Gastric ulcer remains a significant global gastrointestinal condition characterized by disruption of the gastric mucosal barrier, attributed to oxidative stress, inflammation, Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs (aspirin, indomethacin, diclofenac), and compromised tissue repair. While traditional therapies effectively reduce acid secretion and eliminate H. pylori, they often do not actively promote mucosal regeneration and angiogenesis, both of which are crucial for the complete healing of ulcers and the prevention of recurrence. This review integrates molecular mechanisms, preclinical and clinical evidence, advanced delivery strategies, and future translational perspectives to provide a comprehensive overview of phytochemical-mediated gastric ulcer healing. Recent findings suggest that tissue repair mediated by angiogenesis, which is regulated by vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α, nitric oxide, prostaglandins, NF-κB, PI3K/Akt, modulated mitogen-activated protein kinase (MAPK), and fibroblast growth factors, plays a pivotal role in the restoration of the gastric mucosa. Phytochemicals, such as polyphenols, flavonoids, terpenoids, alkaloids, and other bioactive compounds derived from plants, have shown considerable gastroprotective and pro-healing effects in experimental models. Compounds like curcumin, quercetin, naringin, asiaticoside (20 mg/kg, in rats), glycyrrhizin, berberine, and sulforaphane enhance VEGF expression, promote microvascular regeneration, stimulate epithelial restitution, and restore redox balance, thus expediting the healing of ulcers. Moreover, innovative drug delivery methods enhance the bioavailability and therapeutic effectiveness of phytochemicals. They may be promising adjunctive therapeutic agents for gastric ulcer healing through their ability to modulate mucosal regeneration. Integration of advanced methods, biomarker-based clinical studies, systems biology, and the potential of emerging precision medicine strategies may accelerate translational applications and improve future gastric ulcer management strategies.
Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) offer distinct advantages for clinical translation, including accessibility, scalability, and broad immunomodulatory capacity. However, the efficacy of systemically delivered UC-MSCs is constrained by suboptimal in vivo trafficking. Intravascular administration is limited by pulmonary first-pass sequestration, inefficient endothelial recruitment, blood-mediated inflammatory injury, and poor retention. While UC-MSCs homing is often conceptualized through a leukocyte adhesion paradigm, this model incompletely describes culture-expanded UC-MSCs, which exhibit heterogeneous expression of chemokine receptors, adhesion molecules, and selectin ligands. Furthermore, biodistribution and safety are critically determined by biophysical and hemocompatibility parameters, including cell size, deformability, cryopreservation status, and tissue factor (TF/CD142)-dependent procoagulant activity. This review synthesizes current understanding of UC-MSCs trafficking at the translational interface of biology and manufacturing. We examine canonical migratory mechanisms-chemokine signaling, integrin-mediated adhesion, extracellular matrix remodeling, and intracellular motility pathways-alongside underappreciated determinants of therapeutic performance: instant blood-mediated inflammatory reaction (IBMIR), complement-coagulation crosstalk, post-thaw functional impairment, donor variability, and route-dependent biodistribution. We also address the paradox wherein therapeutic benefit occurs despite minimal durable engraftment, implicating paracrine signaling, extracellular vesicles, and apoptosis-associated immune reprogramming as primary effectors. Finally, we evaluate strategies to enhance delivery and efficacy, including preconditioning, glycoengineering, receptor overexpression, route optimization, biomaterial-assisted retention, and migration-relevant potency assays under Good Manufacturing Practice (GMP). Advancing UC-MSCs therapy toward reproducible, mechanism-guided clinical application requires rigorous integration of hemocompatibility assessment, product characterization, and clinically informative cell tracking.
The specific binding of antigenic peptides to major histocompatibility complex class I (MHC-I) molecules is a pivotal step in adaptive immune responses. Post-translational modifications (PTMs) have been shown to profoundly regulate this process and thereby modulate T-cell recognition; however, their atomic-level mechanisms remain insufficiently understood. To address this gap, we employed all-atom molecular dynamics simulations combined with multidimensional energetic and dynamic analyses to systematically dissect PTM-dependent regulatory mechanisms across diverse antigen peptide-MHC-I (pMHC) systems. Representative viral (SARS-CoV-2 spike protein), model (ovalbumin), autoimmune-associated (MBP), and tumor-associated (TVF and RSP) antigen peptides were examined, encompassing acetylation, phosphorylation, citrullination, methylation, hydroxylation, and succinylation modifications. Our results demonstrate that PTM effects are highly context-dependent and governed by both the modified site and the physicochemical nature of the introduced functional group. Charge-altering modifications at critical anchoring positions-such as N-terminal acetylation and phosphorylation-substantially weaken pMHC binding by disrupting electrostatic complementarity, reorganizing hydrogen-bond networks, accompanied by altered collective motions, and expanding the MHC α1/α2 binding groove. In contrast, conservative modifications located in solvent-exposed regions (e.g., lysine methylation) exert minimal structural and energetic perturbations. Notably, citrullination in disease-associated antigens enhances binding affinity through strengthened hydrophobic interactions, optimized hydrogen-bond rearrangements, accompanied by increased dynamic cooperativity, and contraction of the binding groove, providing a mechanistic basis for its immunological consequences. Across all systems, PTMs regulate pMHC recognition through multiscale coupling mechanisms that integrate residue-level energetic redistribution, cooperative motion reprogramming, and global groove geometry remodeling. Importantly, the simulation-derived binding trends are consistent with available experimental observations, supporting the reliability of the computational framework. Collectively, this study establishes a unified structure-energy-dynamics model explaining how PTMs function as atomic-level chemical switches in antigen presentation. Beyond mechanistic insight, the demonstrated agreement with experimental data suggests that this computational strategy possesses predictive potential for estimating PTM-dependent pMHC binding behaviors across diverse immunological contexts.
Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer worldwide. The gut microbiota profoundly influences this cancer by modulating immune responses and therapeutic efficacy. Recently, live biotherapeutic products (LBPs), comprising live resident microorganisms in the gut, have emerged as promising agents to reprogram host immunity and enhance treatment efficacy in preclinical CRC models. However, translation of these findings to clinical practice remains limited due to heterogeneous study designs, poorly defined mechanisms in human hosts, unresolved manufacturing and safety concerns, and lack of personalized treatment strategies. This review briefly introduces LBPs as a new class of medicines, categorize them as single strains, composite strains, and engineered strains, and details their multifaceted mechanisms against CRC, including direct immunomodulation to enhance anti-tumor activity, production of protective metabolites like short-chain fatty acids (SCFAs), and restoring gut microbiota. Additionally, the synergistic potential of LBPs with conventional chemo- and immunotherapies and current LBPs in clinical trials for CRC are summarized, highlighting their translational progress. We further address the manufacturing, regulatory, and safety barriers constraining clinical adoption and propose strategies for integrating preclinical and clinical evidence to meet patient needs. By consolidating current knowledge of LBPs as an emerging oncology drug class, this review offers a practical framework for advancing LBPs from preclinical promise to clinical practice, supporting the development of personalized medicine.
Endoplasmic reticulum (ER) is a multifunctional organelle essential for maintaining proteostasis, lipid and carbohydrate metabolism, and calcium homoestasis. Rapidly dividing cancer cells driven by oncogenes, elevated translational output, increased metabolic demands, and a hostile tissue microenvironment overwhelm the protein-folding machinery of ER, leading to massive accumulation of unfolded proteins within the ER's lumen leading to chronic ER stress. This activates the unfolded protein response (UPR), a conserved signaling network mediated by three principal sensors: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1-alpha (IRE1α), and activating transcription factor 6 (ATF6), which functions to restore proteostasis or induce apoptosis under unresolved ER stress. Accumulating evidence indicates that malignant cells hijack the pro-adaptive function of the UPR pathway not only to thrive but also to promote cancer progression by invasion and metastasis. UPR activation modulates transcriptional and translational programs that contribute to angiogenesis, invasion, metastasis, immune escape, and chemoresistance. In this review, we dissect how cells balance this tightrope between adaptation and cell death in the context of cancer. We also explore how UPR signaling drives angiogenesis, metastasis, immune-evasion, and chemoresistance before finally discussing its therapeutic potential.
Periprosthetic joint infection (PJI) is among the most serious complications after hip and knee arthroplasty and requires timely diagnosis and a close follow-up. In parallel with the digital transformation of medicine, wearables (e.g., inertial sensors) and computer-assisted sensing are increasingly being used to generate objective data on function, mobility, and physiological parameters throughout the entire treatment pathway. In arthroplasty, current evidence for wearables is strongest in rehabilitation and outcome monitoring, although important limitations remain, including device heterogeneity, patient adherence, and the lack of standardized assessment protocols. At present, only a few studies have addressed their role in the prediction, diagnosis, prevention, and rehabilitation of PJI. Potential applications therefore appear to lie less in direct infection detection than in the identification of nonspecific warning signals, such as persistently reduced activity or disturbed circadian patterns, which may trigger structured diagnostic work-up and longitudinal follow-up within established PJI frameworks. Comparable concepts have already been explored in the diagnosis and management of sepsis. For PJI-specific monitoring, implantable sensing concepts ("smart implants") appear particularly promising from a translational perspective, as local parameters such as pH, temperature, and metabolites can already be assessed in experimental as well as early preclinical and clinical settings. This article summarizes the current evidence on wearables in arthroplasty with a focus on PJI and discusses key requirements for clinical utility, validation, data security, and implementation. HINTERGRUND: Periprothetische Gelenkinfektionen (PJI) zählen zu den folgenschwersten Komplikationen nach Hüft- und Knieendoprothetik und erfordern eine zeitnahe Diagnostik sowie engmaschige Verlaufskontrolle. Parallel zur Digitalisierung der Medizin gewinnen Wearables (z. B. inertiale Sensoren) und computerassistierte Sensorik an Bedeutung, um objektive Funktions- und Mobilitätsdaten sowie Vitalparameter über den gesamten Behandlungspfad abzubilden. In der Endoprothetik ist die Evidenz für Wearables bislang vor allem im Rehabilitations- und Outcome-Monitoring am stärksten, zeigt jedoch auch relevante Grenzen durch Geräteheterogenität, Adhärenz und fehlende Standardisierung. Zur Prädiktion, Diagnostik, Prävention und Rehabilitation bei PJI liegen derzeit kaum Arbeiten vor. Potenziell nutzbar sind vielmehr unspezifische Signale wie persistierende Aktivitätsminderung oder gestörte zirkadiane Muster als Trigger für eine strukturierte Abklärung, im Sinne einer frühzeitigen Diagnostik bzw. eines Verlaufs‑/Kontrolldiagnostikums gemäß etablierter PJI-Kriterien. Ähnliche Konzepte sind bereits in der Diagnostik und Behandlung von Patienten mit Sepsis untersucht. Für PJI-spezifisches Monitoring sind implantierbare Sensorkonzepte („smart implants“) translational besonders plausibel: lokale Parameter wie pH, Temperatur und Metabolite lassen sich mit experimentellen bzw. frühen präklinischen/klinischen Ansätzen messen. Dieser Beitrag fasst die aktuelle Evidenz zu Wearables in der Endoprothetik mit Fokus auf PJI zusammen und diskutiert Anforderungen an klinischen Nutzen, Validierung, Datensicherheit und Implementierung.
Biofilms are well-organized, surface-attached colonies of microorganisms that can thrive in host cavities. A balanced, diverse mix of protective microbes in these biofilms helps preserve host health. Dysbiosis in biofilms is responsible for consequential diseases in associated tissues. Dietary factors and other xenobiotics can cause ecological dysbiosis in the oral cavity that underpins dental caries, periodontal diseases, halitosis, and periapical infections. Although the gold standard for oral biofilm elimination remains mechanical removal, it is achieved with manual curettage or an ultrasonic scaler. However, the removal of non-pathogenic microorganisms, which contribute to chemical signaling and metabolic complementation of the host, thereby produces deleterious side effects. Therefore, to maintain ecological balance, alternatives are a major area of research. A 'control without killing' approach to modulating biofilms focuses on maintaining biofilm ecology rather than indiscriminately using antimicrobial agents. The extracellular matrix (ECM) of a biofilm protects the embedded microbial communities; measures that disintegrate it can emerge as a promising modality to control the growth of pathogenic microbes in them. Currently, research focuses on limiting virulence traits (acid production, protease activity, or quorum sensing) to degrade the ECM and slow pathogen growth without eliminating commensals. This article highlights current research on approaches to managing oral cavity biofilms and the translational challenges they pose. Understanding these alternative approaches can help formulation researchers, microbiologists, and materials science experts work integratively to manage microbial biofilms. This article opens gateways to implementing oral biofilm-modulating strategies in the management of other biofilm-associated infections.
This narrative review aims to synthesize current knowledge on the mechanisms governing embolic-agent distribution and to examine the engineering rationale and translational feasibility of closed-loop or semi-automated embolic-agent injection. A structured search and targeted review of experimental, computational, and clinical studies were used to synthesize evidence on particle properties, injection parameters, hemodynamics, imaging feedback, and pressure monitoring related to embolization. Evidence was analyzed from a biomedical engineering perspective, with emphasis on transport mechanisms, sensing modalities, and control-relevant variables. Embolic-agent distribution arises from the coupled effects of particle size, shape, and material properties; injection rate, mode, and catheter configuration; and lesion- and device-induced hemodynamic alterations. Quantitative digital subtraction angiography (qDSA and 4D-DSA) provides spatial and perfusion-related information, whereas local arterial pressure more directly reflects distal resistance evolution and reflux tendency. Taken together, these findings support an engineering interpretation of embolization as a constrained transport-flow-control process in which embolic distribution, endpoint assessment, and procedural safety are jointly influenced by particle characteristics, hemodynamics, and feedback-informed injection strategy. By reframing embolization as a coupled transport and control problem, this review integrates multifactorial distribution mechanisms with multimodal feedback concepts and outlines a preliminary engineering framework for future feedback-informed embolic-agent delivery systems.
Targeted alpha therapy (TAT) has the advantage of localized cytotoxicity using the high linear energy transfer capabilities of alpha particles. Actinium-225 ([225Ac]Ac) has been shown to be suitable for antibody-based targeting but lacks chelate stability and conjugation reproducibility. CD276 (B7-H3) has been shown to be broadly overexpressed in various solid tumors and thus presents as a suitable therapeutic target. We developed and evaluated a well-defined [225Ac]Ac-Macropa-PEG2-Enoblituzumab radioimmunoconjugate prepared using thiol-maleimide-based PEG2-Macropa conjugation strategy. The Enoblituzumab was activated (thiolated) using Traut's reagent followed by conjugation with activated Macropa-PEG2 using EDC/NHS chemistry. The Macropa-PEG2-Enoblituzumab conjugate was characterized by SEC-HPLC and MALDI-TOF MS. Radiolabeling with [225Ac]Ac- was achieved under mild conditions and the [225Ac]Ac-Macropa-PEG2-Enoblituzumab assessed with iTLC and radio-SEC-HPLC. Functional studies involved saturated binding & internalization analyses using CD276-positive DU145-B7-H3 cells and CD276-negative CHO-K1 controls. Biodistribution, dosimetry, and therapeutic effectiveness were assessed using DU145-B7-H3 xenograft-bearing mice model with excess Enoblituzumab blocking and non-target CHO-K1 controls. The conjugate revealed reproducible chelator incorporation (CAR = 3.4 ± 0.12), efficient radiolabeling (>95%), and in vitro stability (>90% intact up to 7 days). High-affinity binding (KD = 0.18 ± 0.05 nM) and time-dependent internalization were observed in DU145-B7-H3 cells, with minimal uptake in CHO-K1 controls. In vivo studies showed gradual tumor accumulation (15.7 ± 1.1%ID/g at 72 h) with sustained retention and favorable tumor-to-background ratios. CHO-K1 xenografts showed minimal uptake, and blocking significantly reduced tumor accumulation, confirming receptor-mediated targeting. Therapy studies demonstrated significant tumor growth inhibition and prolonged survival with good tolerability. [225Ac]Ac-Macropa-PEG2-Enoblituzumab shows strong stability, specificity, and therapeutic efficacy, supporting further development as a promising translational candidate for targeted alpha therapy of B7-H3-expressing malignancies.
The purpose of this study was to determine early phase CBC markers that could predict radiation dose and hematopoietic acute radiation syndrome (H-ARS) severity in a male baboon radiation model, and to determine the translational relevancy of these findings derived with known radiation doses as it pertains to the human algorithms based on reconstructed doses. A panel of hematologic biomarkers was measured from blood-cell samples collected at 0 to 5d after receiving 0-8 Gy of TBI exposures of gamma or mixed field (neutron/gamma) using a standard blood cell counter. The database was used in an initial stepwise multiple-regression model for estimating radiation dose using data from 1-3d. A logistic-regression model-fitting approach was also applied for estimating H-ARS severity using TBI and PBI radiation data consisting of gamma only or mixed field collected from 1-5d. The dose estimation model consisted of the variable's lymphocytes-natural log day 3 (p < .001) and platelets-squared day 3 (p < .0001), which yielded an estimation accuracy of fit of R2 = 0.6760 (p < .001) and accuracy ∼75%. The logistic regression H-ARS severity algorithm consisted of lymphocytes (p < .001) and platelets-natural log (p < .0001) with overall accuracy of 93.4 (0 vs 2.5 & 2 H-ARS), 96.6 (0 vs 2.5 H-ARS), and 99.3 (0 vs 3 H-ARS) %. The predicted H-ARS severity outcome for the 0-5-day models showed area under the curves of 0.974, 0.990, 0.995 respectively by ROC curve analysis. The resultant study supports the proof-of-concept that initial dose estimation and H-ARS severity-response-category algorithms using standard blood-cell parameters can provide both rapid triage and radiation injury assessment following gamma and mixed (neutron/gamma)-field exposures. These findings, based on a baboon radiation model, provide confirmatory evidence of the utility of hematological biomarkers predicting radiation dose and injury severity.
Radiation-induced skin injury (RISI) is common in both radiation therapy and accidental exposure. An appropriate animal model of RISI is of great significance for understanding its injury mechanism and developing medical countermeasures (MCMs). A reproducible, dose-dependent murine model of RISI was established via localized irradiation of the tail skin with graded doses. C57BL/6 mice were employed to establish RISI model by irradiating 2 cm section of the mouse tail with 20 Gy, 30 Gy, and 40 Gy of single irradiation with RS2000 Biological Irradiator. Skin injuries were scored with a modified semi-quantitative scale based on Kumar scale. H&E staining, measurement of the thickness of epidermis and dermis, IHC for dopachrome tautomerase (DTC), IF staining for α-smooth muscle actin (α-SMA) and Masson staining were used for histopathological evaluations of RISI. A murine model of RISI was established via graded-dose X-ray irradiation of the tail, followed by comprehensive characterization and evaluation of its phenotypic traits. Dynamic alterations in cutaneous melanin-excessive early deposition and subsequent reduction-triggered by tail irradiation rendered radiation-induced erythema undetectable. To address this issue, we specifically revised the early damage scoring criteria of the RISI scale based on Kumar scale. As radiation dose increased, mice exhibited typical symptoms in the irradiated area, including dry desquamation (20 Gy), moist desquamation (30 Gy), ulcers and necrosis (40 Gy), which mimic the key features of clinical RISI. Further histopathological assessment demonstrated a strong correlation between the scoring system and histological changes. Concurrently, we discovered that in the later stage of this model, the interstitial tissue at irradiated site presented a fibrotic phenotype with good dose dependence. In conclusion, this study established an easily operable and highly reproducible tail irradiation model, providing one new platform for in-depth research on the mechanisms and translational applications of RISI.
Canine Cognitive Dysfunction (CCD) is a naturally occurring neurodegenerative syndrome in aging dogs that shares clinical and neuropathological parallels with Alzheimer's disease (AD). As the demand for objective diagnostic tools grows, identifying reliable biofluid biomarkers is essential for clinical staging and therapeutic monitoring. This review synthesizes evidence on cerebrospinal fluid (CSF) and blood-based biomarkers (BBM) of CCD, focusing on amyloid-β (Aβ), neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Evidence shows that Aβ42 and Aβ42/Aβ40 ratios exhibit stage-dependent, non-linear alterations resembling early compensatory phases in human AD. In contrast, tau pathology in CCD consists mainly of pre-tangle synaptic hyperphosphorylation rather than abundant neurofibrillary tangles, limiting its current diagnostic utility. GFAP, a marker of astroglial activation, shows inconsistent associations with cognitive decline and remains exploratory. Conversely, NfL has emerged as the most robust biomarker; CSF and plasma NfL levels consistently increase with age, correlate with cognitive impairment, and reflect central axonal pathology, making it the leading candidate for staging and monitoring disease progression. Overall, the CCD biomarker landscape supports a multimodal approach integrating Aβ dysregulation, axonal injury, and glial activation. Advancing this field requires harmonized diagnostic criteria, standardized sampling, and longitudinal studies. Such efforts will strengthen the translational value of CCD as a model for human dementia, accelerating discovery and therapeutic development across species.
Calotropis gigantea has long been used in traditional medicine for the management of pain, inflammation, wounds, infections, and other disorders. This review critically updates the phytochemical and pharmacological evidence published from 2013 to 2026 by integrating compound-isolation studies, LC-MS/GC-MS profiling, activity-guided fractionation, mechanistic assays, and available safety data. Recent investigations have considerably expanded the chemical profile of C. gigantea, particularly its cardiac glycosides and cardenolides, together with triterpenoids, sterols, lignans, flavonoids, β-carboline alkaloids, and pyrrole derivatives. Studies of the latex, leaves, flowers, and root and stem bark consistently identify cardenolides as major contributors to biological potency. In vitro, several cardenolides exhibit nanomolar cytotoxicity against cancer cell lines and regulate HIF-1, Wnt/β-catenin, and Notch signaling, partly through Na+/K+-ATPase-Ca2+-associated mechanisms. Extracts, fractions, and isolated compounds also display antimicrobial, antioxidant, anti-inflammatory, wound-healing, anti-migraine, and organ-protective effects. These activities are supported by mechanistic findings involving oxidative stress, mitochondrial dysfunction, apoptosis, autophagy, and CYP450 modulation, the latter highlighting potential herb-drug interactions. In vivo findings provide preliminary support for several pharmacological effects, although translational evidence remains limited. The plant has also been applied in the green synthesis of Ag, ZnO, CuO, and MgO nanoparticles with additional biomedical properties. The novelty of this review lies in linking updated chemical evidence with potency-driving constituents, molecular mechanisms, safety considerations, and research gaps. Collectively, the findings establish C. gigantea as a valuable source of multi-target lead compounds while emphasizing the need for standardized quality markers, rigorous toxicological assessment, and well-designed preclinical and clinical studies.
Ovarian cancer is the most lethal malignancy of the female reproductive system worldwide. Chemoresistance, particularly platinum resistance, is a major factor limiting improvement in prognosis, and its underlying mechanisms involve complex regulation of and escape from multiple programmed cell death pathways in cancer cells. Disulfidptosis is triggered by high expression of solute carrier family 7 member 11 (SLC7A11) under glucose starvation and shares upstream regulatory nodes with ferroptosis. Necrosis by sodium overload is driven by sodium ion overload mediated by transient receptor potential cation channel subfamily M member 4 (TRPM4), but its role remains to be further investigated. Other programmed cell death pathways are interwoven into a dynamic regulatory network through key regulatory molecules such as tumor protein p53, the caspase family, cysteine-aspartic proteases, and glutathione. Autophagy can inhibit pyroptosis; ferroptosis and pyroptosis can synergistically amplify cell-killing effects through the reactive oxygen species/NOD-like receptor thermal protein domain-associated protein 3 axis; ferroptosis and cuproptosis share the glutathione metabolic axis; and the interaction between ferroptosis and disulfidptosis can shift from antagonism to synergy under specific metabolic stress. Ferroptosis and necrosis by sodium overload mutually promote each other through cascades involving adenosine triphosphate depletion, reactive oxygen species accumulation, and mitochondrial damage. PANoptosis can overcome cancer-cell resistance to a single mode of cell death through the simultaneous activation of multiple cell death pathways. A comprehensive review of the roles and interactive networks of various programmed cell death modalities, including disulfidptosis, necrosis by sodium overload, apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, cuproptosis, and PANoptosis, in platinum resistance in ovarian cancer is expected to provide a solid theoretical basis and potential translational directions for reversing platinum resistance and optimizing clinical treatment strategies. 卵巢癌是全球女性生殖系统中病死率最高的恶性肿瘤，化疗耐药特别是铂耐药是限制其预后改善的主要因素，相关机制涉及癌细胞对多种程序性细胞死亡途径的复杂调控与逃逸。双硫死亡由溶质载体家族7成员11(solute carrier family 7 member 11，SLC7A11)高表达在葡萄糖饥饿条件下触发，与铁死亡共享上游调控节点;钠死亡由瞬时受体电位阳离子通道亚家族M成员4(transient receptor potential cation channel subfamily M member 4，TRPM4)介导的Na⁺过载驱动，其作用尚待深入研究。其他程序性细胞死亡途径通过肿瘤蛋白p53、caspase家族、半胱氨酸天冬氨酸特异性蛋白酶、谷胱甘肽等关键调控分子交织成动态调控网络:自噬可抑制焦亡;铁死亡与焦亡可通过活性氧/NOD样受体热蛋白结构域相关蛋白3轴协同放大细胞杀伤效应。铁死亡与铜死亡共享谷胱甘肽代谢轴，铁死亡与双硫死亡的交互作用可在特定代谢压力下由拮抗向协同转换;铁死亡与钠死亡通过腺苷三磷酸耗竭、活性氧累积、线粒体损伤的级联反应相互促进;泛凋亡则可通过多死亡通路的同步激活，克服癌细胞对单一死亡模式的抵抗。系统综述双硫死亡、钠死亡、凋亡、自噬、坏死性凋亡、焦亡、铁死亡、铜死亡及泛凋亡等多种程序性死亡模式在卵巢癌铂耐药中的作用及其交互网络，有望为逆转铂耐药、优化临床治疗策略提供坚实的理论基础和潜在的转化方向。.
Protein adenylation (AMPylation) is a post-translational modification in which an adenosine monophosphate (AMP) group is covalently attached to target proteins by AMPylases using ATP as a donor. In metazoans, two conserved AMPylase families are known: FIC-domain proteins and SelO. The yeast Saccharomyces cerevisiae lacks a FIC-domain enzyme; its only known AMPylase is the mitochondrial SelO homologue, Fmp40, involved in redox signaling. We conducted the first comprehensive screen for AMPylated proteins in the mitochondrial proteome of S. cerevisiae analyzing both wild-type and fmp40Δ cells using quantitative mass spectrometry. We identified 124 AMPylated mitochondrial proteins in wild-type and 41 in fmp40Δ mitochondria, suggesting the existence of additional AMPylase(s) in yeast. Among the modified targets, seven ATP synthase subunits were AMPylated, many at sites also phosphorylated, underscoring complex PTM regulation of the enzyme. We demonstrated that substitutions of one such residue, serine 29 in the δ subunit (Atp16), to alanine or glutamic acid, altered ATP synthase activity and oxidative phosphorylation coupling under both fermentative and respiratory conditions. This regulation is crucial for maintaining mitochondrial membrane potential. Our study provides the first catalog of AMPylated mitochondrial proteins in yeast, establishing a foundation for future studies on mitochondrial AMPylation.
Zygosaccharomyces rouxii is a halotolerant yeast commonly associated with high-salt fermentations, although its proteome-level adaptation mechanisms are little understood. DIA-based quantitative proteomics was used to characterize the salt-stress responses of Z. rouxii CGMCC 3791 grown at 0, 60, and 120 g/L NaCl. Principal component analysis demonstrated high repeatability and a unique proteome state at 120 g/L of NaCl. Differential analysis revealed 251 differentially expressed proteins (DEPs) (148 up, 103 down) at 60 g/L and 798 DEPs (549 up, 249 down) at 120 g/L, demonstrating significant concentration-dependent remodeling. Under severe stress, GO and KEGG enrichment consistently revealed the reinforcement of central carbon and energy metabolism, peroxisome-associated fatty acid turnover, oxidoreductase/redox activities, and translation and nucleotide metabolic pathways. Heatmap clustering and PPI networks revealed additional tightly coordinated modules that connect bioenergetics, redox regulation, and the translational capacity. These findings provide a proteome-scale framework for understanding halotolerance in Z. rouxii and guidance for future high-salt fermentation engineering.
Cardiovascular diseases (CVDs) remain a leading cause of global mortality, emphasizing the need for novel, mechanism-driven therapeutics. The P2Y₁ receptor (P2Y₁R), a G protein-coupled purinergic receptor activated by extracellular nucleotides, has emerged as a key regulator of cardiovascular function and dysfunction. Upon activation, P2Y₁R triggers phospholipase C (PLC)-dependent signaling, modulating platelet activation, vascular tone, endothelial integrity, and fibrotic remodeling. Dysregulated P2Y₁R signaling is implicated in thrombosis, atherosclerosis, hypertension, and abnormal platelet reactivity, highlighting its therapeutic potential. Nucleotide bisphosphate antagonists have played a pivotal role in elucidating P2Y₁R pharmacology and guiding drug discovery. The first-generation antagonist MRS2179 demonstrated proof-of-concept for competitive inhibition, but was limited by low potency and metabolic instability. Structural optimization led to MRS2279, exhibiting improved receptor affinity and enzymatic stability. Further refinement produced MRS2500, a highly potent and selective antagonist with nanomolar activity and robust in vivo antithrombotic efficacy without compromising hemostasis. This review integrates advances in P2Y₁R signaling, pharmacology, and structure-based design, emphasizing the evolution of nucleotide antagonists and their translational potential. These insights establish P2Y₁R antagonism as a promising strategy for next-generation cardiovascular therapeutics.
Glioblastoma (GBM), the most common malignant brain tumor, remains highly resistant to current standard treatments, highlighting the urgent need for novel treatment strategies. Epidemiological evidence shows a lower incidence rate of GBM in women than in men, suggesting a potential protective role of estrogen. Given that GBM cells disturb cell cycle regulation through uncontrolled proliferation, targeting apoptotic pathways has emerged as a promising therapeutic approach. Raloxifene (RAL), a selective estrogen receptor modulator (SERM), has repeatedly demonstrated anticancer potential. In this study, we investigated whether RAL could induce apoptosis in GBM cells. Using rat C6 cells, we evaluated RAL's effects on cell viability, apoptosis induction, cell cycle progression, migration capacity, and colony formation, as well as on the gene and protein expression profiles of apoptosis-related signaling pathways. Our findings show that RAL significantly induces apoptosis and suppresses cell growth in a concentration- and time-dependent pattern compared to the vehicle control (0.1% DMSO). These findings would position RAL as a promising candidate for GBM therapy, warranting further investigation into its translational potential.
Response inhibition, or the ability to suppress "pre-potent" behavioral responses, is subserved by both motor and inhibitory control processes and linked to the anterior mid-cingulate cortex (aMCC). We utilized an adapted Go/No-Go paradigm combined with proton functional magnetic resonance spectroscopy (1H fMRS) of the dACC to investigate differences in glutamate level between an All-Go (non-selective motor responding) and Go/No-Go (selective motor responding) condition, both compared to a no-response condition. This allowed disambiguation of the excitatory neurochemistry underlying motor vs. inhibitory control processes. 1H fMRS (midline dACC; 4.1 cm3) was acquired in 15 participants at 3T during non-selective (response to 100% of trials) vs. selective motor responding epochs [response to 80% of trials (20% inhibition)]. Each motor response mode was conducted as a separate task run (random order) with interleaved epochs matched for visual stimuli (timing and physical size) but without motor responses. Glutamate was quantified across motor responding modes (selective vs. non-selective), motor demands (present vs. absent), and their interaction. dACC glutamate was significantly higher (3.7%) during non-selective motor responding relative to interleaved periods without motor responding. aMCC glutamate was not significantly different during the selective vs. periods of no-response. A task order effect showed higher glutamate among participants who (randomly) completed the non-selective task run first. Non-selective motor responding drove increased aMCC glutamate relative to periods without motor responding whereas the effect was absent for the selective responding mode. Our findings suggest that generalized motor control processes increased aMCC excitatory neuromodulation drive, whereas the additional engagement of inhibitory control processes did not change the excitatory neuromodulation drive.
Expanded coverage for telehealth during the COVID-19 pandemic allowed providers to bill for telemedicine services that were previously not reimbursable, including telemedicine critical care (TCC) services for critically ill patients. We aimed to characterize TCC billing practices among Medicare beneficiaries before, during, and after the COVID-19 pandemic. This was a serial cross-sectional study of adult Medicare Fee-For-Service beneficiaries with at least one bill for critical care at acute care hospitals from January 2018 to September 2024. TCC billing was identified using provider billing codes; multivariate regression models were used to determine characteristics associated with receipt of TCC. Key outcomes were patient-, provider-, and hospital-level characteristics associated with TCC billing. None. Billing for TCC increased from 0.002% of critical care bills pre-pandemic to 0.01% of critical care bills during and after the pandemic. Patients billed for TCC were disproportionately likely to have COVID-19 but were otherwise relatively similar to critically ill patients not billed for TCC. Internal medicine/critical care providers accounted for the highest proportion of pandemic TCC bills (46.0%). TCC billing occurred more often at minor teaching hospitals (adjusted odds ratio [aOR], 1.21; 95% CI, 1.03-1.43) and at safety-net hospitals (aOR, 1.33; 95% CI, 1.04-1.70). TCC billing was less likely at small-sized hospitals (aOR, 0.39; 95% CI 0.26-0.58) and medium-sized hospitals (aOR, 0.67; 95% CI, 0.47-0.95), government-owned hospitals (aOR, 0.70; 95% CI, 0.57-0.86), for-profit hospitals (aOR, 0.58; 95% CI, 0.48-0.71), rural hospitals (aOR, 0.70; 95% CI, 0.55-0.89), and critical access hospitals (aOR, 0.59; 95% CI, 0.47-0.73). Billing for TCC among hospitalized critically ill Medicare beneficiaries increased during the pandemic but remained low as a proportion of all critical care bills. There was variability in utilization across subspecialties and lesser utilization at rural and critical access hospitals. Further studies are needed to characterize the clinical and economic consequences of this shift.