Sirtuin 6 ameliorates bleomycin-induced pulmonary fibrosis via activation of lipid catabolism.

Pulmonary fibrosis is a chronic and serious interstitial lung disease with little effective therapies currently. Our incomplete understanding of its pathogenesis remains obstacles in therapeutic developments. Sirtuin 6 (SIRT6) has been shown to mitigate multiple organic fibrosis. However, the involvement of SIRT6-mediated metabolic regulation in pulmonary fibrosis remains unclear. Here, we demonstrated that SIRT6 was predominantly expressed in alveolar epithelial cells in human lung tissues by using a single-cell sequencing database. We showed that SIRT6 protected against bleomycin-induced injury of alveolar epithelial cells in vitro and pulmonary fibrosis of mice in vivo. High-throughput sequencing revealed enriched lipid catabolism in Sirt6 overexpressed lung tissues. Mechanismly, SIRT6 ameliorates bleomycin-induced ectopic lipotoxicity by enhancing lipid degradation, thereby increasing the energy supply and reducing the levels of lipid peroxides. Furthermore, we found that peroxisome proliferator-activated receptor α (PPARα) was essential for SIRT6-mediated lipid catabolism, anti-inflammatory responses, and antifibrotic signaling. Our data suggest that targeting SIRT6-PPARα-mediated lipid catabolism could be a potential therapeutic strategy for diseases complicated with pulmonary fibrosis.

A New Full-Dimensional Ab Initio Intermolecular Potential Energy Surface and Rovibrational Energies of the H2O-H2 Complex.

H2O-H2 is a prototypical five-atom van der Waals system, and the interaction between H2O and H2 plays an important role in many physical and chemical environments. However, previous full-dimensional intermolecular potential energy surfaces (IPESs) cannot accurately describe the H2O-H2 interaction in the repulsive or van der Waals minimum region. In this work, we constructed a full-dimensional IPES for the title system with a small root-mean-square error of 0.252 cm-1 by using the permutation invariant polynomial neural network method. The ab initio calculations were performed by employing the explicitly corrected coupled cluster [CCSD(T)-F12a] method with the augmented correlation-consistent polarized valence quintuple-ζ basis set. Based on the newly developed IPES, the bound states of the H2O-H2 complex were calculated within the rigid-rotor approximation. The transition frequencies and band origins agreed well with the experimental values [Weida, M. J.; Nesbitt, D. J. J. Chem. Phys. 1999, 110, 156-167] with errors less than 0.1 cm-1 for most transitions. Those results demonstrate the high accuracy of our new IPES, which would build a solid foundation for the collisional dynamics of H2O-H2 at low temperatures.

Full quantum calculations of the line shape for H2O perturbed by Ar at temperatures from 20 to 300 K.

This work theoretically studied the spectral line shape of H2O perturbed by Ar in the temperature range of 20-300 K for the pure rotational lines below 360 cm-1, as well as three lines (31, 2 ← 44, 1, 54, 2 ← 41, 3, and 73, 5 ← 60, 6) in the v2 band. In order to perform precise dynamical calculations at low collision energies, a full-dimensional long-range potential energy surface was constructed for the H2O-Ar system for the first time to correct the long range of our newly developed intermolecular potential energy surface. Subsequently, the six line-shape parameters (pressure-broadening and -shifting parameters, their speed dependencies, and the complex Dicke parameters) were determined from the generalized spectroscopic cross section by the full quantum time-independent close-coupling approach on this new potential energy surface. Our theoretical results are in good agreement with the available experimental observations. Furthermore, the influence of the speed-dependence and Dicke narrowing effects on the line contour was revealed by comparing the differences among the Hartmann-Tran, quadratic-speed-dependent Voigt, and Voigt profiles. The temperature dependence of each line-shape parameter was further parameterized using the triplet-power-law for three pure rotational 61, 6 ← 52, 3, 41, 4 ← 32, 1, and 31, 3 ← 22, 0 lines. These line-shape parameters will provide a comprehensive set of theoretical references for subsequent experimental measurements.

Single-cell landscape of peripheral immune response in patients with anti-melanoma differentiation-associated gene 5 dermatomyositis.

OBJECTIVE: Anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (DM) is a rare but life-threatening autoimmune disorder with a high risk to develop rapidly progressive interstitial lung disease. Current empirical therapies have limited improvement on patients' survival, as little is known about the aetiology of MDA5 DM. To best understand its immune landscape, we applied single-cell RNA sequencing (scRNA-seq) to peripheral blood samples from DM patients and healthy controls. METHODS: Peripheral blood mononuclear cells (PBMCs) from eight DM patients, comprising three distinct subtypes, as well as two healthy donors, were sequenced by 10X Genomics platform. Additional scRNA-seq data of four healthy donors were incorporated for further bioinformatic analysis. RESULTS: Aberrant increased proportions of CD14+ monocyte and plasma cells were observed in MDA5 DM samples. Moreover, we found overactivated type I interferon response and antiviral immunity in both innate and adaptive immune cells derived from MDA5 DM patients, which was positively correlated with disease severity. Importantly, a unique subset of CD14+ monocyte that highly expressed interferon alpha-inducible protein 27 (IFI27, a biomarker for viral infection) and interferon induced with helicase C domain 1 (IFIH1, encodes MDA5) was specifically identified in MDA5 DM samples for the first time. CONCLUSION: Our study demonstrates the peripheral immune cell atlas of different DM subtypes, provides compelling evidence for viral infection-derived origin of MDA5 DM, and offers potential targets for innovative therapeutic interventions.

Comparison of the inoculum effect of in vitro antibacterial activity of Imipenem/relebactam and Ceftazidime/avibactam against ESBL-, KPC- and AmpC-producing Escherichia coli and Klebsiella pneumoniae.

OBJECTIVE: To evaluate effect of inoculum size of extended-spectrum ß-Lactamase (ESBL)-producing-, AmpC-producing-, and KPC-producing Escherichia coli and Klebsiella pneumoniae on the in vitro antibacterial effects of imipenem/relebactam (IMR) and ceftazidime/avibactam (CZA). METHODS: We compared the impact of inoculum size on IMR and CZA of sixteen clinical isolates and three standard isolates through antimicrobial susceptibility tests, time-kill assays and in vitro PK/PD studies. RESULTS: When inoculum size increased from 105 to 107 CFU/mL, an inoculum effect was observed for 26.3% (5/19) and 52.6% (10/19) of IMR and CZA, respectively; time-kill assays revealed that the concentration of CZA increased from ≥ 4 × MIC to 16 × MIC to reach 99.9% killing rate against K. pneumoniae ATCC-BAA 1705 (KPC-2-, OXA-9- and SHV-182-producing) and 60,700 (SHV-27- and DHA-1-producing). While for IMR, a concentration from 1 × MIC to 4 × MIC killed 99.9% of the four strains. When the inoculum size increased to 109 CFU/mL, neither IMR nor CZA showed a detectable antibacterial effect, even at a high concentration. An in vitro PK/PD study revealed a clear bactericidal effect when IMR administered as 1.25 g q6h when inoculum size increased. CONCLUSION: An inoculum effect on CZA was observed more frequent than that on IMR. Among the ß-lactamase-producing strains, the inoculum effect was most common for SHV-producing and KPC-producing strains.

Full quantum scattering calculations of the line-shape parameters for the P and R branches of HF perturbed by Ar.

This work studied the rovibrational absorption spectral line-shape parameters of the P(1)-P(10) and R(0)-R(9) lines for Hydrogen fluoride perturbed by argon in the 0-0, 1-0, and 2-0 vibrational bands at 20-1000 K. A dataset of beyond-Voigt line-shape parameters (pressure broadening and shifting parameters, their speed dependencies, and the complex Dicke parameters) has been theoretically determined for the first time from generalized spectroscopic cross-section calculated by the full quantum scattering calculations. Then these parameters were employed to predict the line shape and asymmetry based on the partially-correlated speed-dependent hard-collision and the partially-correlated quadratic-speed-dependent hard-collision profiles. The effect of each parameter on the line shape and line asymmetry was further studied, which revealed that the beyond-Voigt effects were indispensable to accurately describe the line shape contour. Our results are in good agreement with the available experimental observations and provide a comprehensive set of theoretical references for further experimental measurements.

Fully quantum calculations of the line shape parameters for 1-0 P(22) and P(31) lines of CO perturbed by He or Ar.

This work reports the full quantum calculations of the spectral line shape parameters for the P(22) line of 13CO and the P(31) line of 12CO in the fundamental band perturbed by He or Ar from 20 to 1000 K for the first time. The generalized spectroscopic cross sections of CO-He/Ar indicate that the Dicke narrowing effect competes with the pressure broadening effect. The pressure broadening can be explained by the dynamic behaviors of intermolecular collisions. The intermolecular inelastic collisions contribute more than 95% to the pressure broadening in both CO-He and CO-Ar systems at high temperatures. Regarding the state-to-state inelastic contributions to pressure broadening, the maximum contribution out of the final state of a given line is close to that out of the initial state. The Dicke narrowing effect influences the line shape profile significantly at high temperatures, which suggests that it is indispensable for reproducing the spectral line profile. With the Dicke narrowing effect, the calculated pressure-broadening coefficients and spectral intensity distribution are in good agreement with the available experimental observations.

A full-dimensional ab initio intermolecular potential energy surface and rovibrational spectra for OC-HF and OC-DF.

We present a full-dimensional ab initio intermolecular potential energy surface (IPES) for the OC-HF van der Waals complex. 3167 ab initio points were computed at the frozen-core (FC) explicitly correlated coupled cluster [FC-CCSD(T)-F12b] level, with the augmented correlation-consistent polarized valence quadruple-zeta basis set plus bond functions. Basis set superposition error correction was also considered by the full counterpoise procedure. Gaussian process regression (GPR) was used to map out the potential energy surface, while a multipole expansion method was employed to smooth the ab initio noise of intermolecular potential in the long range. The global minimum of -1248.364 cm-1 was located at the linear configuration with the C atom pointing toward the H atom of the HF molecule. In addition, a local minimum of -602.026 cm-1 was found at another linear configuration with the O atom pointing toward the H atom of the HF molecule. The eigenstates were calculated on the vibrational averaged four-dimensional IPESs with the mixed radial discrete variable representation/angular finite basis representation method and Lanczos propagation algorithm. The dissociation energy D0 was calculated to be 701.827 cm-1, well reproducing the experimental value of 732 ± 2 cm-1. The dipole moment surfaces were also fitted by GPR from 3132 ab initio points calculated using the coupled cluster method [CCSD(T)] with AVTZ basis set plus bond functions. The frequencies and relative line intensities of rovibrational transitions in the HF (DF) and CO stretching bands were further calculated and compared well with the experimental results. These results indicate the high fidelity of the new IPES.

A Retrospective Analysis of Risk Factors and Outcomes of Carbapenem-Resistant Klebsiella pneumoniae Bacteremia in Nontransplant Patients.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a major problem among nosocomial infections, and it is a serious threat to patients. The clinical characteristics and outcome of CRKP bloodstream infection (BSI) in nontransplant patients remains unelucidated. The aim of this study was as follows: identify the risk factors of CRKP infection; generate new ideas for prevention; and generate new ideas for the most effective therapeutic management in nontransplant patients. METHODS: The study retrospectively analyzed the clinical and microbiological data of nontransplant patients with K pneumoniae (KP) bacteremia from January 2013 to December 2015 to identify risk factors, clinical features, and outcomes using multivariate logistic regression analysis. RESULTS: Of the 371 patients with KP-BSI in nontransplant patients included in this study, 28.0% (N = 104) had CRKP. The 28-day mortality was higher in patients infected with CRKP (55.8%) than in those with carbapenem-susceptible KP (13.9%) (P < .001). Multivariate analysis showed previous gastric catheterization, previous use of carbapenems, hypoproteinemia, and high Acute Physiologic Assessment and Chronic Health Evaluation II scores as independent risk factors for CRKP-BSIs. Carbapenem-resistant KP infection, severe illness, and tigecycline therapy were independent risk factors for death from KP-BSIs. Taken together, inappropriate antibiotic treatment both in empirical and definitive therapy and imipenem minimum inhibitory concentrations (MICs) of >8 mg/L were associated with poor clinical outcome. CONCLUSIONS: Nontransplant patients with CRKP-BSI had higher mortality. Carbapenems exposure was an independent risk factor for CRKP infection. Imipenem MICs of >8 mg/L, tigecycline therapy, and inappropriate treatments increased the 28-day mortality of KP-BSI patients.

Novel Subclone of Carbapenem-Resistant Klebsiella pneumoniae Sequence Type 11 with Enhanced Virulence and Transmissibility, China.

We aimed to clarify the epidemiologic and clinical importance of evolutionary events that occurred in carbapenem-resistant Klebsiella pneumoniae (CRKP). We collected 203 CRKP causing bloodstream infections in a tertiary hospital in China during 2013-2017. We detected a subclonal shift in the dominant clone sequence type (ST) 11 CRKP in which the previously prevalent capsular loci (KL) 47 had been replaced by KL64 since 2016. Patients infected with ST11-KL64 CRKP had a significantly higher 30-day mortality rate than other CRKP-infected patients. Enhanced virulence was further evidenced by phenotypic tests. Phylogenetic reconstruction demonstrated that ST11-KL64 is derived from an ST11-KL47-like ancestor through recombination. We identified a pLVPK-like virulence plasmid carrying rmpA and peg-344 in ST11-KL64 exclusively from 2016 onward. The pLVPK-like-positive ST11-KL64 isolates exhibited enhanced environmental survival. Retrospective screening of a national collection identified ST11-KL64 in multiple regions. Targeted surveillance of this high-risk CRKP clone is urgently needed.

A full-dimensional ab initio intermolecular potential energy surface and ro-vibrational spectra for N2-HF and N2-DF.

A full-dimensional ab initio intermolecular potential energy surface (IPES) is reported in this paper for van der Waals complex N2-HF. The calculations were performed by employing the explicitly correlated coupled cluster [CCSD (T)-F12a] method with the augmented correlation-consistent aug-cc-pVTZ basis set plus bond functions. The basis set superposition error was corrected by the full counterpoise procedure. About 55 000 ab initio points were calculated and then fitted by the permutation invariant polynomial neural network approach with a root-mean-square error of 0.433 cm-1. The potential energy surface features two equivalent linear minima with a well depth of 811.012 cm-1 separated by a barrier of 635.836 cm-1. The ro-vibrational energy levels for N2-HF and N2-DF were calculated based on the vibrationally averaged 4D IPESs with the radial discrete variable representation/angular finite basis representation method and Lanczos propagation algorithm. The calculated frequencies and the relative line intensities in the HF (DF) stretching band agree well with the available observed spectra. The theoretical band origins are all red shifted relative to the isolated HF (DF) molecule and reproduce the experimental values well. The results of ro-vibrational state calculations demonstrate the high accuracy of our new PES.

Comprehensive Genome Analysis of Carbapenem-Resistant Raoultella spp. strains, an Emerging Multidrug-Resistant Bacteria in Hospitals.

We report the characterization of six carbapenem-resistant Raoultella spp.(CRRS) in our hospital and a genomic analysis of 58 publicly available isolates. CRRS isolates are sporadically identified around the world and different transposons carrying carbapenemases were the resistant mechanisms. Mobile genetic elements play an important role in acquiring antibiotic resistant genes from the hospital. An improved understanding of these transposon and targeted control measures will be very valuable to prevent the CRRS dissemination.

High prevalence of a globally disseminated hypervirulent clone, Staphylococcus aureus CC121, with reduced vancomycin susceptibility in community settings in China.

OBJECTIVES: Most vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are derived from hospital-associated MRSA due to treatment failure; however, the prevalence of hVISA/VISA in community settings remains unclear. METHODS: Four hundred and seventy-six community-associated isolates were collected between 2010 and 2011 during national surveillance for antimicrobial resistance in 31 county hospitals across China. Drug susceptibility evaluation and mecA detection were performed by using broth microdilution and PCR analysis, respectively. hVISA/VISA were identified by using macro-Etest and a modified population analysis profile (PAP)-AUC method. The genetic features of all hVISA/VISA isolates were genotyped. RESULTS: Among 476 isolates, MRSA and MSSA accounted for 19.7% (n = 94) and 80.3% (n = 382), respectively. Two VISA and 36 hVISA isolates were identified by PAP-AUC testing. The VISA isolates and 29 of the hVISA isolates were MRSA. The proportion of hVISA/VISA was significantly higher in MRSA (30.9%) than in MSSA (1.8%). The hVISA/VISA isolates were assigned to 18 STs classified into seven clonal complexes (CCs). CC121 (n = 12) followed by ST239 (n = 11) was the most prevalent hVISA/VISA clone. All ST239-hVISA/VISA were MRSA, while 12 CC121-hVISA isolates included 6 MSSA and 6 MRSA isolates. SCCmec III was predominant among MRSA-hVISA/VISA isolates. agr I and agr IV were detected in ST239 and CC121, respectively. All except two strains were positive for Panton-Valentine leucocidin genes. CONCLUSIONS: To the best of our knowledge, this is the first report of CC121 as a prevalent hVISA clone in community settings, highlighting the necessity of surveillance and stricter infection control measures for this globally disseminated lineage.

Molecular insight into chymotrypsin inhibitor 2 resisting proteolytic degradation.

Chymotrypsin inhibitor 2 (CI2) is a special serine protease inhibitor which can resist hydrolysis for several days with a rapid equilibrium between the Michaelis complex and acyl-enzyme intermediate. The energies and conformational changes for subtilisin-catalyzed proteolysis of CI2 were examined in this paper for the first time by employing pseudo bond ab initio QM/MM MD simulations. In the acylation reaction, a low-barrier hydrogen bond between His64 and Asp32 in the transition state together with the lack of covalent backbone constraints makes the peptide bonds of CI2 break more easily than in other serine protease inhibitors. After acyl-enzyme formation, molecular dynamics simulations showed that the access of hydrolytic water to the active site requires partial dissociation of the leaving group. However, retention of the leaving group mainly by the intra- and inter-molecular H-bonding networks hinders the access of water and retards the deacylation reaction. Instead of the dissociation constant of inhibitors, we suggest employing the free energy at the acyl-enzyme state to predict the relative hydrolysis rates of CI2 mutants, which are testified by the experimental relative hydrolysis rates.

A new full-dimensional ab initio intermolecular potential energy surface and vibrational states for (HF)2 and (DF)2.

We present a new full-dimensional ab initio potential energy surface (PES) of a hydrogen fluoride dimer [(HF)2] using the supermolecular approach. The calculations were performed at the coupled-cluster single double triple level, with an augmented correlation-consistent polarized valence quadruple-zeta basis set plus bond functions. The basis set superposition error was corrected by a full counterpoise procedure. With the exchange symmetry of the two HF molecules, the permutation invariant polynomial neural network approach was used to fit the hypersurface with a root-mean-square-error of 0.465 cm-1 for about 110 000 points. The ab initio noise of intermolecular potential in the long range was smoothed by the long-range coefficients method. The equilibrium configuration of the complex was found to be a Cs structure located at two equivalent minima with the well depth of 1573.495 cm-1. The eigenstates were calculated by employing a symmetry-adapted Lanczos propagation algorithm in the mixed radical discrete variable representation/angular finite basis representation. The tunneling splitting for the ground state of (HF)2 is 0.665 cm-1, agreeing well with experimental value of 0.65869 cm-1. Vibrational fundamentals are also very close to the observed values. The results of vibrational states calculations demonstrate the high accuracy of our new PES.

Characterization of Nine Compounds Isolated from the Acid Hydrolysate of Lonicera fulvotomentosa Hsu et S. C. Cheng and Evaluation of Their In Vitro Activity towards HIV Protease.

In this study, we isolated nine compounds from the acid hydrolysate of the flower buds of Lonicera fulvotomentosa Hsu et S. C. Cheng and characterized their chemical structures using 1H-NMR, 13C-NMR, and electron ionization mass spectroscopy (EI-MS). These compounds were identified as ß-sitosterol (1), 5,5'-dibutoxy-2,2'-bifuran (2), nonacosane-10-ol (3), ethyl (3ß)-3,23-dihydroxyolean-12-en-28-oate (4), oleanolic acid (5), ethyl caffeate (6), caffeic acid (7), isovanillin (8), and hederagenin (9), with 4 as a new triterpene compound. Inhibitory activity against human immunodeficiency virus (HIV) protease was also evaluated for the compounds, and only ethyl caffeate, caffeic acid, and isovanillin (6, 7, and 8) exhibited inhibitory effects, with IC50 values of 1.0 µM, 1.5 µM, and 3.5 µM, respectively. Molecular docking with energy minimization and subsequent molecular dynamic (MD) simulation showed that ethyl caffeate and caffeic acid bound to the active site of HIV protease, while isovanillin drifted out from the active site and dissociated into bulk water during MD simulations, and most of the binding residues of HIV protease have been previously identified for HIV protease inhibitors. These results suggest that caffeic acid derivatives may possess inhibitory activities towards HIV protease other than previously reported inhibitory activities against HIV integrase, and thus ethyl caffeate and caffeic acid could be used as lead compounds in developing potential HIV protease inhibitors, and possibly even dual-function inhibitors against HIV.

Predicted infrared spectra in the HF stretching band of the H2-HF complex.

The infrared spectra with hydrogen fluoride (HF) and deuterium fluoride (DF) (v2 = 1 ← 0) for eight isotropic species of H2-HF complex are predicted, based on our newly constructed high-accuracy ab initio potential energy surface [D. Yang et al., J. Chem. Phys. 148, 184301 (2018)]. The radial discrete variable representation/angular finite basis representation method and Lanczos algorithm were used to determine the ro-vibrational energy levels and wave functions for eight species of H2-HF complex (para-H2-HF, ortho-H2-HF, para-D2-HF, ortho-D2-HF, para-H2-DF, ortho-H2-DF, para-D2-DF, and ortho-D2-DF) with separating the inter- and intra-molecular vibrations. Bound states properties including their dissociation energies and rotational constants were presented. The calculated band origins are all red shifted to the isolated HF molecule and in good agreement with available experimental values. The frequencies and line intensities of ro-vibrational transitions in the HF stretching band were further calculated, and the predicted infrared spectra are consistent with available observed spectra. Among them, the spectra for three isotopic species of H2-HF (para-H2-DF, para-D2-DF, and ortho-D2-DF) were predicted for the first time.

Mechanistic insights into a classic wonder drug--aspirin.

Aspirin, one of the oldest and most common anti-inflammatory agents, has recently been shown to reduce cancer risks. The principal pharmacological effects of aspirin are known to arise from its covalent modification of cyclooxygenase-2 (COX-2) through acetylation of Ser530, but the detailed mechanism of its biochemical action and specificity remains to be elucidated. In this work, we have filled this gap by employing a state-of-the-art computational approach, Born-Oppenheimer molecular dynamics simulations with ab initio quantum mechanical/molecular mechanical potential and umbrella sampling. Our studies have characterized a substrate-assisted inhibition mechanism for aspirin acetylating COX: it proceeds in two successive stages with a metastable tetrahedral intermediate, in which the carboxyl group of aspirin serves as the general base. The computational results confirmed that aspirin would be 10-100 times more potent against COX-1 than against COX-2, and revealed that this inhibition specificity between the two COX isoforms can be attributed mainly to the difference in kinetics rate of the covalent inhibition reaction, not the aspirin-binding step. The structural origin of this differential inhibition of the COX enzymes by aspirin has also been elucidated.

Oroxylin A, a broad­spectrum anticancer agent, relieves monocrotaline­induced pulmonary arterial hypertension by inhibiting the Warburg effect in rats.

Pulmonary arterial hypertension (PAH) is a chronic and fatal disease characterized by pulmonary vascular remodeling, similar to the 'Warburg effect' observed in cancer, which is caused by reprogramming of glucose metabolism. Oroxylin A (OA), an active compound derived from Scutellaria baicalensis, which can inhibit glycolytic enzymes [hexokinase 2 (HK2), Lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase 1 (PDK1) by downregulating aerobic glycolysis to achieve the treatment of liver cancer. To the best of our knowledge, however, the impact of OA on PAH has not been addressed. Consequently, the present study aimed to evaluate the potential protective role and mechanism of OA against PAH induced by monocrotaline (MCT; 55 mg/kg). The mean pulmonary artery pressure (mPAP) was measured using the central venous catheter method; HE and Masson staining were used to observe pulmonary artery remodeling. Non­targeted metabolomics was used to analyze the metabolic pathways and pathway metabolites in MCT­PAH rats. Western Blot analysis was employed to assess the levels of glucose transporter 1 (Glut1), HK2), pyruvate kinase (PK), isocitrate dehydrogenase 2 (IDH2), pyruvate dehydrogenase kinase 1(PDK1), and lactate dehydrogenase (LDH) protein expression in both lung tissue samples from MCT­PAH rats. The results demonstrated that intragastric administration of OA (40 and 80 mg/kg) significantly decreased mPAP from 43.61±1.88 mmHg in PAH model rats to 26.51±1.53 mmHg and relieve pulmonary artery remodeling. Untargeted metabolomic analysis and multivariate analysis indicated abnormal glucose metabolic pattern in PAH model rats, consistent with the Warburg effect. OA administration decreased this effect on the abnormal glucose metabolism. The protein levels of key enzymes involved in glucose metabolism were evaluated by western blotting, which demonstrated that OA could improve aerobic glycolysis and inhibit PAH by decreasing the protein levels of Glut1, HK2, LDH, PDK1 and increasing the protein levels of PK and IDH2. In conclusion, OA decreased MCT­induced PAH in rats by reducing the Warburg effect.