2026-07-02 | Alterations in the fecal virome and bacteriome-virome interplay in IPAH.
Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening cardiovascular disorder characterized by complex multisystem disturbances. Although alterations in the gut microbiota have been reported in IPAH, how the gut virome interacts with bacterial communities and host metabolism remains unclear. We enrolled 28 patients with IPAH and 30 age-matched healthy controls (HCs). Fecal viromes and bacteriomes were profiled by metagenomic sequencing, and serum metabolomic data were integrated to construct virus-bacterium-metabolite interaction networks. Random forest models were used to evaluate the diagnostic potential of virome features. IPAH patients exhibited markedly reduced gut virome diversity (Shannon, Simpson, and Pielou indices, p < 0.05) and distinct community structures from HCs (p < 0.01). A total of 499 differential viral operational taxonomic units (vOTUs) were identified, accompanied by extensive reorganization of interaction networks. At the phylum level, Hofneiviricota was enriched and Phixviricota depleted, both correlating with clinical indicators. Virus-bacterium associations were markedly increased in IPAH (44,894 vs. 17,920, r > 0.5). Notably, vOTU2967, vOTU1924, and vOTU4522 were elevated and inversely related to Bacteroides, whose depletion was associated with increased lactic acid levels. Mediation analysis confirmed significant indirect virus-bacterium-metabolite effects (p < 0.05). Random forest models based on vOTUs or viral families effectively distinguished IPAH patients from controls, highlighting the exploratory potential of gut virome features for mechanistic insights. IPAH is characterized by reduced virome diversity, altered viral taxa, and reorganized virus-bacterium-metabolite networks. These findings suggest that gut viruses may influence disease progression by modulating bacterial metabolism, providing a potential avenue for biomarker discovery and therapeutic intervention.
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2026-07-02 | Selective targeting phosphodiesterase-5 (PDE5): clinical progress, design strategies, and emerging prospects.
PDE5 is a subfamily member of the phosphodiesterase (PDE) superfamily. It is encoded by a single PDE5A gene, and its primary function is to specifically hydrolyse cyclic guanosine monophosphate. To date, a few inhibitors targeting PDE5, exemplified by sildenafil, tadalafil, and vardenafil, have been approved for the treatment of several diseases including pulmonary arterial hypertension and erectile dysfunction. However, due to their low subtype selectivity, the currently marketed PDE5 inhibitors cause some severe adverse effects in clinical applications, including headaches and visual disturbances. Therefore, discovering new PDE5 inhibitors featuring novel scaffolds and high subtype selectivity for disease treatment and target research remains to attract significant interest from both academics and industry. This review emphasises the rational design, advantages, and potential limitations of PDE5 inhibitors with diverse scaffolds, aiming to generate insights into the discovery and development of novel subtype-selective PDE5 inhibitors.
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2026-07-01 | Placental Growth Factor Promotes Endothelial Activation and Inflammatory Remodelling in Pulmonary Hypertension.
Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder marked by pulmonary vascular remodelling and vessel loss, paradoxically occurring despite high VEGF signaling. While VEGF/VEGFR pathways are implicated in disease pathogenesis, their role in endothelial and immune cell crosstalk remains poorly understood. Placental growth factor (PlGF), a VEGF family member that selectively binds VEGFR-1, exerts pro-inflammatory effects in other pathological contexts, but its contribution to PAH pathophysiology is unclear. This study explored the contribution of PlGF to endothelial activation and immune-mediated vascular remodelling in PAH. Serum levels of PlGF, VEGF-A, soluble VEGFR-1 (sVEGFR-1), and soluble VEGFR-2 (sVEGFR-2) were measured in 80 treatment-naïve PAH patients from the EFORT cohort and in healthy controls. Their association with survival was then assessed. VEGFR-1 expression was evaluated in human PAH lung tissue. The functional role of PlGF was investigated in Plgf-/- rats exposed to chronic hypoxia or monocrotaline, and in mechanistic studies using primary human pulmonary endothelial cells and monocyte-derived macrophages.Circulating PlGF and sVEGFR-1 were elevated in PAH and associated with worse survival. VEGFR-1 expression was increased in PAH lung endothelium. Genetic deletion of Plgf protected rats from experimental pulmonary hypertension, leading to reduced pulmonary pressures, right ventricular hypertrophy, and vascular remodelling. PlGF deficiency reduced endothelial ICAM-1/VCAM-1 expression, macrophage infiltration, and pro-inflammatory cytokine production (CCL5/RANTES, osteoprotegerin, and LIX/CXCL5). In vitro, PlGF induced endothelial adhesion molecule expression and promoted macrophage polarization toward a pro-remodelling M2-like phenotype. PlGF is upregulated in PAH, its concentration predicts adverse outcomes, and it actively drives vascular remodelling by coupling endothelial activation to immune dysregulation. These findings establish PlGF as both a prognostic biomarker and a promising therapeutic target for PAH.
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