Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH.

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Highlights d cGAS is essential for restricting RNA virus infection d Nuclear cGAS recruits Prmt5 upon virus infection d Prmt5 regulates histone arginine modification of IFN promoters d Prmt5 deficiency impairs the innate antiviral responses

Pulmonary arterial hypertension (PAH) is a vascular disease characterized by persistent precapillary pulmonary hypertension (PH), leading to progressive right heart failure and premature death. The pathological mechanisms underlying this condition remain elusive. Analysis of global metabolomics from lung tissue of patients with PAH (n = 8) and control lung tissue (n = 8) leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted arginine pathways with increased Nitric oxide (NO) and decreased arginine. Our results also showed specific metabolic pathways and genetic profiles with increased Sphingosine-1-phosphate (S1P) metabolites as well as increased Heme metabolites with altered oxidative pathways in the advanced stage of the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to the vascular remodeling in severe pulmonary hypertension. Profiling metabolomic alterations of the PAH lung has provided a new understanding of the pathogenic mechanisms of PAH, which benefits therapeutic targeting to specific metabolic pathways involved in the progression of PAH.

Although multiple, complex molecular studies have been done for understanding the development and progression of pulmonary hypertension (PAH), little is known about the metabolic heterogeneity of PAH. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we found bile acid metabolites, which are normally product derivatives of the liver and gallbladder, were highly increased in the PAH lung. Microarray showed that the gene encoding cytochrome P450 7B1 (CYP7B1), an isozyme for bile acid synthesis, was highly expressed in the PAH lung compared with the control. CYP7B1 protein was found to be primarily localized on pulmonary vascular endothelial cells suggesting de novo bile acid synthesis may be involved in the development of PAH. Here, by profiling the metabolomic heterogeneity of the PAH lung, we reveal a newly discovered pathogenesis mechanism of PAH.

Cowhage is routinely used in human studies of histamine-independent itch. As such, it is of interest to understand its mechanism of action. The active component of cowhage is a cysteine protease called mucunain. As serine proteases can activate members of the protease-activated receptor (PAR) family to induce itch and pain, the mechanism of action of mucunain and cathepsin S, a human cysteine protease, were likewise thought to be through activation of PARs. The demonstration that cathepsin S activates members of the Mas-related G-protein coupled receptor family to induce itch led us to evaluate the activity of mucunain on these receptors. We find that mucunain activates the human receptors MRPGRX1 and MRGPRX2 and induces degranulation of human mast cells. These findings indicate that Mrgprs may be involved in itch induced by cowhage.

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Background/Aim: We aimed to assess the value of early laparoscopic therapy in management of tubo-ovarian abscess (TOA) or pelvic abscess. Methods: This was a retrospective study of all consecutive patients who were initially diagnosed with TOA or pelvic abscess at the local hospital between January 2010 and December 2014. The risks of operation and recurrence were analyzed using logistic analyses. Results: The durations of body temperature > 38.0°C (p = 0.001) and hospitalization (p < 0.001) were longer in the conventional group versus the early laparoscopy group. In the conventional group, 15 (50%) patients finally underwent laparoscopic exploration. The abscess size in the late laparoscopic group was significantly larger than the successful antibiotic treatment group (6.3 ± 1.5 vs. 4.9 ± 1.2 cm, p = 0.010). Abscess > 5.5 cm was independently associated with antibiotic failure (OR 4.571; 95% CI 1.612–12.962). Compared with late laparoscopy, early laparoscopy was associated with a shorter operation time (p = 0.037), less blood loss (p = 0.035), and shorter durations of body temperature > 38.0°C (p < 0.001) and hospitalization (p < 0.001). The cost was the lowest in the patients successfully treated conservatively. Conclusion: Early laparoscopic treatment is associated with shorter time of fever resolution, shorter hospitalization, and less blood loss compared with conventional treatment for TOA or pelvic abscess.