Search Results (288)

Background/Objectives: Geranylgeraniol (GGOH), an isoprenoid intermediate of the mevalonate pathway, regulates bone cell viability and function, particularly by mitigating cellular toxicity induced by nitrogen-containing bisphosphonates (N-BPs). Despite this, its role in osteoporosis remains underexplored. This scoping review synthesises evidence on the effects of GGOH in in vitro and in vivo models of osteoporosis. Methods: PubMed, Scopus, and Ovid were searched using GGOH- and osteoporosis-related terms. Primary studies evaluating GGOH exposure in cellular or animal osteoporosis models were eligible. Twenty-nine studies met the inclusion criteria. Results: In vitro findings demonstrate that GGOH reverses N-BP-induced depletion of geranylgeranyl pyrophosphate, restoring protein prenylation which is essential for osteoclast and osteoblast survival, cytoskeletal organisation, and differentiation. GGOH reduced osteoclast apoptosis, restored nuclear factor of activated T-cells 1 and carbonic anhydrase II expression, and prevented N-BP-associated suppression of bone resorption. In osteoblasts and mesenchymal stem cells, GGOH improved viability, upregulated osteogenic markers including runt-related transcription factor 2, alkaline phosphatase, collagen type I, and bone morphogenetic proteins, and rescued mineralisation impaired by alendronate or zoledronate. Independent of N-BPs, GGOH exerted divergent effects on osteoclasts, by inhibiting osteoclastogenesis or promoting retinoic acid receptor-mediated bone resorption and attenuating zoledronate protection in vascular calcification settings in a model-specific manner. In vivo, dietary GGOH supplementation improved trabecular and cortical bone parameters and reduced serum C-terminal telopeptide of type I collagen in obese mice, indicating suppression of bone resorption. Conclusions: Overall, although GGOH shows osteoprotective potential, its capacity to antagonise N-BP efficacy limits systemic co-administration. Current evidence suggests that local delivery may warrant future investigation as a strategy to mitigate N-BP-induced skeletal toxicity. However, studies evaluating bone tissue exposure, pharmacokinetics, and clinically achievable concentrations are required before this approach can be translated. Full article

Background: Produced by indoor Stachybotrys and Trichoderma spp., macrocyclic trichothecenes (MTs), a type of cytotoxic respirable molecule (<0.01–0.03 µm), inhibit protein/DNA/RNA production, damage mitochondria, and induce apoptosis. Dust-bound MTs remain toxic despite remediation/disinfection. Inhaled MTs easily cross tissue barriers, potentially reaching the placenta and the unborn. Methods: Retrospective medical record abstraction of pregnant females and offspring cohort exposed to indoor MTs, Stachybotrys, or Trichoderma to correlate professional indoor testing, exposure variables, mold species, environmental MTs, medical symptomatology, outcomes, and urine/milk MTs excretion. Results: In eight women from seven MT/mold-contaminated homes, with 21 pregnancies, complications occurred in 19 (90%) pregnancies, including miscarriages (38%) and premature labor (33%). Placental abnormalities in two women (25%) from the same home (calcification, chronic villitis, placental infarcts, double placenta, gritty membranitis). Birth defects in infants (38%) included renal hypertrophy, levocardia, patent foramen ovale, ventriculoseptal defect, ptosis, teeth, and “goosebump” black/grey skin discoloration. Later abnormalities included developmental delay, oropharyngeal hypotonic dysphagia, refractory eczema, and refractory perirectal rash progressing to intussusception. Lactation difficulties included grey-black oronasal drainage, thrush, projectile vomiting, choking, oropharyngeal neurologic damage, apnea, and respiratory arrest. Aspergillus +/− Penicillium exposure was documented in all, Stachybotrys (75%), Chaetomium (62%), Trichoderma (38%), and indoor MT contamination exposure (75%). Conclusions: In-utero indoor MTs and Stachybotrys exposure correlate strongly with adverse gestational, neonatal complications (miscarriage, congenital defects, and placental abnormalities). Exposure timing and severity correlate with adverse outcomes. Breastfeeding with indoor exposure appears hazardous. Environmental/human MTs testing appears useful for identifying MT contaminaion and/or exposure. Full article

Purpose: This paper aimed to identify dosimetric, clinical, and CT-based densitometric predictors of radiation-induced pulmonary events in breast cancer patients treated with moderately hypofractionated radiotherapy. Materials and Methods: A single-institution cohort of 1172 consecutive patients treated with 3D conformal whole-breast radiotherapy (40 Gy/15 fractions) before 2017 was analyzed. Ipsilateral lung DVHs and CT densitometry metrics were extracted. Clinical variables and cardiac calcification (CAC) scores (Agatston_score, CAC_volume, Max_HU_Heart) were included. Univariable and multivariable logistic regressions were performed; collinearity was assessed via Spearman correlation and VIF. Optimal thresholds were derived using the Youden index. Internal validation used bootstrap resampling. Results: After a median follow-up of 6.5 years, 18 patients developed moderate/severe pulmonary events. The univariable analysis showed associations with lung densitometric features (median/mean HU, 10th percentile, the lung volume with HU < −850 (V850)), V37 Gy, lung volume, and CAC scores. Lower lung HU values and larger lung volumes were linked to higher risk. The best models combined V850 (or lung volume) with a CAC metric. The model including V850 > 175 cc and continuous Max_HU_Heart achieved an optimism-corrected AUC of 0.68, with good fit and calibration (Hosmer–Lemeshow p = 0.33, R² = 0.847). Conclusions: The baseline cardiopulmonary status, captured by lung and heart densitometry, predicts pulmonary toxicity better than dosimetry. V850 > 175 cc was associated with a 4-fold higher risk, consistent with air trapping, known as a marker of emphysema. Full article

Self-healing materials have attracted increasing attention as a strategy to enhance durability, extend service life, and reduce maintenance in advanced material systems. Among these, cellulose-based self-healing materials represent a sophisticated intersection between sustainable macromolecular chemistry and adaptive materials science. This review provides a synthesis of recent advancements in the field, systematically categorizing materials derived from cellulose raw materials. We evaluate the fundamental chemical strategies employed to achieve autonomous repair, distinguishing between extrinsic mechanisms—utilizing cellulose-based micro/nano-capsules to sequester healing agents—and intrinsic mechanisms governed by dynamic covalent chemistry (Schiff-base, boronic ester, Diels–Alder) and supramolecular interactions (hydrogen bonding, metal–ligand coordination, and host–guest assemblies). The analysis highlights how cellulose’s hierarchical structure and abundant surface functionality are leveraged to overcome the traditional trade-off between mechanical toughness and healing efficiency. Particular emphasis is placed on the transition from simple structural hydrogels to sophisticated multifunctional systems. These include ultra-stretchable strain and pressure sensors for e-skin applications, biocompatible and injectable matrices for chronic wound management and stem cell delivery, and advanced anti-freezing eutectogels for performance in extreme environments. Furthermore, we explore the integration of cellulose into traditional sectors, such as self-healing concrete utilizing microbe-induced calcification and smart, eco-friendly coatings for corrosion protection. Finally, we discuss critical challenges, including environmental stability, scalability, and the development of standardized evaluation protocols, providing a roadmap for the next generation of bio-derived, sustainable and intelligent materials. Full article

Pancreatic tumors frequently exhibit calcification, suggesting potential osteogenic-related phenotypic plasticity. This study aimed to systematically evaluate whether pancreatic ductal adenocarcinoma (PDAC) cells acquire osteogenic-like features under induction conditions and to assess the associated phenotypic and molecular changes. PDAC cell lines and non-malignant pancreatic epithelial cells were subjected to osteogenic induction. Mineralization, alkaline phosphatase (ALP) activity, osteogenic marker expression, and malignant phenotypes were evaluated. RNA sequencing was performed at defined time points to characterize transcriptional changes. Pharmacological inhibition of MEK and siRNA-mediated knockdown of RUNX2 were applied to examine the involvement of MAPK–ERK signaling and downstream transcriptional regulation. Osteogenic induction led to calcium deposition and increased ALP activity in a subset of PDAC cell lines, accompanied by upregulation of osteogenic-associated markers, including RUNX2 and SPP1. Induced cells exhibited reduced migration, clonogenicity, invasion, and proliferation. Transcriptomic analysis revealed activation of osteogenesis-related and calcium-transport pathways, along with downregulation of cell cycle programs. MAPK–ERK signaling was activated during induction, and MEK inhibition attenuated RUNX2 and ALP expression as well as mineralization-associated changes. Furthermore, RUNX2 knockdown reduced ALP expression and mineralization levels, indicating its contribution to the osteogenic-like phenotype. PDAC cells can acquire osteogenic-like features under defined induction conditions, accompanied by coordinated transcriptional reprogramming and reduced malignant phenotypes. The observed mineralization-associated phenotypes may reflect a combination of active processes and passive calcium deposition. In addition, the MAPK–ERK–RUNX2 axis appears to be involved in this process, although it may reflect a broader adaptive or stress-associated reprogramming rather than lineage commitment. These findings provide insight into the potential relationship between tumor calcification and phenotypic plasticity in PDAC. Full article

Vascular calcification is an actively regulated process driven by vascular smooth muscle cell (VSMC) osteogenic reprogramming and promoted by oxidative stress and extracellular matrix remodeling. We investigated whether the novel histone deacetylase inhibitor YAK577 mitigates calcification by modulating an MMP14–NOX2/ROS-associated pathway in calcification medium (CM)-treated VSMCs and a vitamin D₃-induced arterial calcification model in 8-week-old male C57BL/6N mice. Calcification was assessed by Alizarin Red S/von Kossa staining and calcium quantification; osteogenic markers (BMP2, RUNX2, MSX2) and MMPs were examined by qRT-PCR and immunoblotting; intracellular ROS was measured by DHE staining with N-acetylcysteine as an antioxidant control; and MMP14 was manipulated by siRNA knockdown or plasmid overexpression. YAK577 was non-cytotoxic at effective concentrations and reduced CM-induced calcium deposition and osteogenic marker expression. YAK577 reduced MMP14 expression and suppressed CM-induced NOX2/p47phox activation and ROS accumulation, while GSK2795039 attenuated CM-induced DHE fluorescence. MMP14 silencing attenuated, whereas MMP14 overexpression enhanced, osteogenic signaling and increased NOX2. In vivo, YAK577 reduced vitamin D₃-induced aortic calcium burden, histological calcification, and the expression of MMP14, NOX2, and osteogenic markers. These data support a working model in which YAK577 alleviates vascular calcification, at least in part, by suppressing an MMP14-associated NOX2/p47phox–ROS axis. Full article

Background: Chronic kidney disease (CKD) associated vascular calcification (VC) is a leading cause of cardiovascular mortality, partially driven by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation cellular process. However, the precise role and mechanism of CMA in CKD-associated vascular calcification remain unknown. Methods: We studied calcified arteries from CKD patients and rats fed on a high-phosphate diet using histological and ultrastructural methods. VSMCs’ calcification was induced by a calcification medium containing high phosphate and calcium. CMA activity was measured by a KFERQ reporter and lysosomal staining. The expression of LAMP2a and HSP90AA1 was knocked down by siRNA, overexpressed by plasmid, and activated by QX77.1. Bioinformatic analysis, protein interaction studies, immunofluorescence and co-immunoprecipitation were performed to investigate the potential mechanism of CMA in VC. Results: The expression of LAMP2a was increased in human calcified radial artery tissues (n = 3, p < 0.05) and rats’ calcified aortic tissues (n = 3, p < 0.01), accompanied by lysosomal abnormalities. The activity of CMA was increased during the osteogenic transdifferentiation of VSMCs, as indicated by increased expression of RUNX2 and reduced expression of SM22α (p < 0.05). LAMP2a knockdown attenuated VSMCs’ calcification (p < 0.05), whereas pharmacological activation of CMA aggravated calcification in VSMCs (p < 0.01). Bioinformatic screening identified HSP90AA1 as a candidate involved in CMA in vascular calcification. Elevated HSP90AA1 expression was observed in human calcified radial artery tissues (n = 3, p < 0.01) and rat calcified aortic tissues (n = 3, p < 0.01), which promoted osteogenic transdifferentiation of VSMCs (p < 0.05). HSP90AA1 interacted with LAMP2a and positively regulated its expression (p < 0.01). Conclusions: These findings support an association between CMA activation and CKD vascular calcification. It suggests that HSP90AA1 facilitates vascular calcification in chronic kidney disease involving chaperone-mediated autophagy. Full article

Myocardial calcification is an uncommon complication associated with end-stage chronic kidney disease (CKD) in feline patients. This report describes the clinical and multimodal imaging features of metastatic calcification in a 10-year-old castrated male mixed-breed cat. The patient presented with dyspnea and anorexia, and was diagnosed with IRIS Stage 4 CKD. Laboratory findings revealed severe hyperphosphatemia and an elevated calcium–phosphorus product (CPP) of 135 mg²/dL², based on total calcium. This value significantly exceeds 70 mg²/dL², a threshold associated with a high probability of inducing soft tissue mineralization. Echocardiography revealed extensive hyperechoic foci with posterior acoustic shadowing in the interventricular septum and left ventricular wall. Functional assessment demonstrated a restrictive diastolic filling pattern, suggesting increased myocardial stiffness and congestive heart failure. Computed tomography (CT) further visualized systemic involvement, showing diffuse, amorphous calcifications (400–900 HU) in the myocardium, multifocal aortic wall, and extracardiac tissues. Despite intensive treatment with diuretics and renal support, the patient was euthanized eight days later due to progressive renal failure. This case illustrates that the interaction between metastatic calcification and uremic cardiomyopathy (UC) can result in refractory heart failure, underscoring the value of combined echocardiography and CT in evaluating end-stage renal disease. Full article

Background and Objectives: Chronic kidney disease (CKD) is associated with severe coronary calcification and increased procedural risks. We aimed to evaluate the impact of CKD on contrast-induced nephropathy (CIN), bleeding, and clinical outcomes in patients undergoing rotational atherectomy (RA). Materials and Methods: This study retrospectively analyzed 652 patients who underwent RA for calcified coronary lesions from the multicenter ROCK registry and a single-center extension between 2010 and 2025. Patients were classified into CKD (eGFR < 60 mL/min/1.73 m², n = 66) and non-CKD (n = 586) groups, excluding those on dialysis. The primary endpoint was a composite of CIN and in-hospital bleeding. Secondary endpoints included 3-year target vessel failure (TVF), myocardial infarction (MI), and total bleeding. Results: The primary composite outcome occurred more frequently in the CKD group (16.7% vs. 5.1%, p = 0.001). Specifically, CIN was significantly higher in CKD patients (15.2% vs. 1.7%, p < 0.001), while in-hospital bleeding did not differ significantly. In multivariate analysis, CKD was an independent predictor of the primary outcome (adjusted OR 3.02; 95% CI 1.36–6.69; p = 0.006). At 3-year follow-up, total bleeding (10.6% vs. 3.9%, p = 0.008) and MI (6.1% vs. 2.1%, p = 0.024) were higher in the CKD group, whereas TVF and cardiac death showed no significant difference. Conclusions: CKD is a robust independent risk factor for CIN and long-term bleeding in patients undergoing RA. However, comparable clinical efficacy outcomes suggest that RA remains a feasible strategy in CKD patients when early complications are carefully managed with contrast-minimizing strategies. Full article

Background: The aim of our study was to analyze the supply of various forms of genistein (nano, micro, and classic) on the content of four macroelements—calcium, magnesium potassium, and sodium—in the kidneys, brains, hearts, livers, spleens and femurs of rats under conditions of mammary gland neoplasia (induced by 7,12-dimethylbenz[a]anthracene (DMBA)). Methods: Thirty-two 30-day-old Sprague-Dawley rats were included in this study. The animals were randomly assigned to four experimental groups: the control group received only a standard diet (without supplementation), while three groups were supplemented with genistein in different forms—nanoparticles (0.1 mg/mL; size 92 ± 41 nm), microparticles (0.1 mg/mL; size 587 ± 83 nm), or macromolecular genistein (0.1 mg/mL). To induce mammary gland cancer, all rats were administered DMBA. Results: In the presented studies, significant changes in the content of elements in the organs of rats supplemented with various forms of genistein were observed. Of particular importance was the occurrence of soft tissue calcifications caused by the dietary supplementation of rats with various forms of genistein, ranging from the classic form to the nanometric form, in the context of an existing mammary gland neoplastic process. Calcium accumulation occurred in various tissues—the brain (from 252% to 449%); the heart (from 159% to 661%); the liver (from 90% to 613%), regardless of the form of genistein; and the spleen (by 127%) and femurs (by 294%) only in the case of nanogenistein supplementation—compared to rats from the control group not supplemented with any form of genistein in conditions of induced mammary gland cancer. Conclusions: Genistein supplementation in cancer conditions affects mineral homeostasis in rats. Full article

Vascular ageing is a complex process marked by progressive endothelial dysfunction, chronic low-grade inflammation (“inflammageing”), and reduced regenerative capacity, driven in part by an imbalance between protective endothelial autophagy and cellular senescence characterized by a proinflammatory senescence-associated secretory phenotype (SASP). Disruption of this autophagy–senescence axis accelerates vascular inflammation, arterial stiffening, and atherogenesis. High-intensity interval training (HIIT), consisting of repeated bouts of near-maximal anaerobic effort with recovery periods, is widely used by both elite and recreational athletes and is increasingly recognized as an effective nonpharmacological strategy to enhance endothelial function, arterial elasticity, and mitochondrial biogenesis. However, excessively intense or poorly structured HIIT, particularly in the absence of adequate recovery or in individuals with underlying cardiometabolic or vascular vulnerability, may induce endothelial stress and promote maladaptive vascular remodelling, including calcification and plaque instability. These considerations underscore the need for refined individualized exercise prescription strategies that balance performance benefits with endothelial protection. Based on these observations, here, we introduce a novel conceptual framework, “shear dose–calibrated HIIT,” designed to understand and define an optimal shear dose capable of maximizing autophagic flux while minimizing SASP activation. Experimental and clinical evidence of HIIT-induced effects on flow-mediated dilation (FMD), pulse wave velocity (PWV), and redox biomarkers is presented, followed by the proposal of a biomarker panel for assessing autophagic flux and cellular senescence in peripheral samples (peripheral blood mononuclear cells (PBMCs), extracellular vehicles (EVs), and plasma). This integrative approach, which combines vascular mechanotransduction, redox biology, and autophagic signalling, provides a novel translational perspective on how individually calibrated HIIT can promote vascular longevity and reduce cardiometabolic risk associated with aging and metabolic syndrome. Full article

Background: Cardiovascular diseases (CVDs) are the leading global cause of mortality, with vascular calcification (VC) as a major predictor of adverse outcomes. Although vascular smooth muscle cells (VSMCs) are established contributors, the role of endothelial cells (ECs), particularly via the endothelial–mesenchymal transition (EndMT) and exosome signaling, remains less defined. Objective: This study investigated whether the gut microbiota-derived metabolite Trimethylamine-N-oxide (TMAO) induces EndMT in ECs and whether exosomes from TMAO-treated ECs regulate the VSMC phenotype and calcification. Methods: Human umbilical vein endothelial cells (HUVECs) were exposed to TMAO at physiological and pathological levels (10–50 µM). EndMT markers were analyzed by Western blotting and qPCR. Exosomes were isolated, characterized, and applied to HAVSMCs in graded doses. Osteogenic and contractile markers, β-catenin signaling, and calcification were quantified. Exosomal miR-30 and miR-222 were studied. Results: TMAO triggered dose-dependent EndMT, decreasing CD31/VE-cadherin and increasing α-SMA, N-cadherin, and vimentin. Exosomes from TMAO-treated ECs reprogrammed VSMCs, downregulating contractile proteins and upregulating RUNX2, OPN, TNAP, and β-catenin, causing calcium accumulation. These exosomes displayed elevated miR-222 and reduced miR-30, changes that activated β-catenin signaling and promoted the osteogenic reprogramming of VSMCs. Conclusions: Pathophysiological TMAO levels induce EndMT and mediate the formation of exosomes, which drive the osteogenic reprogramming and calcification of VSMCs. Full article

KCa3.1 encodes the intermediate-conductance calcium-activated potassium channel KCa3.1, a regulator of membrane potential and calcium-dependent signalling in cardiovascular and immune cells. Increasing evidence indicates that KCa3.1 is a shared driver of vascular remodelling, inflammation, fibrosis, and electrical instability across multiple cardiovascular diseases. In ischaemic heart disease (IHD), KCa3.1 is upregulated in endothelial cells, vascular smooth muscle cells, macrophages, and T lymphocytes, where it promotes smooth muscle proliferation, neointimal formation, and chronic vascular inflammation. Genetic deletion or pharmacological blockade of KCa3.1 reduces atherosclerotic plaque burden and restenosis in animal models. In atrial fibrillation (AF), KCa3.1 contributes to electrical remodelling by shortening atrial action potential duration and to structural remodelling by driving fibroblast activation and collagen deposition. KCa3.1 also regulates macrophage polarisation and pro-inflammatory cytokine release in atrial tissue, linking immune activation to arrhythmogenic substrate formation. Inhibition of KCa3.1 prolongs atrial refractoriness, attenuates atrial fibrosis, and reduces AF inducibility in multiple preclinical models. Emerging data in valvular heart disease suggest that KCa3.1 is upregulated in valvular interstitial cells and regions of active calcification, where it supports myofibroblast differentiation, osteogenic signalling, and inflammatory crosstalk, implicating the channel in fibrocalcific valve degeneration. Collectively, these findings position KCa3.1 as a central molecular integrator of electrical, fibrotic, and inflammatory pathways in cardiovascular disease. The availability of selective KCa3.1 inhibitors with established human safety profiles supports the feasibility of therapeutic translation. Targeting KCa3.1 may enable disease-modifying strategies that extend beyond symptom control to suppress maladaptive cardiovascular remodelling. Full article

Background: Well-known risk factors for soft tissue heterotopic ossification (HO) include aging and mechanical stress, which may be linked to oxidative stress and downstream nucleotide metabolites. Thus, we investigated the involvement of extracellular ATP (ex-ATP) and its metabolites in the oxidative stress-induced mineralization of TT-D6 cells and primary mouse tendon cells. Methods: An osteogenic culture with the intermittent addition of hydrogen peroxide was monitored for two weeks using metabolomic and gene expression analyses. Results: Calcium deposition was significantly enhanced by 0.3 mM hydrogen peroxide in the osteogenic media after 2 weeks, with minimal calcification in its absence. Similar results were observed in a medium transfer experiment using 3-day-old hydrogen peroxide-treated conditioned medium, which led to an increased expression of osterix and alkaline phosphatase. Metabolomic analysis revealed a gradual increase in ex-ATP and its metabolites, including ADP, AMP, and adenosine, in the medium. The metabolite increase was enhanced by hydrogen peroxide after 12 h. Moreover, exogenous adenosine (100 μM) increased mineralization in osteogenic media. Additionally, 1 μM dipyridamole, an inhibitor of equilibrative nucleoside transporter 1 (Ent1), also increased it in response to low-dose (0.1 mM) hydrogen peroxide. Conclusions: The enhanced osteogenic calcification of the tendon cell culture by hydrogen peroxide was associated with an increase in extracellular nucleotide metabolites, especially adenosine, with some evidence of causality. Full article

Pseudoxanthoma elasticum (PXE) is an autosomal-recessive disorder caused by mutations in ATP-binding cassette subfamily C member 6 (ABCC6). In addition to the calcification and fragmentation of elastic fibers as the pathomechanistic cause of PXE, systemic and cellular oxidative stress have been reported. Human mesenchymal stem cells (hMSCs) with an ABCC6 knockdown were chosen to further investigate the oxidative stress associated with ABCC6 deficiency. The cells were treated with hydrogen peroxide to mimic external oxidative stress and the antioxidant Trolox to examine the cells’ reaction to decreased oxidative stress. The level of different types of reactive species (RS) like nitric oxide and reactive oxygen species, the senescent phenotype, oxidative damage and mRNA expression of oxidative stress-related genes were evaluated. Knockdown of ABCC6 was shown to increase RS levels in hMSCs, induce a p53-dependent senescence-like phenotype and increase oxidative damage, while the mRNA expression of oxidative defense genes was elevated. The ABCC6-deficient cells exhibited an altered reaction to additional oxidative stress and the incubation with Trolox reversed these changes induced by ABCC6 knockdown. Our findings provide further evidence linking ABCC6-deficiency to oxidative stress and a senescence-like phenotype, while pointing towards antioxidants as part of a potential treatment for PXE. Full article