Pulmonary infections are a major global cause of morbidity, exacerbated by an increasing threat from antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on ever greater significance. Pseudomonas aeruginosa is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced in vivo by the innate immune modulatory properties of antimicrobial host defence peptides from the cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents, cathelicidins are now recognised as multifunctional antimicrobial immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that P . aeruginosa infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to P . aeruginosa . We demonstrate that this is mechanistically dependent upon cathepsin B release, and NLRP3-dependent activation of caspase 1. These result in LL-37-mediated release of IL-1β and IL-18 in a manner that is synergistic with P . aeruginosa infection, and can induce caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that cathelicidin can therefore act as a second signal, required by P . aeruginosa infected epithelial cells to promote an inflammasome-mediated altruistic cell death of infection-compromised epithelial cells and act as a “fire alarm” to enhance rapid escalation of protective inflammatory responses to an uncontrolled infection. Understanding this novel modulatory role for cathelicidins, has the potential to inform development of novel therapeutic strategies to antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.

Heart failure (HF) is marked by distinctive changes in myocardial uptake and utilization of energy substrates. Among the different types of HF, HF with preserved ejection fraction (HFpEF) is a highly prevalent, complex, and heterogeneous condition for which metabolic derangements seem to dictate disease progression. Changes in intermediate metabolism in cardiometabolic HFpEF—among the most prevalent forms of HFpEF—have a large impact both on energy provision and on a number of signalling pathways in the heart. This dual, metabolic vs. signalling, role is played in particular by long-chain fatty acids (LCFAs) and short-chain carbon sources [namely, short-chain fatty acids (SCFAs) and ketone bodies (KBs)]. LCFAs are key fuels for the heart, but their excess can be harmful, as in the case of toxic accumulation of lipid by-products (i.e. lipotoxicity). SCFAs and KBs have been proposed as a potential major, alternative source of energy in HFpEF. At the same time, both LCFAs and short-chain carbon sources are substrate for protein post-translational modifications and other forms of direct and indirect signalling of pivotal importance in HFpEF pathogenesis. An in-depth molecular understanding of the biological functions of energy substrates and their signalling role will be instrumental in the development of novel therapeutic approaches to HFpEF. Here, we summarize the current evidence on changes in energy metabolism in HFpEF, discuss the signalling role of intermediate metabolites through, at least in part, their fate as substrates for post-translational modifications, and highlight clinical and translational challenges around metabolic therapy in HFpEF.

Background Ovarian tumors (OTs) are common gynecological tumors in women. It is very important to correctly distinguish benign and malignant OTs. Purpose To assess the diagnostic performance of the American College of Radiology (ACR) Ovarian-Adnexal Reporting and Data System (O-RADS) and evaluate the clinical value of O-RADS combined with serum carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) in differentiating benign from malignant OTs. Material and Methods A retrospective analysis was performed on 431 cases including pathology and clinical data. The receiver operating characteristic (ROC) curve was drawn, and sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. Results In premenopausal women, O-RADS and O-RADS combined with serum CA125 and HE4 showed sensitivity at 92.2% and 94.8%, specificity at 91.8% and 93.4%, and accuracy at 91.9% and 93.8%, respectively. In postmenopausal women, the sensitivity of O-RADS, O-RADS combined with serum CA125 and HE4 was 94.8% and 95.8%, specificity was 83.9% and 93.6%, and accuracy was 90.5% and 95.6%, respectively. The sensitivity, specificity, and accuracy of O-RADS combined with CA125 and HE4 in premenopausal and postmenopausal women were higher than that of O-RADS ( P<0.05). Conclusion O-RADS has high diagnostic performance in OTs. When O-RADS is combined with CA125 and HE4 in the diagnosis of OTs, the sensitivity and specificity are improved, which is helpful to improve the diagnostic efficiency of OTs and has high clinical application value.