Na+ and participates in the activation of HSCs and the occurrence and development of many inflammatory diseases, suggesting that ASIC1a plays an important role in liver fibrosis. A previous study by the project team found that when the membrane channel protein ASIC1a was opened, intracellular Ca2+ levels increased, the expression of CaM/CaMKII in HSCs was high, and HSC was activated and proliferated. Therefore, we established an SD rat model of hepatic fibrosis and induced HSC-T6 activation by stimulating ASIC1a with acid in vitro. In vivo, CCl4 was used to induce liver fibrosis in rats, and different doses of KN93 (0.5, 1, and 2 mg/kg/d) and colchicine (0.1 mg/kg/d) were administered. Eight weeks later, the activities of ALT and AST in serum were measured and hematoxylin-eosin and Masson staining in liver tissue, and immunohistochemistry analysis were performed in SD rats. The expressions of ASIC1a, α-SMA, Collagen-1, CaM, and CaMKII were detected. In vitro, we activated HSC-T6 cells by stimulating ASIC1a with acid. The results showed that inhibition of ASIC1a could improve acid-induced HSCs activation. In addition, CaM/CaMKII was expressed in HSC of rats with hepatic fibrosis regulated by ASIC1a. After blocking or silencing the expression of CaMKII, the fibrosis marker protein can be down-regulated. KN93 also reduced inflammation and improved the activation, proliferation and fibrosis of HSC. In summary, we concluded that CaM/CaMKII participates in ASIC1a regulation of the proliferation and activation of HSC and promotes the occurrence of liver fibrosis.

[Effects of 12-week Tai Chi exercise on the microvascular reactivity of the middle-aged and elderly patients with mild hypertension and its mechanism].

Objective: To study the effects of 12-week Taijiquan exercise on the microvascular reactivity of middle-aged and elderly patients with mild hypertension and to explore the mechanisms of microvascular reactivity. Methods: Thirty patients with mild hypertension were divided into exercise group (53.8±6.3 years old) and control group (52.6±7.5 years old). The number and gender ratio of the two groups were the same. The exercise group performed Tai Chi exercise for 12 weeks, and the control group maintained the original lifestyle and did not do other regular sports. The two groups of subjects were tested for microvascular reactivity, blood pressure, serum nitric oxide content, and nitric oxide synthase activity before exercise intervention, 6th week and 12th week, respectively. Results: There was no significant difference in the basic values of each index between the two groups of subjects before the test (P＞ 0.05). In the 6th week, the microvascular reactivity (blood flow increase rate), systolic blood pressure, diastolic blood pressure, nitric oxide content, nitric oxide synthase activity of the exercise group did not significantly change from the basic value (P＞0.05). At the 12th week, the microvascular reactivity, nitric oxide content, c nitric oxide synthase activity were significantly higher than those of the base values and the control group (P＜0.05), but the systolic blood pressure and diastolic blood pressure were significantly lower than those of the base values and control group (P＜0.05). In the control group, there were no significant changes in the 6th and 12th week values of each index from the basic value (P＞0.05). Conclusion: Twelve weeks of Taijiquan exercise can improve the microvascular reactivity of middle-aged hypertensive patients, reduce blood pressure, and increase the nitric oxide content and c nitric oxide synthase of patients. The increase of endogenous nitric oxide production is one of the biological mechanisms of Tai Chi exercise to improve the microvascular responsiveness of hypertension patients.

Silencing of Gasdermin D by siRNA-Loaded PEI-Chol Lipopolymers Potently Relieves Acute Gouty Arthritis through Inhibiting Pyroptosis.

Gasdermin D (GSDMD) plays a causal role in NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis eruption, which has been regarded as a potential therapeutic target for pyroptosis-related diseases including acute gouty arthritis. In the present study, the synthesized PEI-Chol (cholesterol grafted polyethylenimine) was assembled with GSDMD small interfering RNA (siRNA) to form PEI-Chol/siGSDMD polyplexes, which provided high transfection efficiency for siRNA-mediated GSDMD knockdown. Then we evaluated the effect of GSDMD siRNA-loaded PEI-Chol on inflammatory cascades in bone-marrow-derived macrophages (BMDMs) and acute gouty arthritis animal models under MSU exposure. When accompanied by pyroptosis blockade and decreased release of interleukin-1 beta (IL-1ß), NLRP3 inflammasome activation was also suppressed by GSDMD knockdown in vivo and in vitro. Moreover, in MSU-induced acute gouty arthritis mice, blocking GSDMD with siRNA significantly improved ankle swelling and inflammatory infiltration observed in histopathological analysis. Furthermore, investigation using a mouse air pouch model verified the effect of siGSDMD-loaded PEI-Chol on pyroptosis of recruited macrophages and related signaling pathways in response to MSU. These novel findings exhibited that GSDMD knockdown relieved acute gouty arthritis through inhibiting pyroptosis, providing a possible therapeutic approach for MSU-induced acute gouty arthritis molecular therapy using PEI-Chol as a nucleic acid delivery carrier.

[Comparison of clinical efficacy of femoral calcar prosthesis replacement and intramedullary nail in the treatment of elderly patients with intertrochanteric fracture].

OBJECTIVE: To analyze the clinical efficacy of hip arthroplasty with femoral calcar prosthesis and proximal femoral nail fixation(PFNA) in the treatment of elderly patients(≥80 years old) with unstable intertrochanteric fractures(Evans Ⅲ, Ⅳ). METHODS: From June 2016 to March 2018, 60 elderly patients with unstable intertrochanteric fractures treated with prosthetic replacement and PFNA were retrospectively analyzed. According to the surgical methods, they were divided into PFNA group and prosthesis group. In PFNA group there were including 21 males and 15 females, with an average age of(84.3± 2.9) years old;in the prosthetic group, there were 10 males and 14 females with an average age of (82.9±2.4) years old. The operation time, hemoglobin difference between preoperative and postoperative 1 day, postoperative ambulation time, hospitalization time and complications were observed and compared between the two groups. Harris hip score was performed 3 and 12 months after operation. RESULTS: All patients were followed up for 12 to 24 months (19.3±4.8) months. One patient in the prosthesis group died of lung cancer one year later and the follow-up was terminated. The operation time of prosthetic group was longer than that of PFNA group(P<0.05);hemoglobin difference before and after operation had no difference between prosthetic group and PFNA group(P>0.05);the time of ambulation in prosthetic group was earlier than that in PFNA group(P<0.05); the number of complications in prosthetic group was less than that in PFNA group(P<0.05);there was no significant difference in Harris score between prosthetic group and PFNA group before treatment, but scores of both groups were significantly increased after treatment (P <0.05). After 3 months of follow-up, the score of prosthesis group was higher than that of intramedullary nail group(P<0.05), but there was no significant difference at 12 months after operation(P>0.05). CONCLUSION: The elderly patients with intertrochanteric arthroplasty can reduce the burden of intertrochanteric arthroplasty and improve the quality of life.

ERα and/or ERß activation ameliorates cognitive impairment, neurogenesis and apoptosis in type 2 diabetes mellitus mice.

Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 2 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERß on the cognition, neurogenesis and apoptosis in high-fat diet and streptozocin-induced diabetic mice. We found that ERα and/or ERß activation using their agonists (0.5 mg/kg E2, PPT or DPN) ameliorate memory impairment in the Morris water maze and Y-maze tests, increase hippocampal neurogenesis and prevent hippocampal apoptotic responses. Importantly, treatment with the pharmacologic ERs agonists caused significant increases in the membrane ERα and ERß expression and subsequent PI3K/Akt, CREB and BDNF activation in the hippocampus of type 2 diabetes mellitus mice. Our data indicate that ERα and ERß are involved in the cognitive impairment in type 2 diabetes, and that activated ERs, such as application of ERs agonists, could be a novel and promising strategy for the treatment of diabetic cognitive impairment.

Activation of ERα and/or ERß ameliorates cognitive impairment and apoptosis in streptozotocin-induced diabetic mice.

Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 1 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERß on the memory impairment and apoptosis in streptozotocin-induced diabetic mice. We found that ERα and/or ERß activation using their agonists (0.5 mg/kg E2, PPT or DPN) ameliorate memory impairment in the Morris water maze (MWM) and Y-maze tests and suppress apoptosis as evidenced by decreased caspase-3 activity and increased ratio of Bcl-2/Bax. Importantly, treatment with the pharmacologic ERs agonists caused significant increases in the membrane ERα and ERß expression and subsequent PI3K/Akt, CREB and BDNF activation in the hippocampus of diabetic mice. Our data indicate that ERα and ERß are involved in the cognitive impairment of type 1 diabetes and that activation of ERs via administration of ERs agonists could be a novel and promising strategy for the treatment of diabetic cognitive impairment.

Impact of Pituitary-Gonadal Axis Hormones on Pulmonary Arterial Hypertension in Men.

The association of sex hormone (estradiol, testosterone, and progesterone) with cardiopulmonary disease has already attracted great attention, especially in pulmonary arterial hypertension (PAH). However, the impact of sex hormones and their pituitary stimulators (follicle-stimulating hormone and luteinizing hormone) on PAH in men remains unclear. We conducted a prospective cohort study recruiting 95 patients with idiopathic PAH from 2008 to 2014 and following up for a median of 65 months for death. Compared with control, abnormal plasma levels of sex hormones were more common in patients with PAH. Higher estradiol and estradiol/testosterone levels were associated with risk of PAH diagnosis (odds ratio per ln estradiol, 3.55; P<0.001; odds ratio per ln estradiol/testosterone, 4.30; P<0.001), whereas higher testosterone and progesterone were associated with a reduced risk (odds ratio per ln testosterone, 0.48; P=0.003; odds ratio per ln progesterone, 0.09; P<0.001). Fifty patients died during follow-up. Men with higher estradiol had increased mortality (hazard ratio per ln estradiol, 2.02; P=0.007), even after adjustment for baseline characteristics and PAH treatment. According to receiver operating characteristic analysis, patients with PAH with higher estradiol level (≥145.55 pmol/L) had worse 5-year survival rate compared with those with lower estradiol (38.6% versus 68.2%; log-rank test P=0.001). Therefore, our data show higher estradiol, estradiol/testosterone ratio, lower testosterone, and progesterone were associated with increased risk of PAH. Meanwhile, higher estradiol was independently associated with higher mortality in men with PAH. Further studies are needed to explain the origin of these hormonal derangements and their potential pathophysiological implications in PAH.