Search Results (647)

Introduction: Despite proven efficacy of anti-TNF agents in inflammatory bowel disease, primary non-response affects up to one-third of patients, while secondary loss of response occurs at 13–21% per patient-year, often requiring dose optimization or switching to alternative advanced therapies. Methods: The present single-center cohort study at the University Hospital of Ioannina included biologic-naïve patients receiving anti-TNF therapy as their first biologic treatment. First anti-TNF treatment failure was defined as discontinuation due to persistent IBD activity despite maximal dose optimization (infliximab 10 mg/kg every 4 weeks, adalimumab 40 mg weekly). Patients with measurable anti-drug antibodies prior to anti-TNF dose intensification or discontinuation were excluded. Of 528 anti-TNF-treated patients, 286 (173 with CD, 113 with UC) met the inclusion criteria and were included in the final statistical analysis. Results: Anti-TNF failure occurred in 32.7% of Crohn’s (CD) and 32.9% of ulcerative colitis (UC) patients. Multivariable Cox regression identified complicated phenotype (stricturing or/and penetrating CD; HR = 1.9, p = 0.032) and concomitant corticosteroid use at anti-TNF initiation (HR = 2.03, p = 0.012) as independent predictors of anti-TNF failure in CD. Age at CD diagnosis showed a trend for statistical significance (HR = 1.02, p = 0.061), and after stratification, age at diagnosis ≥ 40 years conferred higher risk (HR = 1.93, p = 0.016), alongside persistent effects of complicated phenotype (HR = 1.83, p = 0.027) and corticosteroid use (HR = 2.01, p = 0.013). In UC patients, female sex predicted anti-TNF failure (HR = 2.13, p = 0.025). IBD-related bowel resection occurred in 26.6% of patients with CD and in 5.3% of patients with UC. Conclusions: Anti-TNF failure remains common despite optimization. Identifying immunogenicity-independent predictors may enable personalized treatment strategies and improve outcomes. Full article

The remarkable ecological success of fungi is supported by their capacity for rapid and often reversible molecular responses to fluctuating environments. While conventional evolutionary theory has largely emphasized mutation and selection as central drivers of adaptation, many environmentally responsive fungal traits are also shaped by molecular processes that generate reversible phenotypic variation on ecological or developmental timescales. This review synthesizes current knowledge on reversible genetic and epigenetic mechanisms underlying fungal phenotypic plasticity by integrating insights from programmed genetic rearrangements such as mating-type switching, transposable element activity, variation in tandem repeats and the behavior of accessory chromosomes, together with dynamic epigenetic processes including histone modifications, DNA methylation, chromatin remodeling and RNA mediated regulation. Together, these mechanisms form an interconnected framework that enables rapid and, in many cases, reversible phenotypic diversification, although their consequences range from transient regulatory shifts to partially or fully irreversible sequence-level changes. We highlight the molecular machinery that governs reversibility and its evolutionary implications for fungal pathogenesis, symbiosis, and biotechnology. By uniting genetic and epigenetic perspectives, this review advances a holistic framework in which reversibility is treated as a key property of fungal phenotypic plasticity, helping fungi balance stability with flexibility under environmental challenge. Understanding these mechanisms provides new insights into fungal evolution, and opens new avenues for antifungal intervention and the rational design of industrially valuable fungal strains. Full article

Vascular remodeling driven by the phenotypic switching of vascular smooth muscle cells (VSMCs) poses a significant health risk to astronauts during long-duration spaceflight. While the morphological and molecular changes are well recognized, the underlying metabolic drivers and potential translational countermeasures remain elusive. To investigate the metabolic determinants of VSMCs phenotypic switching, human aortic smooth muscle cells (HASMCs) were subjected to cyclic mechanical stretch, an in vitro model offering indirect mechanistic insights into mechanical loading conditions relevant to spaceflight-associated hemodynamic alterations. An integrated approach combining quantitative proteomics, flux analysis (Seahorse), and functional assays (cell cycle, wound healing, transwell) was used to characterize the accompanying metabolic and phenotypic alterations. Molecular mechanisms were assessed using immunoprecipitation, protein crosslinking, and immunofluorescence. Mechanical stretch triggered a contractile-to-synthetic phenotypic switch in HASMCs, accompanied by a shift from oxidative phosphorylation to aerobic glycolysis. Pyruvate kinase M2 (PKM2) was identified as a central metabolic regulator of this process, its silencing reversed the pro-synthetic phenotype. Notably, lactate, a glycolytic product, was found to exert a self-limiting feedback signal. Exogenous lactate suppressed the synthetic switch in associated with increased PKM2 lactylation. Further analysis indicated that PKM2 lactylation was associated with enhanced stability of its active tetrameric conformation, which was associated with a metabolic shift toward oxidative phosphorylation and restored expression of contractile markers. Although specific lactylation sites on PKM2 were not identified in this study, and direct causality between lactylation and tetramerization remains to be established, these findings identify a previously unrecognized association. This study reveals a novel metabolic regulatory mechanism in which lactate correlates with the suppression of synthetic switching of VSMCs, linked to PKM2 lactylation and tetramer stabilization. The observed lactate-PKM2 axis represents a candidate metabolic node associated with VSMCs phenotype regulation and offers a potential therapeutic target for modulating vascular remodeling. Upon direct validation under relevant conditions in future studies, this mechanism may inform the development of novel therapeutic strategies for managing vascular adaptation during long-duration spaceflight and other aerospace-related physiological challenges. Full article

Intracranial atherosclerosis (ICAS) is a distinct, inflammation-dominant vasculopathy and a leading cause of global stroke morbidity. Unlike extracranial atherosclerosis (ECAS), which often utilizes compensatory positive remodeling to maintain patency, ICAS is characterized by a unique architecture and a localized antioxidant gap that favor maladaptive negative remodeling. We critically analyze the molecular cascade initiated by the breakdown of the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) and the Krüppel-like factor 2/4 (KLF2/4) mechanotransduction axis, which triggers endothelial nitric oxide synthase (eNOS) uncoupling and establishes a state of chronic inflammation. This environment facilitates the subendothelial lipid retention of oxidized low-density lipoprotein (oxLDL), a process exacerbated by the intracranial deficiency of Apolipoprotein A-I (ApoA-I) and impaired glymphatic clearance. Crucially, we evaluate how these metabolic and mechanical insults drive vascular smooth muscle cell (VSMC) phenotypic switching; the transdifferentiation of contractile VSMCs into macrophage-like foam cells accounts for up to 60% of the plaque’s lipid-laden pool and destabilizes the fibrous cap. This vascular failure directly compromises the neurovascular unit (NVU), leading to pericyte dropout and blood–brain barrier breakdown. Beyond environmental stressors, we highlight the ring finger protein 213 (RNF213) variant as a critical genetic determinant of this susceptibility. Shifting the clinical paradigm from simple luminal narrowing toward the identification of the vulnerable plaque, we discuss how High-Resolution Vessel Wall Imaging (HR-VWI) and microRNA biomarkers can identify unstable lesions. By integrating these molecular and imaging signatures, we propose a precision medicine framework centered on the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the NVU to effectively mitigate the high residual recurrence risk that persists under conventional therapy. Full article

Climate change has transformed extreme heat from a transient environmental perturbation into a persistent threat that worsens cardiovascular outcomes. Epidemiological studies show a lag between heat exposure and peaks in acute myocardial infarction (AMI) mortality, indicating a subclinical, latent vulnerability. This latent vulnerability likely originates at the level of the microvasculature, as cardiac microvascular endothelial cells (CMECs)—the heart’s primary “thermal sensors”—are uniquely susceptible to proteotoxic stress. The existing literature suggests that this sensitivity may be mediated by thermodynamically gated activation of the activating transcription factor 6 (ATF6) branch of the unfolded protein response (UPR), which could function as a master switch that reprograms endothelial cells from a pro-repair to a maladaptive, anti-angiogenic phenotype. However, this mechanism is derived primarily from preclinical studies and lacks direct validation in humans. The resulting “endothelial memory” is sustained by epigenetic modifications and organelle uncoupling; it persists beyond the initial insult and impairs subsequent neovascularization. As a result, ischemia occurs later in a compromised microenvironment, promoting a fibrosis–conduction mismatch that drives infarct expansion and arrhythmic risk. Thus, the post-exposure latent phase emerges as a novel therapeutic window: Precision targeting of the ER stress–angiogenesis axis during this period offers a focused strategy to protect heat-vulnerable individuals Full article

Neurodegenerative diseases (NDs) are increasingly considered neurometabolic disorders driven by early mitochondrial dysfunction, neuroinflammation, and synaptic alterations that precede clinical symptoms. This review summarises pre-clinical and experimental evidence suggesting that intermittent fasting (IF) may influence these early pathogenic processes by promoting metabolic switching, enhancing autophagy and mitochondrial quality control, and modulating neuroimmune pathways. We discuss recent advances in biomarker research supporting the early detection of neurodegenerative changes, including ultrasensitive analytical platforms that can identify neuronal, glial, and synaptic injury during preclinical stages. By integrating these biomarker developments with findings from human and experimental intermittent fasting studies, we highlight how high-sensitivity assays provide quantifiable insights into the neurometabolic effects of fasting. Furthermore, we discuss how precision nutrition strategies incorporating multimarker panels, phenotypic and epigenetic signatures, and longitudinal multi-omics profiling may facilitate personalised intermittent fasting protocols and improve monitoring of biological responses. Overall, these findings underscore the relevance of a clinical biochemistry perspective integrating advanced biomarker technologies to evaluate the neurometabolic effects of intermittent fasting as a potential early neuroprotective strategy for individuals at risk of neurodegeneration. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, arising from profound metabolic reprogramming and widespread epigenetic dysregulation. However, the role of epigenetic aberrations in modulating metabolic reprogramming and the interplay between cis-regulatory elements (CREs), such as promoters, enhancers and super-enhancers, and metabolic adaptation have not been systematically summarized. Therefore, this review aims to integrate current evidence to elucidate the mechanisms of how cis-regulatory elements (CREs) drive oncogenic and metabolic signals in HCC progression. For instance, enhancers and super-enhancers transcriptionally activate key metabolic genes involved in aerobic glycolysis (GLUT1, HK2, PKM2, LDHA), de novo lipogenesis (ACLY, FASN, ACC), glutaminolysis (SLC1A5, GLS), and nucleotide synthesis. Meanwhile, many metabolic intermediates, including acetyl-CoA, succinyl-CoA and lactate, act as cofactors or substrates for epigenetic modifiers, creating bidirectional feedback loops that reinforce CRE-driven malignant phenotypes. Therefore, aberrant CREs acts as “metabolic switches” that sense and respond to various metabolic conditions to sustain HCC growth. Consequently, targeted intervention against oncogenic CREs, such as super-enhancers or their co-activators, to disrupt CRE-mediated metabolic vulnerabilities, has emerged as a highly promising new paradigm for precision therapy in HCC. Full article

Background: Hypoxic and oxidative stress states tightly regulate bone and periodontal remodeling, yet the field lacks an integrated conceptual framework explaining how fluctuating oxygen availability and redox signaling determine anabolic versus catabolic outcomes. Although hypoxia-inducible factor-1α (HIF-1α), reactive oxygen species (ROS), and reperfusion injury are individually well-studied, their coordinated role in defining tissue remodeling thresholds remains unclear. Methods: This Perspective synthesizes mechanistic evidence from cellular, molecular, and tissue-level studies on hypoxia, redox biology, perfusion dynamics, osteoimmunology, and bone remodeling. Published data were evaluated to characterize how oxygen tension, ROS generation, and inflammatory signaling interact under mechanical or metabolic stress. A conceptual model (“Hypoxostat Model”) was constructed to describe the regulatory balance between hypoxia-driven catabolism and oxygenation-driven anabolism. Hypothesis: The Hypoxostat Model proposes that tissues operate within a dynamic oxygen-dependent regulatory window. Moderate hypoxia transiently activates HIF-1α, angiogenesis, and osteogenic compensation, whereas deeper or sustained hypoxia collapses perfusion, increases ROS, amplifies IL-1β/TNF-α/IL-17A signaling, and promotes RANKL-mediated osteoclastogenesis. Reoxygenation phases trigger additional oxidative bursts, further biasing tissues toward destructive remodeling. Thin periodontal phenotypes exhibit reduced perfusion reserve and increased sensitivity to hypoxia–ROS transitions, lowering their threshold for entry into catabolic remodeling domains. Conclusions: Hypoxia and redox signaling function as a bistable regulatory system controlling bone and periodontal remodeling. The Hypoxostat Model provides a unifying framework linking oxygen tension, ROS dynamics, inflammatory cytokines, and remodeling outcomes. Recognizing hypoxia–reoxygenation behavior as a mechanistic switch may improve prediction of tissue vulnerability and guide therapeutic strategies aimed at modulating redox balance or enhancing local perfusion. Full article

Background and Clinical Significance: Deep thalamic and periventricular lesions are uncommon in adults but can result in significant loss of function because of their convergence on three interdependent processes: thalamocortical state regulation, throughput of periventricular long association systems, and ventricular compartmental compliance. The resulting combination of executive control collapse, retrieval-weighted language fragility, and load-sensitive gait instability may occur early after a lesion forms an atrial/posterior horn interface, and pressure-linked autonomic symptoms may be late to develop. Screening deficits will likely be minimal and therefore underreported. Objective/Aim: To present a thalamic–atrial/posterior horn tumor case with quantified load-sensitive cognitive–language–gait dysfunction and to detail a physiology-guided, sequence-driven decompression approach emphasizing ventricular relaxation and perforator-preserving, interface-limited thalamic resection. Case Presentation: A 56-year-old female patient experienced a 3-month, rapidly progressive decline in her cognitive and language abilities. The clinical progression was not stepwise or punctuated by a single “sentinel” event. She had a moderate level of cognitive impairment consistent with both Broca’s and Wernicke’s aphasias (MoCA: 22/30) and suffered from significant interference effects and increased cost of task-switching. Her ability to generate novel responses and name objects was significantly impaired; however, she was able to repeat words and phrases appropriately. In addition, she exhibited a severe sustained attention signature and a high error rate during dual-task performance, indicating severe gait instability, although her overall global anchors were nearly neutral (GCS 15; FOUR 15/16; NIHSS 2). Nausea and vomiting occurred simultaneously with the cognitive and language decline, suggesting decreased intracranial compliance. MRI revealed a heterogeneous left-sided thalamic tumor extending into the posterior horn of the lateral ventricle. The tumor caused deformation of the lateral ventricle and midline displacement. The patient underwent microsurgical intervention using a physiology-conscious sequence of graded cerebrospinal fluid (CSF) equilibration and primary mechanical removal of the tumor from the ventricular system. Additionally, decompression of the thalamus was performed in a manner that was cognizant of the boundaries formed by the perforating arteries of the thalamus. Early resolution of pressure symptoms was noted postoperatively. Objective measures demonstrated significant improvement in the patient’s executive functioning, language skills, attentional errors, and dual-task performance stability. The patient remained functionally independent at discharge and at subsequent follow-up visits. Surveillance imaging did not demonstrate any evidence of tumor recurrence. Conclusions: The clinical presentation described above is supportive of a model in which the synergy between deep network damage and distortion of the posterior ventricular compartment amplifies network dysfunction. Additionally, the use of quantitative stress-phenotyping makes it possible to identify deep network pathology early in its course. Finally, the physiology-guided decompression approach that was used in this case has the potential to increase functional reserve in patients with pathology that requires millimeter transitions. Full article

DNA methylation is a fundamental epigenetic regulator in hepatocellular carcinoma (HCC). However, a key paradox remains: how do ubiquitously expressed enzymes like DNMTs and TETs achieve locus-specific regulation without intrinsic sequence specificity? This review aims to elucidate the “lncRNA–DNA methylation axis,” examining how long non-coding RNAs (lncRNAs) confer specificity and plasticity to methylation machinery. We synthesized current literature focusing on the structural mechanisms (e.g., R-loops, DNA:RNA triplexes) by which lncRNAs interact with DNMTs and TETs. We further analyzed the bidirectional regulation between lncRNAs and methylation enzymes and their impact on HCC phenotypes. lncRNAs function as modular scaffolds and guides, directing methylation machinery to specific genomic loci. Rather than binary switches, they act as an “epigenetic rheostat,” fine-tuning methylation intensity to balance stability with plasticity. Crucially, a reciprocal feedback loop exists: aberrant DNA methylation suppresses tumor-suppressive lncRNAs, which in turn unleashes DNMT activity, locking cells into a malignant state. This axis drives proliferation, metastasis, metabolic reprogramming, and therapeutic resistance. The lncRNA–DNA methylation axis is a central determinant of epigenetic heterogeneity in HCC. Moving beyond descriptive cataloging to a mechanistic understanding of this network offers new perspectives for developing targeted epigenetic therapies and biomarkers. Full article

Cells adapt their phenotypes in noisy microenvironments while maintaining robust decision-making. We develop a coarse-grained theoretical framework in which cellular phenotypic adaptation is described as Bayesian decision-making coupled to replication and diffusion. This leads to an effective Fokker-Planck equation with an emergent fitness landscape governing phenotypic dynamics. We identify distinct phenotypic regimes homeostatic fixation, bistable decision-making, critical switching, and runaway explosion and propose a biological interpretation in which homeostatic and bistable landscapes correspond to healthy differentiated cell states, whereas explosive landscapes capture stem-like or cancer-like behavior. In the Gaussian setting, the correlation between intrinsic and extrinsic states directly encodes mutual information and acts as a bifurcation parameter: high correlation produces shallow or explosive landscapes associated with phenotypic plasticity, while reduced correlation stabilizes differentiated fates by deepening potential wells. We further show that proliferation reshapes these landscapes in a nontrivial manner. Proliferation conditionally stabilizes local homeostasis without altering global confinement, or cooperates with biased environmental sensing to eliminate homeostasis/bistability and drive cancer-like phenotypic explosion even at high phenotypic fidelity. Finally, we show that negative intrinsic–extrinsic correlations suppress explosive dynamics but also reduce bistable plasticity, suggesting a robustness–plasticity trade-off. Together, our results suggest that development, tissue homeostasis, and carcinogenesis can be understood as information-driven deformations of a Bayesian phenotypic fitness landscape. Full article

Aortic diseases, including thoracic and abdominal aneurysms as well as aortic dissections, represent life-threatening vascular disorders characterized by progressive wall degeneration and inflammation. Increasing evidence indicates that oxidative stress is a central driver of aortic pathology through the induction of DNA damage in vascular smooth muscle cells and endothelial cells. Oxidative DNA lesions activate the DNA damage response (DDR), a highly coordinated network of damage sensors, signaling kinases, and repair effectors that determines cell fate decisions such as DNA repair, apoptosis, or cellular senescence. In aortic tissue, persistent or dysregulated DDR signaling contributes to chronic inflammation, extracellular matrix degradation, and loss of vascular integrity. Key molecular regulators, including base excision repair enzymes OGG1 and APE1, as well as DDR mediators such as ATM, ATR, p53, PARP, and NOTCH1, integrate oxidative stress signals with pro-inflammatory and pro-degenerative pathways. Aberrant activation of these mechanisms promotes vascular smooth muscle cell VSMC phenotypic switching from contractile to synthetic phenotype, endothelial dysfunction, and senescence-associated secretory responses, thereby accelerating aortic wall weakening and aneurysm progression. This review highlights the mechanistic links between oxidative stress-induced DNA damage, DDR pathway activation, and vascular remodeling in aortopathies. A deeper understanding of these molecular interactions may uncover novel biomarkers and therapeutic targets aimed at limiting inflammation, preserving genomic stability, and preventing catastrophic aortic events. This work represents a narrative review and therefore has inherent limitations in terms of systematic literature search and selection. Full article

Over the past decade, research in tumor biomechanics has increasingly shown that cancer cells adapt to changing physical microenvironments by rewiring adhesion, cytoskeletal organization, and force-responsive signaling pathways, thereby shaping survival, invasion, and responses to therapy. Prostate cancer (PCa), like other solid tumors, resides in a highly dynamic mechanical milieu molded by extracellular matrix (ECM) remodeling, solid stress, and fluid shear forces. Available evidence generally supports that malignant prostate tissue is stiffer than benign tissue. During metastatic progression, however, the mechanical phenotype of PCa cells appears to undergo context-dependent remodeling. Such mechanical adaptations may help tumor cells withstand the physical challenges associated with circulation, adhesion switching, and colonization, and may intersect with the development of therapy resistance. Here, we synthesize recent advances in PCa biomechanics, highlight the intricate interplay between mechanical cues and tumor biology, and discuss opportunities to incorporate a mechanical perspective into diagnostic and therapeutic strategies. A deeper understanding of these processes may ultimately enable the development of emerging “mechanotherapies” for prostate cancer. Full article

Chloroplast development plays a crucial role in plant de-etiolation, a process in which plants switch from growth in darkness to light-driven development, known as photomorphogenesis. This study provides evidence that CIA2 (Chloroplast Import Apparatus 2) and CIL (CIA2-Like) contribute to chloroplast biogenesis, likely by affecting and regulating PSII activity and related gene expression. Although their precise molecular roles remain unclear, our findings support their possible involvement in chloroplast development. This is indicated by downregulation of foliar chlorophyll content, chlorophyll a fluorescence parameters, chloroplast size, and gene expression of PSII molecular markers in the cia2cil double mutant during de-etiolation. Chlorophyll a fluorescence and quantitative gene expression analysis during de-etiolation revealed a significant reduction in PSII maximal efficiency and non-photochemical quenching, as well as deregulated expression of genes such as LHCB2.1 and psbA. According to the immunoblotting and microscopy imaging results, there is an impaired function of PSII and a compromised ultrastructure of the chloroplast membranes in cia2cil plants. However, in CIA2p::CIA2_cia2cil and 35Sp::CIA2_cia2cil complementation lines, reversion of this phenotype was observed. These results suggest a supporting role for CIA2 and CIL in the plant de-etiolation process, expanding our understanding of chloroplast biogenesis regulation. Full article

In-stent restenosis (ISR) remains a clinically relevant cause of recurrent ischemia and repeat revascularization despite progressive refinements in stent design and implantation technique. Contemporary data indicate that restenosis-related target lesion revascularization (TLR) has declined from bare-metal stent (BMS) to early- and newer-generation drug-eluting stents (DESs), yet ISR continues to accumulate over long-term follow-up and is associated with worse outcomes than PCI for de novo lesions. Mechanistically, ISR is a time-dependent, heterogeneous process dominated early by neointimal hyperplasia—triggered by mechanical endothelial injury, delayed re-endothelialization, inflammation/oxidative stress, vascular smooth muscle cell phenotypic switching, and extracellular matrix deposition—and later by in-stent neoatherosclerosis, which may confer a higher-risk plaque substrate and overlap with thrombotic complications. Clinically, ISR frequently presents as an acute coronary syndrome (ACS) rather than stable symptoms, underscoring the prognostic relevance of prompt recognition and mechanism-informed management. Patient-level risk determinants repeatedly reported across cohorts include diabetes mellitus, chronic kidney disease, dyslipidemia, hypertension, and smoking, while lesion/procedural factors include small vessel caliber, long/complex or bifurcation lesions, multiple stent layers, and suboptimal stent expansion. Intravascular imaging (OCT/IVUS) is central to phenotyping ISR mechanisms (e.g., underexpansion, calcific neoatherosclerosis, stent fracture, homogeneous hyperplasia) and can guide targeted prevention and therapy. This review synthesizes current evidence on ISR biology and risk factors to support risk stratification, preventive strategies, and individualized management. Full article