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OBJECTIVE: In systemic sclerosis (SSc) microvascular endothelial cells (MVECs), angiogenesis is blocked by matrix metalloproteinase 12-dependent cleavage of domain 1 of the urokinase-type plasminogen activator receptor (uPAR). Since integrins are associated with the invasive activity of uPAR in angiogenesis, this study was undertaken to show whether full-size and truncated uPAR are differentially associated with integrins and with motor components of the cytoskeleton. METHODS: SSc and normal MVECs were isolated from human skin biopsy specimens and studied by confocal laser scanning microscopy and immunoprecipitation to assess the mechanisms of association of truncated and full-size uPAR with integrins and the actin cytoskeleton. The integrin composition of the MVECs was studied by reverse transcription-polymerasechain reaction. Cell migration and capillary morphogenesis were studied on fibrinogen substrates. Involvement of Rac and Cdc42 was evaluated by Western blotting. RESULTS: Only full-size uPAR showed a connection with the actin cytoskeleton in ECs. This connection was mediated by the uPAR-associated alphaMu- and alphaX-subunits of beta2 integrin, and was absent from SSc MVECs. The cleaved uPAR was not associated with beta2 integrins or with actin. beta3 integrins were associated with both the full-size and cleaved uPAR at focal contacts. The uncoupling of uPAR from beta2 integrins in SSc MVECs impaired the activation of Rac and Cdc42 (thus inhibiting their mediation of uPAR-dependent cytoskeletal rearrangements and cell motility) and blocked the integrin-engagement-delivered signals to the actin cytoskeleton. Invasion and capillary morphogenesis on fibrinogen-coated substrates indicated that ligation of uPAR by uPA empowers the beta2/beta3 integrin-dependent invasion of fibrinogen, and that this system is impaired in SSc MVECs. CONCLUSION: The reduced angiogenic properties of SSc MVECs can be explained by the effects of uPAR truncation and the subsequent loss of the beta2 integrin-mediated connection of uPAR with the actin cytoskeleton in these ECs. [ABSTRACT FROM AUTHOR]

Combined heparin -cortisone treatment induces regression of growth in a variety of murine tumors including menaoma. We injected 92 inbred C 57 b1/6 male mice each with 5 × 105 melanoma cells (B16, B16 F1, and B16 A6 lines) with different metastatic potential. Heparin (400 U/ml) and cortisone acetate (250 mg/kg SC injections) were given daily. Control experiments were performed both with the administration of no drugs and with administration of cortisone alone. Plasminogen activator activity, which is notoriously related to tumor growth, was evaluated using fibrin plate technique in 10 fragments taken before and 20 days after the combined heparin-cortisone treatment slowed tumor growth, but no tumour regression was observed. Cutaneous fibrinolytic activity appeared increased in all specimens after the treatment. [ABSTRACT FROM AUTHOR]

Introduction: Heart failure (HF) is a global health challenge that requires a multidisciplinary approach. Despite recent advances in pharmacological and interventional therapy, morbidity and mortality in these patients remain high. For this reason, and because of its interplay with other cardiovascular and non-cardiovascular diseases, HF represents a major area of research, with new trials being published every year and international guidelines constantly updated., Areas Covered: The authors review the current status and possible future developments in HF pharmacotherapy., Expert Opinion: The treatment of HF has made significant advances in recent years, and the current recommendations are based on large outcome trials. This has led to significant reductions in both mortality and morbidity, but the death rate remains unacceptably high. In this context, a patient-centered approach that considers comorbidities and specific clinical scenarios when dosing HF medication is essential. Prevention of hospital admissions for cardiac decompensation is of utmost importance in patients with HF as is the enablement of activities of daily living, an endpoint which has only recently been incorporated into major HF trials.

Cellular senescence is a permanent cell growth arrest that occurs in response to various intrinsic and extrinsic stimuli and is associated with cellular and molecular changes. Long non-coding RNAs (lncRNAs) are key regulators of cellular senescence by affecting the expression of many important genes involved in senescence-associated pathways and processes. Here, we evaluated a panel of lncRNAs associated with senescence for their differential expression between young and senescent human dermal fibroblasts (NHDFs) and studied the effect of a known senomorphic compound, resveratrol, on the expression of lncRNAs in senescent NHDFs. As markers of senescence, we evaluated cell growth, senescence-associated (SA)-β-Gal staining, and the expression of p21, Lamin B1 and γH2AX. We found that H19 and PURPL were the most altered lncRNAs in replicative, in doxorubicin (DOXO) and ionising radiation (IR)-induced senescence models. We then investigated the function of H19 and PURPL in cell senescence by siRNA-mediated silencing in young and senescent fibroblasts, respectively. Our results showed that H19 knockdown reduced cell viability and induced cell senescence and autophagy of NHDFs through the regulation of the PI3K/AKT/mTOR pathway; conversely, PURPL silencing reversed senescence by reducing (SA)-β-Gal staining, recovering cell proliferation with an increase of S-phase cells, and reducing the p53-dependent DNA damage response. Overall, our data highlighted the role of H19 and PURPL in the senescent phenotype and suggested that these lncRNAs may have important implications in senescence-related diseases., (© 2024. The Author(s).)

The study aims to analyse ground displacement conditions observed over an Underground Gas Storage (UGS) site located at Hatfield Moors (United Kingdom), with a focus on understanding its implications for decarbonization efforts. The location serves as an active onshore storage site and was used as an analogy to assess ground motion implications around Carbon Capture and Storage (CCS) by the British Geological Survey (BGS) as part of the SENSE (Assuring integrity of CO 2 storage sites through ground surface monitoring) project. Given the value of continuous and real-time monitoring of ground movements induced by gas storage activities, the study leverages satellite Interferometric Synthetic Aperture Radar (InSAR) data to assess the environmental impact of UGS operations. Using free and open-source Sentinel-1 satellite data, ground motion patterns over Hatfield Moors are analysed, highlighting displacements ranging from - 5.0 to -10.0 mm/year within the peat bog. In addition, the Time Series (TS) of ground displacement from January 2018 to December 2022 reveals a seasonality in ground motion, with uplift observed in late winter and subsidence in late summer, showing a periodicity of approximately 1 year and a magnitude of +/-10.0 mm. Through in-depth analysis, the study highlights the need to understand the underlying causes of ground fluctuations at gas storage sites. This paper shows that InSAR has the versatility to integrate seamlessly with different monitoring tools and methodologies, opening avenues for comprehensive and holistic analyses. Cross-correlation analyses further elucidate temporal relationships between different datasets by evaluating InSAR time series, UGS injection/withdrawal data and piezometric data. This involves decomposing the TS into distinct components, including trend, seasonality and residuals. The case of Hatfield Moors shows a significant discrepancy between the UGS data and the InSAR TS, while also demonstrating a clear correlation between the groundwater data and the InSAR TS. By integrating insights from geology, hydrology and remote sensing technologies, the study navigates the complexities inherent in areas of overlapping phenomena. Accurate interpretation is essential for informed decision making, particularly at sites such as Hatfield Moors, where the convergence of natural peat motion and storage operations highlights the need for interdisciplinary analysis to understand the underlying causes of ground fluctuation., (© 2024. The Author(s).)

Spaceborne-based monitoring for environmental purposes has become a well-established practice. The recent progress of synthetic aperture radar (SAR) sensors, including through the European Space Agency's (ESA) Sentinel-1 constellation, has enabled the scientific community to identify and monitor several geohazards, including subsidence ground deformations. A case study in the Tuscany Region, Italy, highlights the effectiveness of interferometric synthetic aperture radar (InSAR) in detecting abrupt increases in ground deformation rates in an industrial area of Montemurlo municipality. In this case, InSAR data enabled prompt identification of the phenomenon, supporting the authorities in charge of environmental management to thoroughly investigate the situation. First, an on-site validation was performed via field surveys confirming the presence of cracks and fissures on some edifices. Further analysis, including water pumping rates, settlement gauge and topographic levelling, corroborated the InSAR data's findings regarding vertical deformation. Integration of collected data allowed for spatial identification and assessment of the subsidence bowl and its source depth recognized by the remote sensing data. The Montemurlo case offers a procedural guideline for managing abrupt accelerations, identified by InSAR data in subsidence-prone areas due to fluid overexploitation. In fact, these data proved useful in helping local authorities responsible for hydrogeomorphological risk management. With the exacerbation of deformation issues in subsidence-prone regions due to climate change, early detection and monitoring of such phenomena are increasingly crucial, with InSAR data playing a central role in achieving this goal., (© 2024. The Author(s).)

This study investigates the distinctive characteristics of iron oxide magnetic nanoparticles (mNPs) and their potential application in cancer therapy, focusing on melanoma. Three types of mNPs, pre-validated for safety, underwent molecular analysis to uncover the activated signaling pathways in melanoma cells. Using the Western blot technique, the study revealed that mNPs induce cytotoxicity, hinder proliferation through ERK1/2 dephosphorylation, and prompt proapoptotic effects, including DNA damage by inducing H2AX phosphorylation. Additionally, in vitro magnetic hyperthermia notably enhanced cellular damage in melanoma cells. Moreover, the quantification of intracellular iron levels through Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis unveils the precise dosage required to induce cellular damage effectively. These compelling findings not only shed light on the therapeutic potential of mNPs in melanoma treatment but also open exciting avenues for future research, heralding a new era in the development of targeted and effective cancer therapies. Indeed, by discerning the effective dose, our approach becomes instrumental in optimizing the therapeutic utilization of iron oxide magnetic nanoparticles, enabling the induction of precisely targeted and controlled cellular responses.

Background: In the past decades studies on anti-tumoral drugs inhibiting matrix metalloproteinase (MMPs) were disappointing. Recently, we demonstrated that mature endothelial cells (ECs) and endothelial colony forming cells (ECFCs) can switch between invasion modes to cope with challenging environments, performing the "amoeboid angiogenesis" in the absence of proteases activity., Methods: We first set out to investigate by ELISA if the inhibitors of the main protease family involved in angiogenesis were differently expressed during breast cancer progression. We used Marimastat, a broad-spectrum MMP inhibitor, as a means of inducing amoeboid characteristics and studied VEGF role in amoeboid angiogenesis. Thus, we performed invasion and capillary morphogenesis assay, morphological, cell signaling and in vivo mouse studies., Results: Our data showed that TIMP1, TIMP2, alpha2-antiplasmin, PAI-1 and cystatin increase in breast cancer serum of patients with primary cancer and lymph node positive compared to healthy women. In vitro results revealed that the most high-powered protease inhibitors able to induce amoeboid invasion of ECFCs were TIMP1, 2 and 3. Surprisingly, Marimastat promotes ECFC invasion and tubular formation in vitro and in vivo, inducing amoeboid characteristics. We observed that the combination of Marimastat plus VEGF doesn't boost neither cell invasion nor vessel formation capacity. Moreover, inhibition of VEGF activity with Bevacizumab in the presence of Marimastat confirmed that amoeboid angiogenesis is independent from the stimulus of the main vascular growth factor, VEGF., Conclusions: We underline the importance to consider the amoeboid mechanism of endothelial and cancer cell invasion, probably responsible for the failure of synthetic metalloproteinase inhibitors as cancer therapy and tumor resistance to VEGF-targeted therapies, to set-up new drugs to be used in cancer therapy., (© 2023. The Author(s).)

Objective: Emerging evidence demonstrates that excessive accumulation of senescent cells is associated with some chronic diseases and suggests a pathogenic role of cellular senescence in fibrotic processes, such as that occurring in ageing or in SSc. Recently we demonstrated that parvovirus B19 (B19V) activates normal human dermal fibroblasts and induces expression of different profibrotic/pro-inflammatory genes. This observation prompted us to investigate whether it is also able to induce fibroblast senescence as a potential pathogenetic mechanism in B19V-induced fibrosis., Methods: Primary cultures of fibroblasts were infected with B19V and analysed for the acquisition of senescence markers, such as morphological modifications, senescence-associated β-galactosidase (SA-β-gal) activity, DNA damage response and expression of senescence-associated secretory phenotype (SASP)-related factors., Results: We demonstrated that B19V-infected fibroblasts develop typical senescence features such as enlarged and flat-shaped morphology and SA-β-gal activity similar to that observed in SSc skin fibroblasts. They also developed an SASP-like phenotype characterized by mRNA expression and release of some pro-inflammatory cytokines, along with activation of the transcription factor nuclear factor κB. Moreover, we observed B19V-induced DNA damage with the comet assay: a subpopulation of fibroblasts from B19V-infected cultures showed a significantly higher level of DNA strand breaks and oxidative damage compared with mock-infected cells. An increased level and nuclear localization of γH2AX, a hallmark of DNA damage response, were also found., Conclusions: B19V-induced senescence and production of SASP-like factors in normal dermal fibroblasts could represent a new pathogenic mechanism of non-productive B19V infection, which may have a role in the fibrotic process., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)