Search Results (356)

Cancer cells rely on elevated ribosomal biogenesis and protein synthesis to sustain their rapid proliferation. This heightened translational demand imposes significant stress on the fidelity of protein synthesis, thereby necessitating ribosomal quality control (RQC) activation, which safeguards proteostasis by degrading incomplete nascent polypeptide chains. At present, RQC is no longer only a peripheral pathway, it is a decisive arbiter of proteostasis whose malfunction rewires the course of cancer progression. Emerging evidence suggests that RQC factors can function as pro-tumorigenic or anti-tumorigenic in a context-dependent manner across different cancer types. This review highlights mechanistic models of how translation stalling, ribosome collision, and ribotoxic stress response influence neurodegeneration, tumor progression, metastasis, stemness, and drug resistance. By framing RQC as a critical regulator of cancer fate, we will identify verifiable and experimentally tractable hypotheses for therapeutic targeting and biomarker discovery in cancer. Full article

Background/Objectives: The oncoprotein EWS::FLI1 is a chimeric transcription factor that aberrantly brings transcriptional deregulation relevant to Ewing sarcoma. It is also regarded as a therapeutic target for suppressing oncogenic progression, but the inhibition and clearance of the EWS::FLI1 oncoprotein remain a challenge. Methods: We apply a polyglutamine (polyQ) fusion strategy to directly target EWS::FLI1 in suppression of its transcriptional malfunction in A673 cells derived from Ewing sarcoma. Based on the template of the N-terminal fragment of polyQ-expanded ataxin-7 (Atx7_93Q-N172) and the homologous peptides of EWS::FLI1, we have designed and constructed three polyQ fusion proteins, namely Atx7_93Q-N172-SYGQ1, Atx7_93Q-N172-SYGQ2, and Atx7_93Q-N172-LCD. Results: Supernatant/pellet fractionation and immunofluorescence imaging reveal that the polyQ fusion proteins co-precipitate and co-localize with EWS::FLI1 in A673 cells, indicating that the polyQ fusions we have designed can sequester endogenous EWS::FLI1 into insoluble aggregates and reduce its cellular availability. Moreover, these polyQ fusions, especially Atx7_93Q-N172-LCD, alter the expression of EWS::FLI1 downstream genes, with an increase in P21 (CDKN1A) and a decrease in c-Myc. Conclusions: These results demonstrate that the engineered polyQ fusions entrap endogenous EWS::FLI1 protein into aggregates and reduce its soluble fraction in Ewing sarcoma cells. This study provides an alternative potential for treating Ewing sarcoma and other tumors by directly targeting the oncogenic proteins in the future. Full article

Systemic sclerosis (SSc) is a disease in which malfunctioning immune cells lead to the formation of autoantibodies that damage blood vessels and body tissues. Fibrosis then develops in the affected organs. Its complex pathogenesis involves multiple immune and stromal cell types, soluble mediators, and dysregulated tissue repair, resulting in heterogeneous clinical manifestations and poor prognosis. Current disease-modifying therapies provide only modest benefits, often slowing but rarely reversing disease progression, and are associated with considerable adverse effects. These limitations have spurred the development of cell-based therapeutic strategies aimed at restoring immune tolerance and promoting tissue repair. In this review, we summarize recent advances in hematopoietic stem cell transplantation, mesenchymal stem cell therapy, and adoptive regulatory T cell transfer and highlight the emerging role of chimeric antigen receptor (CAR)-T cell therapy as a transformative approach for SSc. Collectively, these evolving strategies hold the potential to improve survival, achieve durable remissions, and significantly enhance quality of life for patients with SSc. Full article

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways. Full article

Objectives: The injection of bioactive compounds into the delicate urethral sphincter muscle to facilitate sphincter regeneration in incontinent patients poses a surgical challenge. In previous preclinical animal studies, approximately half of the 96 pigs treated by transurethral needle injection exhibited misplaced cells or cell loss. We, therefore, investigated whether pressure-controlled waterjet injections delivered nano- and microparticles or liquids more precisely in the urethra and without a risk of full penetration. Methods: Fresh cadaveric urethrae were prepared from 12 female pigs. Nano- and microparticles or liquids were injected by waterjet in a proximal (i.e., H5) and distal (i.e., H10) position of the urethral tissue samples employing waterjet pressures of effect 40 (E40), E60, and E80. The injection depths and widths were investigated by histochemistry. Results: E40 injections were not sufficient to inject particles into the tissue, while E60 and E80 injections delivered the components into the urethral mucosa, submucosa and close to the urethral muscle. However, employing E80 increased the risk of full penetration of the urethrae. Significant differences in injection depth were not observed between nano- and microparticles. Liquids, however, penetrated the tissue somewhat deeper. Using the optimised pressure protocols facilitated the injection of cells by a novel waterjet prototype with excellent viability into capture fluid. Conclusions: Target-specific and pressure-controlled waterjet injections deliver liquids and particles with high precision in the urethra. For future injections of bioactive components, including cells, waterjet injections into the urethrae of incontinent pigs with a pressure of E60 are most promising to investigate the efficacy of regenerative therapies in animal models of urinary incontinence and other diseases or malfunctions. Full article

Microplastics (MPs) have become widespread environmental contaminants, with increasing evidence of their harmful impacts on human health. MPs generally enter the human body via ingestion, inhalation, or dermal exposure, with the gastrointestinal tract acting as a crucial entrance route. This work utilized the SHIME system to evaluate the effects of polystyrene (PS) MPs on gut microbiota and short-chain fatty acid (SCFA) metabolism in distinct colonic areas. The results demonstrated regional and individual-specific variations in microbial diversity, significant shifts in Firmicutes/Bacteroidetes (F/B) ratio, and declines in beneficial bacteria, such as Bifidobacteriaceae. Moreover, SHIME supernatants were then tested with a co-cultured cell model (Caco-2/HT29-MTX-E12). Results indicated a deteriorative effect on the intestinal model, characterized by enhanced oxidative stress and mitochondrial malfunction. No significant effect on intestinal barrier integrity or mucus secretion was detected. These findings highlight the potential systemic toxicity of PS-MPs on human gut microbiota-mediated mechanisms, emphasizing the necessity for immediate mitigation efforts. Full article

Given that we have demonstrated that miR-155-5p is increased in CLL PBMCs and that its reduction with inhibitory siRNA partially restores the immune checkpoint BTLA protein level in CLL B cells, risk stratification for using anti-miR-155-based immunotherapy in CLL seems reasonable, particularly with its potential impact on T cells. Therefore, we aimed to assess the role of miR-155-5p in the epigenetic modification of BTLA levels in CLL T cells, especially since we observed that BTLA expression unfavorably promotes increased proliferative activity and IL-4 secretion in T cells, thus suggesting BTLA malfunction in the CLL T cell subset. Transfection of PBMCs with an inhibitor of miR-155-5p (INH) led to about a ten-fold down-regulation of miR-155-5p levels compared to control siRNA (NC) both in CLL patients and healthy individuals (HC), as assessed by RT-qPCR. Additionally, we did not find any significant differences in BTLA protein expression in T cells after silencing miR-155-5p in either examined group. We demonstrated for the first time that immunotherapy approaches based on systemic administration of anti-miR-155-5p therapeutics would be a favorable strategy in CLL, since they do not affect BTLA expression in T cell populations and could benefit CLL patients with impaired BTLA levels on CLL cells. Full article

Lithium-ion batteries are essential to electric vehicles, so it is crucial to continuously monitor and control their health. However, since today’s battery packs consist of hundreds or thousands of cells, monitoring all of them is challenging. Additionally, the performance of the entire battery pack is often limited by the weakest cell. Therefore, developing effective monitoring techniques that can reliably forecast the remaining time to depletion (RTD) of lithium-ion battery cells is essential for safe and efficient battery management. However, even in robust systems, this data can be lost due to electromagnetic interference, microcontroller malfunction, failed contacts, and other issues. Gaps in voltage measurements compromise the accuracy of data-driven forecasts. This work systematically evaluates how different voltage reconstruction methods affect the performance of recurrent neural network (RNN) forecast models trained to predict RTD through quantile regression. The paper uses experimental battery pack data based on the behavior of an electric vehicle under dynamic driving conditions. Artificial gaps of 500 s were introduced at the beginning, middle, and end of each discharge phase, resulting in over 4300 reconstruction cases. Four reconstruction methods were considered: a zero-order hold (ZOH), an autoregressive integrated moving average (ARIMA) model, a gated recurrent unit (GRU) model, and a hybrid unscented Kalman filter (UKF) model. The results presented here reveal that the UKF model, followed by the GRU model, outperform alternative reconstruction methods. These models minimize signal degradation and provide forecasts similar to the original past data signal, thus achieving the highest coefficient of determination and the lowest error indicators. The reconstructed signals were fed into LSTM and GRU RNNs to estimate RTD, which produced confidence intervals and median values for decision-making purposes. Full article

The immune system is crucial in protecting against disease, but it can also contribute to chronic illnesses when it malfunctions, with different conditions involving either inflammation or immune suppression. Current treatments often fall short due to limited effectiveness and side effects. Nanomedicine, particularly cerium oxide nanoparticles (nanoceria), offers promising potential due to its unique therapeutic properties and role in modulating macrophages. Nanoceria (<5 nm) possess the catalytic ability to mimic natural enzymes such as superoxide dismutase, peroxidase, and catalase, enabling effective scavenging of reactive oxygen species (ROS), which play a central role in the pathogenesis of chronic inflammation and cancer. This review comprehensively summarizes the current advances in the application of nanoceria for inflammatory and anti-inflammatory therapy, including their modulatory effects on immune cell activation, cytokine production, and resolution of inflammatory responses. We discuss the mechanisms underlying their immunomodulatory actions in various disease contexts, such as rheumatoid arthritis, women’s health conditions (e.g., endometriosis), wound healing, and cancer. Additionally, the review highlights biocompatibility, therapeutic efficacy, adaptability in imaging (theranostics), and challenges in translating nanoceria-based therapies into clinical practice. The multifunctionality of nanoceria positions them as innovative candidates for next-generation immunotherapy aimed at efficiently controlling inflammation and promoting tissue repair. Full article

This research investigates the use of a fiber optic sensor for detecting hydrogen gas during a thermal runaway of lithium-ion batteries (LIBs). Timely detection of thermal runaway in LIBs, particularly in storage and logistics, is crucial for effective safety management and preventing the escalation of incidents to adjacent cells. The sensors employed in this study utilize fiber Bragg grating (FBG) technology. The FBG sensors are coated with palladium nanoparticles, enabling the detection of hydrogen concentrations up to 5%. In abuse tests, the sensors successfully identified hydrogen emissions. Cross-sensitivity effects were observed during a secondary test and were thoroughly investigated. These interferences were found to be primarily caused by carbon monoxide (CO), a common byproduct of battery venting. While the presence of CO can interfere with hydrogen detection, both signals remain independently valuable as indicators of cell malfunction. This dual-response behavior enhances the robustness of fault detection under real-world battery failure scenarios. Full article

Despite their crucial biological role as metabolites, reactive oxygen and reactive nitrogen species (ROS and RNS) can have a negative effect on organisms when their cellular contents overwhelm the normal equilibrium provided by antioxidant defenses. Important biomolecules, such as lipids, proteins, and nucleic acids (i.e., DNA), can be damaged by their oxidative effects, resulting in malfunction or a shorter lifespan of cells and, eventually, of the whole organism. Oxidative stress can be defined as the consequence of an imbalance of pro-oxidants and antioxidants due to external stress sources (e.g., exposure to xenobiotics, UV radiation, or thermic stress). It can be evaluated by monitoring specific biomarkers to determine the state of health of breathing organisms. Assessments of ROS, RNS, specific degenerative oxidative reaction products, and antioxidant system efficiency (antioxidant enzyme activities and antioxidant compound contents) have been extensively performed for this purpose. A wide variety of analytical methods for measuring these biomarkers exist in the literature; most of these methods involve indirect determination via spectrophotometric and spectrofluorometric techniques. This review reports a collection of studies from the last decade regarding contaminant-induced oxidative stress in insects, with a brief description of the analytical methods utilized. Full article

The Constrained Disorder Principle (CDP) characterizes systems by their inherent variability, which is regulated within dynamic boundaries to ensure optimal function and adaptability. In biological systems, this variability, or “noise”, is crucial for resilience and flexibility at various scales, ranging from genes and cells to more complex organ systems. Disruption of the boundaries that control this noise—whether through amplification or suppression—can lead to malfunctions and result in pathological conditions. White noise (WN), defined by equal intensity across all audible frequencies, is an exemplary clinical application of the CDP. It has been shown to stabilize disrupted processes and restore functional states by utilizing its stochastic properties within the auditory system. This paper explores WN-based therapies, specifically for the masking, habituation, and alleviation of tinnitus, a subjective perception of sound. It describes the potential to improve WN-based therapies’ effectiveness by applying the CDP and CDP-based second-generation artificial intelligence systems. Understanding the characteristics and limitations of these approaches is essential for their effective implementation across various fields. Full article

Bone integrity is maintained through continuous remodeling, orchestrated by the coordinated actions of osteocytes, osteoblasts, and osteoclasts. Once considered passive bystanders, osteocytes are now recognized as central regulators of this process, mediating biochemical signaling and mechanotransduction. Malfunctioning osteocytes contribute to serious skeletal disorders such as osteoporosis. Mesenchymal stromal cells (MSCs), multipotent stem cells capable of differentiating into osteoblasts, have emerged as promising agents for bone regeneration, primarily through the paracrine effects of their secreted exosomes. MSC-derived exosomes are nanoscale vesicles enriched with proteins, lipids, and nucleic acids that promote intercellular communication, osteoblast proliferation and differentiation, and angiogenesis. Notably, they deliver osteoinductive microRNAs (miRNAs) that influence osteogenic markers and support bone tissue repair. In vivo investigations validate their capacity to enhance bone regeneration, increase bone volume, and improve biomechanical strength. Additionally, MSC-derived exosomes regulate the immune response, creating pro-osteogenic and pro-angiogenic factors, boosting their therapeutic efficacy. Due to their cell-free characteristics, MSC-derived exosomes offer benefits such as diminished immunogenicity and minimal risk of off-target effects. These properties position them as promising and innovative approaches for bone regeneration, integrating immunomodulatory effects with tissue-specific regenerative capabilities. Full article

Background/Objectives: Restored CD4 absolute counts (CD4AC) and CD4/CD8 ratio in the setting of continuous antiretroviral treatment (ART) do not exclude a low-level immune activation associated with HIV reservoirs, microbial translocation, or the side effects of ART itself, which accelerates the aging of people living with HIV (PLHIV). To delineate biomarkers of incomplete immune restoration in PLHIV on successful ART, we evaluated T-lymphocyte mitochondrial parameters in relation to phenotypic markers of immune exhaustion and senescence. Methods: PLHIV with sustained viral suppression, CD4AC > 500 and CD4/CD8 ratio >0.9 on ART (n = 39) were compared to age-matched ART-naïve donors (n = 27) and HIV(–) healthy controls (HC, n = 35). CD4 and CD8 differentiation and effector subsets (CCR7/CD45RA and CD27/CD28), activation, exhaustion, and senescence markers (CD38, CD39 Treg, CD57, TIGIT, and PD-1) were determined by flow cytometry. Mitochondrial mass (MM) and membrane potential (MMP) of CD8 and CD4 T cells were evaluated with MitoTracker Green and Red flow cytometry dyes. Results: ART+PLHIV differed from HC by increased CD4 TEMRA (5.3 (2.1–8.8) vs. 3.2 (1.6–4.4), p < 0.05), persistent TIGIT+CD57–CD27+CD28– CD8+ subset (53.9 (45.5–68.9) vs. 40.1 (26.7–58.5), p < 0.05), and expanding preapoptotic TIGIT–CD57+CD8+ effectors (9.2 (4.3–21.8) vs. 3.0 (1.5–7.3), p < 0.01) in correlation with increased CD8+ MMP (2527 (1675–4080) vs.1477 (1280–1691), p < 0.01). These aberrations were independent of age, time to ART, or ART duration, and were combined with increasing CD4 T cell MMP and MM. Conclusions: In spite of recovered CD4AC and CD4/CD8 ratio, the increased CD8+ MMP, combined with elevated markers of exhaustion and senescence in ART+PLHIV, signals a malfunction of the CD8 effector pool that may compromise viral reservoir latency. Full article

Bestrophinopathies are a group of inherited retinal diseases caused by mutations in the BEST1 gene. The protein encoded by this gene, bestorphin-1 (hBest1), is a calcium-dependent transmembrane channel localized on the basolateral membrane of retinal pigment epithelial (RPE) cells. We have already demonstrated the surface behavior and organization of recombinant hBest1 and its interactions with membrane lipids such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), sphingomyelin (SM) and cholesterol (Chol) in models of biological membranes, which affect the hBest1 structure–function relationship. The main aim of our current investigation is to integrate pure hBest1 protein into lipid bilayer nanostructures. We synthesized and characterized various hBest1-containing nanostructures based on 1,2-Dipalmitoylphosphatidylcholine (DPPC), SM, glycerol monooleate (GMO) and Chol in different ratios and determined their cytotoxicity and incorporation into cell membranes and/or cells by immunofluorescence staining. Our results show that these newly designed nanoparticles are not cytotoxic and that their incorporation into MDCK II cell membranes (used as a model system) may provide a mechanism that could be applied to RPE cells expressing mutated hBest1 in order to restore their ion transport functions, affected by mutated and malfunctioning hBest1 molecules. Full article