Identification of new therapeutic targets related to endoplasmic reticulum stress and mitochondrial dysfunction to reduce the risk of rupture in degenerative ascending aortic aneurysm. / Identificación de nuevas dianas terapéuticas relacionadas con el estrés del retículo endoplasmático y con la disfunción mitocondrial para reducir el riesgo de rotura en el aneurisma de aorta ascendente degenerativo.

BACKGROUND: Ascending Thoracic Aortic Aneurysm (ATAA) is a progressive dilation of the aorta that can be complicated by its dissection leading to death in 80-90% of the patients. When associated with aging and atherosclerosis, the outcome is worse and reconstructive surgery is the only effective therapy. Our objective was to characterize differential expressed genes (DEG) involved in endoplasmic reticulum (ER) and mitochondria dysfunction in patients with degenerative ATAA. METHODS: A transcriptomic analysis was performed by RNA sequencing using RNA isolated from ATAA of patients classified as degenerative (n=13) and multi-organ healthy donors (n=6). DEGs related to ER stress and mitochondrial dysfunction were identified with the DESeq2 package. Enriched pathway (Reactome) and protein interaction (PPI) analysis was performed with the clusterProfiles package. PPI of the selected DEGs was analyzed based on the string database and visualized by Cytoscape software. RESULTS: Histology revealed a complete disorganization of the extracellular matrix (ECM) and cell loss in the aortic wall of ATAA patients where the upregulation of 15 DEGs and the downregulation of 13 DEGs that encode proteins related to ER stress (ATF4, EIF2AK3, HSPA5, ERN1, SEL1L), mitochondrial dysfunction (DNML1, IMMT, MT-CO3, MT-CYB, MT ND2, TIMM17B, MT-ERF1, TOMM5) and ECM was detected. The results of GO term and enriched pathway analysis indicated that these DEGs are mainly enriched in pathways related to aortic diseases. CONCLUSIONS: Our data show that proteins related to mitochondrial dysfunction and ER stress might be therapeutic targets for the treatment of ATAA.

Edge-on anchored discotic liquid crystals in spherical shells: A computational study of the phases and defects.

The self-assembly of liquid crystal droplets and shells represents a captivating frontier in soft matter physics, promising precision engineering of functional materials. In this study, we delve into the phase behavior and investigate defect formation patterns in spherical shell-confined discotic liquid crystals (DLCs) through NpT Monte Carlo simulations. These shells are created by confining DLCs between two spherical surfaces, promoting the same anchoring. In this study, we focus on the case when both surfaces promote edge-on (planar) anchoring. Our study confirms a general result which states that, when a liquid crystal is under strong confinement, the nature of the isotropic-nematic transition changes from first order into continuous. Furthermore, as expected, topological defects at the spherical surface arise due to the topological constraints on the director field. Notably, our investigation reveals a unique topological defect configuration, characterized by the formation of four disclination lines that bridge the inner and external surfaces. Additionally, we observe a mixed ±1/2 wedge-twist disclination line that forms an arch that terminates at the outer surface. This arch decreases its length with decreasing temperature to eventually disappear.

Effectiveness of conservative treatment of dentigerous cyst in the pediatric patient: A systematic review.

The dentigerous cyst is defined as a pathological cavity whose origin is produced by developmental alterations. Most usual treatment is the enucleation of the cyst with the extraction of the tooth. The current approach tends to preserve the tooth. The aim of this study was to determine the total and partial success of the conservative treatment of the dentigerous cyst in terms of eruption of the associated permanent tooth. Pub-Med, Scopus and the Cochrane Central Register of Controlled Trials were searched from January 2012 to December 2023, including patients aged 18 years old or less with a dentigerous cyst associated with a repositionable permanent tooth in the arch. 118 articles were found and 24 were included in full text. 40 cases were reported in the mandible (83 %) and 8 in the maxilla (17 %). 29 cases of marsupialization were included (60 %), 17 of enucleation (36 %) and 2 of decompression (4 %). The percentage of teeth that erupted spontaneously, either completely or partially, after marsupialization, enucleation and decompression was 83 %, 59 % and 100 % respectively. No recurrences have been described in any case. This study highlights that the conservative treatment was a predictable procedure with a total success of 83 % by marsupialization and 100 % after decompression.

NADPH Oxidase 5 (NOX5) Upregulates MMP-10 Production and Cell Migration in Human Endothelial Cells.

NADPH oxidases (NOXs) have been described as critical players in vascular remodeling, a mechanism modulated by matrix metalloproteinases. In this study, we describe for the first time the upregulation of MMP-10 through the activation of NOX5 in endothelial cells. In a chronic NOX5 overexpression model in human endothelial cells, MMP-10 production was measured at different levels: extracellular secretion, gene expression (mRNA and protein levels), and promoter activity. Effects on cell migration were quantified using wound healing assays. NOX5 overexpression increased MMP-10 production, favoring cell migration. In fact, NOX5 and MMP-10 silencing prevented this promigratory effect. We showed that NOX5-mediated MMP-10 upregulation involves the redox-sensitive JNK/AP-1 signaling pathway. All these NOX5-dependent effects were enhanced by angiotensin II (Ang II). Interestingly, MMP-10 protein levels were found to be increased in the hearts of NOX5-expressing mice. In conclusion, we described that NOX5-generated ROS may modulate the MMP-10 expression in endothelial cells, which leads to endothelial cell migration and may play a key role in vascular remodeling.

Geometrical impacts of platonic particles on nematic liquid crystal dynamics.

Platonic-solid-like particles in liquid crystals offer intriguing opportunities for engineering complex materials with tailored properties. Inspired by platonic solids' geometric simplicity and symmetry, these particles possess well-defined shapes such as cubes, tetrahedra, octahedra, dodecahedra, and icosahedra. When dispersed within nematic liquid-crystalline media, these particles interact with the surrounding medium in intricate ways, influencing the local orientational order of liquid crystal molecules. In this work, we implement continuum simulations to study how the combination of particle shape and surface anchoring gives rise to line defects that follow the edges of the particles and how they are affected by the presence of a Poiseuille flow. Platonic-solid-like particles in liquid crystals have shown promise in diverse applications ranging from photonics and metamaterials to colloidal self-assembly and responsive soft materials.

Maxillary Sinus Augmentation with Autogenous Tooth Grafting Material: A Systematic Review.

The aim of this systematic review was to determine whether autogenous tooth grafting material (ATGM) is as safe and effective as other bone substitutes used for maxillary sinus augmentation procedures, evaluating histomorphometric and/or histological data, implant primary stability, associated complications and radiographic bone height measurements. An automated electronic search was conducted using four databases (Medline/PubMed, Scopus, Web of Science and Cochrane Library), supplemented by a manual search, to identify clinical human studies using particulate ATGM for the aforementioned procedure. The included studies had a sample size of at least four patients and were published before 31st July 2024. The Newcastle-Ottawa scale (NOS) and Joanna Briggs Institute (JBI) Critical Appraisal Checklist were used to assess the risk of bias in cohort studies and case series, respectively. Seven studies were included in the descriptive analysis, obtaining 128 participants (46.8% only treated with ATGM) and 192 placed implants. Due to the heterogeneity of the studies, meta-analysis could not be performed. The authors concluded that ATGM appears to be a feasible and safe alternative for maxillary sinus augmentation procedures. These results should be interpreted with caution due to the limited amount of scientific evidence on this topic and the heterogeneity between the included studies.

Assessment of Changes in the Outcome of Autogenous Tooth Grafts Over Time: A Clinical Study Evaluating Periodontal Healing in Bone Defects After Lower Third Molar Removal.

BACKGROUND: The removal of impacted lower third molars (ILTMs) is associated with bone defects in the distal area of second molars. Different methods have been described to minimize these defects. PURPOSE: The primary objective was to assess changes in probing depth (PD) over time (up to 36 months) between test (grafted) and control (ungrafted) groups; the graft was obtained from the extracted ILTM. STUDY DESIGN, SETTING, SAMPLE: This split-mouth randomized clinical trial was conducted at the Postgraduate Course in Oral Surgery of the Faculty of Dentistry of the Complutense University of Madrid. Adult patients requiring bilateral ILTM extraction with adjacent second molars were recruited, excluding pregnant/lactating women, patients in treatment with nonsteroidal anti-inflammatory drugs and patients with periodontal diseases. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: The predictor variable was the graft technique. The bone defect after ILTM removal was treated with autogenous tooth graft (ATG) in the test group, leaving the control group ungrafted. MAIN OUTCOME VARIABLE: PD on the distobuccal, distomedial, and distolingual surfaces was recorded in both groups and averaged at baseline (T0), 3 (T1), 6 (T2), and 36 months (T3) postoperatively. COVARIATES: Sex, age, surgical time, ILTM situation and position between groups were assessed. ANALYSES: ANOVA repeated measures for comparisons between groups and the Friedman test for comparisons within the groups over time were applied. Statistical significance was established with a confidence interval of 95% (P < .05). RESULTS: The sample comprised 22 patients (6 males, 16 females) with a mean age of 21.68 ± 2.19 years; 44 ILTM extractions were performed. Statistically significant differences in PD average were found between groups (P < .001, 95% confidence interval) at 3 (1.63 ± 0.29), 6 (1.76 ± 0.3), and 36 months (1.74 ± 0.36). Reductions from T0 to T3 of 2.74 ± 0.28 (P < .001) and 0.54 ± 0.3 (P = .43) were observed in test and control groups, respectively. CONCLUSION AND RELEVANCE: ATG placed on the distal surface of lower second molars and almost completely filling the extraction socket improved PD 3, 6 and 36 months after ILTM. Furthermore, no significant changes in PD were observed over time; no major complications occurred. ATG appears to be a viable alternative graft material for this procedure.

The Influence of Anxiety on Postoperative Quality of Life Regarding Implant Treatments: An Epidemiological Study.

Dental treatment anxiety is highly prevalent worldwide. This is particularly important in the field of implantology since, in daily clinical practice, it translates into an increase in the difficulty of treatments, extending surgical times and having repercussions in the postoperative period. The aim of this multicentre, cross-sectional, epidemiological study was to determine the influence of anxiety levels in the postoperative period of an implant treatment on patients treated at two dental departments in Extremadura (Spain). To analyse anxiety levels, the modified Corah's Dental Anxiety Scale questionnaire was administered before surgical treatment. To analyse the postoperative period, another questionnaire was provided 7 days after surgery. The study was conducted on a total of 102 patients (55 men and 47 women), with a mean age of 47.99 years. The results indicated that patients with a high and severe degree of anxiety had a poorer quality of life in general. Patients with a higher degree of anxiety perceived greater swelling at 24, 48, 72 h and one week after surgery.

Lysyl Oxidase in Ectopic Cardiovascular Calcification: Role of Oxidative Stress.

Lysyl oxidase (LOX)-mediated extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease; however, this enzyme also induces oxidative stress. We addressed the contribution of LOX-dependent oxidative stress to cardiovascular calcification. LOX is upregulated in human-calcified atherosclerotic lesions and atheromas from atherosclerosis-challenged LOX transgenic mice (TgLOXVSMC) and colocalized with a marker of oxidative stress (8-oxo-deoxyguanosine) in vascular smooth muscle cells (VSMCs). Similarly, in calcific aortic valves, high LOX expression was detected in valvular interstitial cells (VICs) positive for 8-oxo-deoxyguanosine, while LOX and LOXL2 expression correlated with osteogenic markers (SPP1 and RUNX2) and NOX2. In human VICs, mito-TEMPO and TEMPOL attenuated the increase in superoxide anion levels and the mineralization induced by osteogenic media (OM). Likewise, in OM-exposed VICs, ß-aminopropionitrile (a LOX inhibitor) ameliorated both oxidative stress and calcification. Gain- and loss-of-function approaches in VICs demonstrated that while LOX silencing negatively modulates oxidative stress and calcification induced by OM, lentiviral LOX overexpression exacerbated oxidative stress and VIC calcification, effects that were prevented by mito-TEMPO, TEMPOL, and ß-aminopropionitrile. Our data indicate that LOX-induced oxidative stress participates in the procalcifying effects of LOX activity in ectopic cardiovascular calcification, and highlight the multifaceted role played by LOX isoenzymes in cardiovascular diseases.

Early automated cerebral edema assessment following endovascular therapy: impact on stroke outcome.

BACKGROUND: Cerebral edema (CED) is associated with poorer outcome in patients with acute ischemic stroke (AIS). The aim of the study was to investigate the factors contributing to greater early CED formation in patients with AIS who underwent endovascular therapy (EVT) and its association with functional outcome. METHODS: We conducted a multicenter cohort study of patients with an anterior circulation AIS undergoing EVT. The volume of cerebrospinal fluid (CSF) was extracted from baseline and 24-hour follow-up CT using an automated algorithm. The severity of CED was quantified by the percentage reduction in CSF volume between CT scans (∆CSF). The primary endpoint was a shift towards an unfavorable outcome, assessed by modified Rankin Scale (mRS) score at 3 months. Multivariable ordinal logistic regression analyses were performed. The ∆CSF threshold that predicted unfavorable outcome was selected using receiver operating characteristic curve analysis. RESULTS: We analyzed 201 patients (mean age 72.7 years, 47.8% women) in whom CED was assessable for 85.6%. Higher systolic blood pressure during EVT and failure to achieve modified Thrombolysis In Cerebral Infarction (mTICI) 3 were found to be independent predictors of greater CED. ∆CSF was independently associated with the probability of a one-point worsening in the mRS score (common odds ratio (cOR) 1.05, 95% CI 1.03 to 1.08) after adjusting for age, baseline mRS, National Institutes of Health Stroke Scale (NIHSS), and number of passes. Displacement of more than 25% of CSF was associated with an unfavorable outcome (OR 6.09, 95% CI 3.01 to 12.33) and mortality (OR 6.72, 95% CI 2.94 to 15.32). CONCLUSIONS: Early CED formation in patients undergoing EVT was affected by higher blood pressure and incomplete reperfusion. The extent of early CED, measured by automated ∆CSF, was associated with worse outcomes.

A Physiological Approach to Explore How Thioredoxin-Glutathione Reductase (TGR) and Peroxiredoxin (Prx) Eliminate H2O2 in Cysticerci of Taenia.

Peroxiredoxins (Prxs) and glutathione peroxidases (GPxs) are the main enzymes of the thiol-dependent antioxidant systems responsible for reducing the H2O2 produced via aerobic metabolism or parasitic organisms by the host organism. These antioxidant systems maintain a proper redox state in cells. The cysticerci of Taenia crassiceps tolerate millimolar concentrations of this oxidant. To understand the role played by Prxs in this cestode, two genes for Prxs, identified in the genome of Taenia solium (TsPrx1 and TsPrx3), were cloned. The sequence of the proteins suggests that both isoforms belong to the class of typical Prxs 2-Cys. In addition, TsPrx3 harbors a mitochondrial localization signal peptide and two motifs (-GGLG- and -YP-) associated with overoxidation. Our kinetic characterization assigns them as thioredoxin peroxidases (TPxs). While TsPrx1 and TsPrx3 exhibit the same catalytic efficiency, thioredoxin-glutathione reductase from T. crassiceps (TcTGR) was five and eight times higher. Additionally, the latter demonstrated a lower affinity (>30-fold) for H2O2 in comparison with TsPrx1 and TsPrx3. The TcTGR contains a Sec residue in its C-terminal, which confers additional peroxidase activity. The aforementioned aspect implies that TsPrx1 and TsPrx3 are catalytically active at low H2O2 concentrations, and the TcTGR acts at high H2O2 concentrations. These results may explain why the T. crassiceps cysticerci can tolerate high H2O2 concentrations.

Lysyl oxidase expression in smooth muscle cells determines the level of intima calcification in hypercholesterolemia-induced atherosclerosis. / La expresión de la lisil oxidasa en las células musculares lisas determina el nivel de calcificación de la íntima en la aterosclerosis inducida por hipercolesterolemia.

INTRODUCTION: Cardiovascular calcification is an important public health issue with an unmeet therapeutic need. We had previously shown that lysyl oxidase (LOX) activity critically influences vascular wall smooth muscle cells (VSMCs) and valvular interstitial cells (VICs) calcification by affecting extracellular matrix remodeling. We have delved into the participation of LOX in atherosclerosis and vascular calcification, as well as in the mineralization of the aortic valve. METHODS: Immunohistochemical and expression studies were carried out in human atherosclerotic lesions and experimental models, valves from patients with aortic stenosis, VICs, and in a genetically modified mouse model that overexpresses LOX in CMLV (TgLOXCMLV). Hyperlipemia and atherosclerosis was induced in mice through the administration of adeno-associated viruses encoding a PCSK9 mutated form (AAV-PCSK9D374Y) combined with an atherogenic diet. RESULTS: LOX expression is increased in the neointimal layer of atherosclerotic lesions from human coronary arteries and in VSMC-rich regions of atheromas developed both in the brachiocephalic artery of control (C57BL/6J) animals transduced with PCSK9D374Y and in the aortic root of ApoE-/- mice. In TgLOXCMLV mice, PCSK9D374Y transduction did not significantly alter the enhanced aortic expression of genes involved in matrix remodeling, inflammation, oxidative stress and osteoblastic differentiation. Likewise, LOX transgenesis did not alter the size or lipid content of atherosclerotic lesions in the aortic arch, brachiocephalic artery and aortic root, but exacerbated calcification. Among lysyl oxidase isoenzymes, LOX is the most expressed member of this family in highly calcified human valves, colocalizing with RUNX2 in VICs. The lower calcium deposition and decreased RUNX2 levels triggered by the overexpression of the nuclear receptor NOR-1 in VICs was associated with a reduction in LOX. CONCLUSIONS: Our results show that LOX expression is increased in atherosclerotic lesions, and that overexpression of this enzyme in VSMC does not affect the size of the atheroma or its lipid content, but it does affect its degree of calcification. Further, these data suggest that the decrease in calcification driven by NOR-1 in VICs would involve a reduction in LOX. These evidences support the interest of LOX as a therapeutic target in cardiovascular calcification.

Upregulation of NOR-1 in calcified human vascular tissues: impact on osteogenic differentiation and calcification.

Cardiovascular calcification is a significant public health issue whose pathophysiology is not fully understood. NOR-1 regulates critical processes in cardiovascular remodeling, but its contribution to ectopic calcification is unknown. NOR-1 was overexpressed in human calcific aortic valves and calcified atherosclerotic lesions colocalizing with RUNX2, a factor essential for osteochondrogenic differentiation and calcification. NOR-1 and osteogenic markers were upregulated in calcifying human valvular interstitial cells (VICs) and human vascular smooth muscle cells (VSMCs). Gain- and loss-of-function approaches demonstrated that NOR-1 negatively modulates the expression of osteogenic genes relevant for the osteogenic transdifferentiation (RUNX2, IL-6, BMP2, and ALPL) and calcification of VICs. VSMCs from transgenic mice overexpressing NOR-1 in these cells (TgNOR-1VSMC) expressed lower basal levels of osteogenic genes (IL-6, BMP2, ALPL, OPN) than cells from WT littermates, and their upregulation by a high-phosphate osteogenic medium (OM) was completely prevented by NOR-1 transgenesis. Consistently, this was associated with a dramatic reduction in the calcification of both transgenic VSMCs and aortic rings from TgNOR-1VSMC mice exposed to OM. Atherosclerosis and calcification were induce in mice by the administration of AAV-PCSK9D374Y and a high-fat/high-cholesterol diet. Challenged-TgNOR-1VSMC mice exhibited decreased vascular expression of osteogenic markers, and both less atherosclerotic burden (assessed in whole aorta and lesion size in aortic arch and brachiocephalic artery) and less vascular calcification (assessed either by near-infrared fluorescence imaging or histological analysis) than WT mice. Our data indicate that NOR-1 negatively modulates the expression of genes critically involved in the osteogenic differentiation of VICs and VSMCs, thereby restraining ectopic cardiovascular calcification.

Asymptomatic parenchymal haemorrhage following endovascular treatment: Impact on functional outcome in patients with acute ischaemic stroke.

BACKGROUND AND PURPOSE: In patients with acute ischaemic stroke (AIS), haemorrhagic transformation (HT) following endovascular treatment (EVT) is associated with poor functional outcome. However, the impact of asymptomatic HT, not linked to neurological deterioration in the acute phase, is unknown. We aimed to investigate the impact of asymptomatic PH1 (aPH1) and PH2 (aPH2) subtypes of HT on the functional outcome of patients treated with EVT. METHODS: We conducted a retrospective study of patients with AIS who were consecutively admitted to our comprehensive stroke centre between January 2019 and December 2022, and who underwent EVT. We collected clinical, radiological, and procedural data. HTs were categorized according to the Heidelberg classification. The primary outcome was the shift on the modified Rankin Scale (mRS) at 3 months of follow-up. We performed bivariate and multivariable ordinal regression analyses to test the association between aPH1/aPH2 and the primary outcome. RESULTS: We included 314 patients (mean age = 72.5 years [SD = 13.6], 171 [54.5%] women). We detected 54 (17.2%) patients with HT; 23 (7.3%) were classified as PH2 (11 asymptomatic) and 17 (5.4%) as PH1 (16 asymptomatic). The adjusted common odds ratio for aPH2 of worsening 1 point on the 3-month mRS was 3.32 (95% confidence interval = 1.16-9.57, p = 0.026). No association was observed for aPH1. aPH2 was also independently associated with lower odds of achieving a favourable outcome (mRS = 0-2). Neither aPH1 nor aPH2 was associated with mortality. CONCLUSIONS: In patients with AIS treated with EVT, aPH2 is independently associated with unfavourable functional outcome.

Rolipram impacts on redox homeostasis and cellular signaling in an experimental model of abdominal aortic aneurysm. / Impacto del tratamiento con rolipram sobre la homeostasis rédox y la señalización celular en un modelo experimental de aneurisma de aorta abdominal.

INTRODUCTION: Cyclic nucleotide phosphodiesterases (PDEs) of the PDE4 subfamily are responsible for the hydrolysis and subcellular compartmentalization of cAMP, a second messenger that modulates vascular functionality. We had shown that PDE4B is induced in abdominal aortic aneurysms (AAA) and that PDE4 inhibition by rolipram limits experimental aneurysms. In this study we have delved into the mechanisms underlying the beneficial effect of rolipram on AAA. METHODS: AAA were induced in ApoE-/- mice by angiotensin II (Ang II) infusion. Aneurysm formation was evaluated by ultrasonography. The expression of enzymes involved in rédox homeostasis was analyzed by real-time RT-PCR and the activation of signaling pathways by Western blot. RESULTS: Induction of PDE4B in human AAA has been confirmed in a second cohort of patients. In Ang II-infused ApoE-/- mice, rolipram increased the percentage of animals free of aneurysms without affecting the percentage of aortic ruptures. Quantitative analyses determined that this drug significantly attenuated aortic collagen deposition. Additionally, rolipram reduced the increased Nox2 expression triggered by Ang II, exacerbated Sod1 induction, and normalized Sod3 expression. Likewise, PDE4 inhibition decreased the activation of both ERK1/2 and the canonical Wnt pathway, while AKT activity was not altered. CONCLUSIONS: The inhibition of PDE4 activity modulates the expression of enzymes involved in rédox homeostasis and affects cell signaling pathways involved in the development of AAA.

PDE4 Phosphodiesterases in Cardiovascular Diseases: Key Pathophysiological Players and Potential Therapeutic Targets.

3',5'-cyclic adenosine monophosphate (cAMP) is a second messenger critically involved in the control of a myriad of processes with significant implications for vascular and cardiac cell function. The temporal and spatial compartmentalization of cAMP is governed by the activity of phosphodiesterases (PDEs), a superfamily of enzymes responsible for the hydrolysis of cyclic nucleotides. Through the fine-tuning of cAMP signaling, PDE4 enzymes could play an important role in cardiac hypertrophy and arrhythmogenesis, while it decisively influences vascular homeostasis through the control of vascular smooth muscle cell proliferation, migration, differentiation and contraction, as well as regulating endothelial permeability, angiogenesis, monocyte/macrophage activation and cardiomyocyte function. This review summarizes the current knowledge and recent advances in understanding the contribution of the PDE4 subfamily to cardiovascular function and underscores the intricate challenges associated with targeting PDE4 enzymes as a therapeutic strategy for the management of cardiovascular diseases.

Photonic features of blue phase liquid crystals under curved confinement.

Blue phase (BP) liquid crystals represent a fascinating state of soft matter that showcases unique optical and electro-optical properties. Existing between chiral nematic and isotropic phases, BPs are characterized by a three-dimensional cubic lattice structure resulting in selective Bragg reflections of light and consequent vivid structural colors. However, the practical realization of these material systems is hampered by their narrow thermal stability and multi-domain crystalline nature. This feature article provides an overview of the efforts devoted to stabilizing these phases and creating monodomain structures. In particular, it delves into the complex relationship between geometrical confinement, induced curvature, and the structural stability and photonic features of BPs. Understanding the interaction of curved confinement and structural stability of BPs proves crucially important for the integration of these materials into flexible and miniaturized devices. By shedding light on these critical aspects, this feature review aims to highlight the significance of understanding the coupling effects of physical and mechanical forces on the structural stability of these systems, which can pave the way for the development of efficient and practical devices based on BP liquid crystals.

Lysyl oxidase-dependent extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease.

Extracellular matrix (ECM) is an active player in cardiovascular calcification (CVC), a major public health issue with an unmet need for effective therapies. Lysyl oxidase (LOX) conditions ECM biomechanical properties; thus, we hypothesized that LOX might impact on mineral deposition in calcific aortic valve disease (CAVD) and atherosclerosis. LOX was upregulated in calcified valves from two cohorts of CAVD patients. Strong LOX immunostaining was detected surrounding calcified foci in calcified human valves and atherosclerotic lesions colocalizing with RUNX2 on valvular interstitial cells (VICs) or vascular smooth muscle cells (VSMCs). Both LOX secretion and organized collagen deposition were enhanced in calcifying VICs exposed to osteogenic media. ß-aminopropionitrile (BAPN), an inhibitor of LOX, attenuated collagen deposition and calcification. VICs seeded onto decellularized matrices from BAPN-treated VICs calcified less than cells cultured onto control scaffolds; instead, VICs exposed to conditioned media from cells over-expressing LOX or cultured onto LOX-crosslinked matrices calcified more. Atherosclerosis was induced in WT and transgenic mice that overexpress LOX in VSMC (TgLOXVSMC) by AAV-PCSK9D374Y injection and high-fat feeding. In atherosclerosis-challenged TgLOXVSMC mice both atherosclerosis burden and calcification assessed by near-infrared fluorescence (NIRF) imaging were higher than in WT mice. These animals also exhibited larger calcified areas in atherosclerotic lesions from aortic arches and brachiocephalic arteries. Moreover, LOX transgenesis exacerbated plaque inflammation, and increased VSMC cellularity, the rate of RUNX2-positive cells and both connective tissue content and collagen cross-linking. Our findings highlight the relevance of LOX in CVC and postulate this enzyme as a potential therapeutic target for CVC.

Novel pharmacological approaches in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.

Targeting lysyl-oxidase (LOX) may facilitate intramural periarterial drainage for the treatment of Alzheimer's disease.

Alzheimer's disease is the commonest form of dementia. It is likely that a lack of clearance of amyloid beta (Aß) results in its accumulation in the parenchyma as Aß oligomers and insoluble plaques, and within the walls of blood vessels as cerebral amyloid angiopathy (CAA). The drainage of Aß along the basement membranes of blood vessels as intramural periarterial drainage (IPAD), could be improved if the driving force behind IPAD could be augmented, therefore reducing Aß accumulation. There are alterations in the composition of the vascular basement membrane in Alzheimer's disease. Lysyl oxidase (LOX) is an enzyme involved in the remodelling of the extracellular matrix and its expression and function is altered in various disease states. The expression of LOX is increased in Alzheimer's disease, but it is unclear whether this is a contributory factor in the impairment of IPAD in Alzheimer's disease. The pharmacological inhibition of LOX may be a strategy to improve IPAD and reduce the accumulation of Aß in the parenchyma and within the walls of blood vessels.