Recent studies have demonstrated that fascial fibroblasts are susceptible to mechanical stimuli, leading to the remodeling of the extracellular matrix (ECM). Moreover, the extensive literature on Yes-associated protein (YAP) has shown its role in cell mechanics, linking cell properties, such as shape, adhesion, and size, to the expression of specific genes. The aim of this study was to investigate the presence of YAP in deep fascia and its activation after a mechanical stimulus was induced via a focal extracorporeal shockwave (fESW) treatment. Thoracolumbar fascia (TLF) samples were collected from eight patients (age: 30–70 years; four males and four females) who had undergone spine elective surgical procedures at the Orthopedic Clinic of University of Padova. YAP was measured in both tissue and TLF-derived fibroblasts through immunoblotting. COL1A1 and HABP2 gene expression were also evaluated in fibroblasts 2, 24, and 48 h after the fESW treatment. YAP was expressed in all the examined tissues. The ratio between the active/inactive forms (YAP/p-YAP) of the protein significantly increased in fascial fibroblasts after mechanical stimulation compared to untreated cells (p = 0.0022). Furthermore, COL1A1 and HABP2 gene expression levels were increased upon treatment. These findings demonstrate that YAP is expressed in the deep fascia of the thoracolumbar region, suggesting its involvement in fascial mechanotransduction processes, remodeling, regeneration, and fibrogenesis. This study indicates, for the first time, that YAP is a “new player” in the mechanobiology of deep fascia.

Success of adrenal vein sampling (AVS) is verified by the selectivity index (SI), i.e., by a step-up of cortisol levels between the adrenal vein and the infrarenal inferior vena cava samples, beyond a given cut-off. We tested the hypothesis that androstenedione, metanephrine, and normetanephrine, which have higher gradients than cortisol, could increase the rate of AVS studies judged to be bilaterally successful and usable for the clinical decision making. We prospectively compared within-patient, head-to-head, the selectivity index of androstenedione (SI_A), metanephrine (SI_M), and normetanephrine (SI_NM), and cortisol (SI_C) in consecutive hypertensive patients with primary aldosteronism submitted to AVS. Main outcome measures were rate of bilateral success, SI values, and identification of unilateral PA. We recruited 136 patients (55 + 10 years, 35% women). Compared to the SI_C, the SI_A values were 3.5-fold higher bilaterally, and the SI_M values were 7-fold and 4.4-fold higher on the right and the left side, respectively. With the SI_A and the SI_M the rate of bilaterally successful AVS increased by 14% and 15%, respectively without impairing the identification of unilateral PA. We concluded that androstenedione and metanephrine outperformed cortisol for ascertaining AVS success, thus increasing the AVS studies useable for the clinical decision making.

Blockers of the renin-angiotensin system (RAS) have been reported to increase the angiotensin converting enzyme (ACE)2, the cellular receptor of SARS-CoV-2, and thus the risk and course of COVID-19. Therefore, we investigated if angiotensin (Ang) II and RAS blockers affected ACE2 expression and SARS-CoV-2 infectivity in human epithelial bronchial Calu-3 cells. By infectivity and spike-mediated cell–cell fusion assays, we showed that Ang II acting on the angiotensin type 1 receptor markedly increased ACE2 at mRNA and protein levels, resulting in enhanced SARS-CoV-2 cell entry. These effects were abolished by irbesartan and not affected by the blockade of ACE-1-mediated Ang II formation with ramipril, and of ACE2- mediated Ang II conversion into Ang 1-7 with MLN-4760. Thus, enhanced Ang II production in patients with an activated RAS might expose to a greater spread of COVID-19 infection in lung cells. The protective action of Angiotensin type 1 receptor antagonists (ARBs) documented in these studies provides a mechanistic explanation for the lack of worse outcomes in high-risk COVID-19 patients on RAS blockers.

Even though SARS-CoV-2 was declared by WHO as constituting no longer a public health emergency, the development of effective treatments against SARS-CoV-2 infection remains a critical issue to prevent complications, particularly in fragile patients. The protease inhibitor nafamostat, currently used in Japan and Korea for pancreatitis, owing to its anticoagulant properties for disseminated intravascular coagulation (DIC), is appealing for the treatment of COVID-19 infection, because it potently inhibits the transmembrane protease serine 2 (TMPRSS2) that, after virus binding to ACE-2, allows virus entry into the cells and replication. Moreover, it could prevent the DIC and pulmonary embolism frequently associated with COVID-19 infection. The goal of the RAndomized Clinical Trial Of NAfamostat (RACONA) study, designed as a prospective randomized, double-blind placebo-controlled clinical trial, was to investigate the efficacy and safety of nafamostat mesylate (0.10 mg/kg/h iv for 7 days), on top of the optimal treatment, in COVID-19 hospitalized patients. We could screen 131 patients, but due to the predefined strict inclusion and exclusion criteria, only 15 could be randomized to group 1 (n = 7) or group 2 (n = 8). The results of an ad interim safety analysis showed similar overall trends for variables evaluating renal function, coagulation, and inflammation. No adverse events, including hyperkalemia, were found to be associated with nafamostat. Thus, the RACONA study showed a good safety profile of nafamostat, suggesting that it could be usefully used in COVID-19 hospitalized patients.

The large environmental contamination of drinking water by perfluoroalkyl substances (PFAS) markedly increased the plasma levels of pentadecafluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in a Northern Italy population with a high prevalence of arterial hypertension and cardiovascular disease. As the link between PFAS and arterial hypertension is unknown, we investigated if they enhance the biosynthesis of the well-known pressor hormone aldosterone. We found that PFAS increased aldosterone synthase (CYP11B2) gene expression by three-fold and doubled aldosterone secretion and cell and mitochondria reactive oxygen species (ROS) production over controls (p < 0.01 for all) in human adrenocortical carcinoma cells HAC15. They also enhanced the effects of Ang II on CYP11B2 mRNA and aldosterone secretion (p < 0.01 for all). Moreover, when added 1 h before, the ROS scavenger tempol abolished the effect of PFAS on CYP11B2 gene expression. These results indicate that at concentrations mimicking those found in human plasma of exposed individuals, PFAS are potent disruptors of human adrenocortical cell function, and might act as causative factors of human arterial hypertension via increased aldosterone production.

The deep fascia, traditionally regarded as a passive structural tissue, is now recognized as a metabolically and biologically active structure where biochemical signals and biomechanical forces interact to influence proprioception, pain, force transmission, and adaptation to mechanical load. In this study, the convergence point between Angiotensin II (Ang II) signaling via its receptor, Angiotensin type 1 receptor (AT1R), and the mechanosensor Yes-associated protein (YAP) was investigated in human fascial fibroblasts. The presence of angiotensin II (Ang II) receptors was confirmed in fibroblasts from the deep fascia, with the AT1 receptor being the most prevalent subtype. Short-term exposure to Ang II (15–30 min) caused YAP dephosphorylation and its translocation to the nucleus, indicating YAP activation. Notably, prolonged Ang II treatment (7 days) significantly increased the expression of fibrosis-related genes, including collagen types I and III (COL1A1, COL3A1), and hyaluronan binding protein 2 (HABP2). This gene expression was decreased by pretreatment with the AT1R antagonist irbesartan or the YAP inhibitor verteporfin. Additionally, Ang II promoted fibroblast proliferation/migration, key features of fibrotic progression, through AT1R-dependent pathways. These findings show that Ang II acts as both a biochemical and biomechanical signal in the deep fascia, activating YAP signaling and promoting fibrotic remodeling. Our results uncover a new Ang II–YAP pathway in fascial fibroblasts, offering potential targets for therapy in fibrosis and related conditions involving the deep fascia.