Clostridium perfringens forms temperature-responsive pellicle biofilms at 25°C, characterized by a fibrous matrix composed of BsaA proteins. In addition to BsaA, extracellular DNA (eDNA) contributes to biofilm structural integrity. However, the mechanism underlying its release remains unclear. This study aimed to determine the genetic determinants of eDNA release during pellicle biofilm maturation. We visualized the release of nucleic acids during C. perfringens proliferation using anaerobic live-cell imaging and quantified dead-cell frequency and eDNA levels. We analyzed biofilm matrix-associated RNA by RNA-seq. We deleted candidate genes to assess their roles in biofilm formation and eDNA release. Promoter activity was evaluated using fluorescence reporter assays. Live-cell imaging demonstrated that, during growth, a subpopulation released nucleic acids via cell lysis. Dead-cell frequency and eDNA levels increased as a function of pellicle biofilm maturation, suggesting that eDNA released from dead cells contributed to biofilm integrity. We found that biofilm matrix-associated extracellular nucleic acids contained RNA, which likely reflects the transcriptome of lysed cells. RNA-seq revealed transcripts enriched in the matrix fraction, thereby identifying several genes required for pellicle biofilm maturation. Among them, deletion of cpe2430 markedly reduced eDNA levels and impaired biofilm structural stability. Promoter-reporter analysis showed bimodal expression of cpe2430, with high expression limited to ∼3 of the population. We identified genetic factors governing eDNA release and biofilm maturation in C. perfringens. Our findings suggest a model in which regulated lysis of a subpopulation drives eDNA release, thereby reinforcing biofilm architecture.
The neuromodulator histamine regulates key processes in many circuits of the adult and developing brain, including striatum. However, striatal innervation by histaminergic afferents is very sparse making the physiological sources of histamine unclear. Here sources of striatal histamine were investigated during early postnatal development and specifically during the second postnatal week in mice of either sex. Firstly, a combination of patch-clamp recording and optogenetic stimulation in brain slices demonstrates that during this period exogenously applied histamine modulates both the intrinsic properties of developing D1 and D2 striatal spiny projection neurons (SPNs) and synaptic transmission at afferents coming from the mPFC and visual cortex. Secondly, immunohistochemistry for histamine reveals a brain region adjacent to the caudal striatum densely innervated by histaminergic axons and corresponding to the oval nucleus of bed nucleus of stria terminalis (ovBNST). Thirdly, electrical stimulation of the ovBNST leads to significant and detectable levels of histamine in striatum, as assessed by fast scan cyclic voltammetry and fluorescent histamine sensors in brain slices as well as in vivo. Lastly, electrical stimulation of the ovBNST nucleus, at frequencies mimicking normal active histamine neurons, can release sufficient levels of histamine to modulate excitatory synaptic transmission from mPFC onto striatal SPNs through histamine H3 receptors. Together, these results provide evidence for the existence of the ovBNST as an extrastriatal source of histamine during early brain development and postulates a new view of the modus operandi of histamine in that it can cross anatomical and functional boundaries and act as a paracrine neuromodulator.Significance statement The neuromodulator histamine is synthesized by neurons located in the tuberomammillary nucleus (TMN) of the hypothalamus and is released from their axons in many brain regions. There the histaminergic system regulates many key processes, and has been shown to be dysregulated in a variety of neurological and neurodevelopmental disorders. Key to understanding the physiological roles of histamine and to generate possible interventions when dysregulated is to know both the local sources of histamine and its mode of action. Using the striatum as an exemplar we provide here the first evidence that sources of histamine may lie outside of anatomical boundaries and that histamine can act as a paracrine neuromodulator during early brain development contrasting with many other neuromodulators.
Radiation cystitis is a common complication of pelvic radiotherapy that significantly compromises clinical outcomes. A principal pathogenic factor is the accumulation of cell-free DNA (cfDNA) released from damaged cells, which promotes inflammatory cytokine production and disturbs tissue homeostasis. The study aims to engineer a self-propelled nanozyme motor that clears cfDNA and restores redox balance as a dual-mechanistic therapy for radiation cystitis. The system operated using endogenous urea, a naturally abundant metabolite present in bladder urine, enabling sustained and coordinated autonomous propulsion following intravesical instillation. This mobility facilitated extensive mucosal coverage and deeper penetration, allowing the motors to capture cfDNA deposited on the irradiated mucosal surface. The nanozyme core eliminated radiation-induced reactive oxygen species, resulting in a reduction of oxidative stress. These combined effects suppressed activation of the cGAS-STING signaling pathway and lowered the release of pro-inflammatory cytokines. Both in vitro and in vivo investigations verified the anti-inflammatory activity of this platform, indicating its translational relevance for radiation cystitis treatment.
Micro(nano)plastics (MNPs) are emerging environmental contaminants, yet pharmaceuticals and medical procedures represent a distinct, direct exposure pathway that bypasses primary physiological barriers. This access, via intravenous administration, implants, or injections, is hypothesized to alter toxicokinetic profiles compared to environmental ingestion, representing a unique but unquantified risk. This review synthesizes current knowledge on MNPs introduced via pharmaceutical and clinical routes through a systematic analysis of 27 core studies identified from Web of Science, PubMed, Scopus, and Google Scholar. Our analysis reveals a bifurcated research landscape: one domain focuses on the intentional engineering of particles for drug delivery systems, while the other investigates unintentional contamination from clinical applications. A critical finding is the disconnection between exposure confirmation and hazard characterization. While studies confirm significant iatrogenic exposure, ranging from thousands of particles in intravenous fluids to millions released from degrading sutures, regulatory-relevant toxicological data linking these exposures to adverse human health outcomes are largely lacking. Furthermore, we identify a lack of standardization in analytical processes; methods vary between direct characterization of engineered particles and inconsistent isolation protocols for detecting contaminants in clinical matrices. Consequently, current evidence establishes the presence of iatrogenic MNPs but remains insufficient for robust risk assessment, underscoring the need for standardized analytical methods and foundational toxicological research to bridge the gap between exposure detection and safety management in healthcare.
Deep learning has driven major breakthroughs in protein structure prediction; however, one of the next critical steps forward is accurately predicting how proteins interact with small-molecule ligands, to enable real-world applications such as drug discovery. Recent cofolding methods aim to address this challenge, but evaluating their performance has been inconclusive because of the lack of relevant benchmarking datasets. Here we present a comprehensive evaluation of four leading all-atom cofolding methods using our newly introduced benchmark dataset, Runs N' Poses. Runs N' Poses comprises 2,600 high-resolution protein-ligand systems released after the training cutoff used by these methods. We demonstrate that current cofolding approaches largely memorize ligand poses from their training data, hindering their use for de novo drug design. With this assessment and benchmark dataset, we aim to accelerate progress in the field by allowing for a more realistic assessment of the current state-of-the-art deep learning methods for predicting protein-ligand interactions.
We present CaryaData, an image dataset of Chinese hickory (Carya cathayensis Sarg.) fruit maturity acquired in natural orchards in Zhejiang Province, China. The dataset comprises 1,661 canopy images (3024 × 3024 pixels) spanning key developmental stages from fruit enlargement to harvest. Within these images, 3,211 visually discernible fruit instances are annotated with axis-aligned bounding boxes and assigned to three maturity levels (maturity1-maturity3) or an unknown class for visually uncertain cases (labelled as unknown in the released annotations), based on pericarp colour, surface blemishes and cracking status. Data construction followed a rigorous quality-control workflow, including automated image quality filtering, standardised maturity interpretation, and a two-round annotation process with double-blind cross-validation of all images. To facilitate modelling and quantitative analysis, CaryaData also provides a derived subset uniformly resized to 640 × 640 pixels, together with image-level and instance-level metadata describing illumination, maturity composition and geometric properties of targets. Physical detachment force experiments confirmed the biological consistency of the maturity grading, and benchmark experiments showed that CaryaData supports deep learning-based fruit maturity assessment, offering a reusable resource for research on maturity evaluation, yield estimation and intelligent harvesting in Chinese hickory orchards.
Efficient delivery of therapeutic agents to target lesions persists as a significant challenge in cancer therapy. Herein, we report a biomimetic, near-infrared (NIR)/ultrasound (US)-responsive bifunctional drug delivery system that provides spatiotemporally programmed chemo-photodynamic therapy (PDT)/sonodynamic therapy (SDT) for prostate cancer. The designed formulation comprises reduction-sensitive nanogels encapsulated within RBC membranes, surface-functionalized with LHRH for targeted delivery (termed LHRH-RBC/Ce6-NG/HCPT). Chlorin e6 (Ce6), a photosensitizer and sonosensitizer, was embedded within the RBC membrane shell, while the anticancer compound 10-hydroxycamptothecin (HCPT) was encapsulated within the nanogel core structure of poly(L-glutamic acid)-poly(L-phenylalanine-co-L-cystine) nanogels. Compared with free Ce6 and HCPT, the designed formulation markedly extended systemic retention and improved intratumoral deposition. Furthermore, tumor‑localized NIR or US stimulation induced the production of reactive oxygen species (ROS), which enhanced nanovesicle uptake by increasing tumor cell membrane fluidity and concurrently disrupted the RBC membrane, leading to the rapid, intracellular glutathione-triggered release of HCPT. The released HCPT further synergized with PDT/SDT to amplify ROS generation and exacerbate mitochondrial dysfunction, thereby enhancing tumor cell killing. The spatiotemporally coupled dynamic-chemotherapy maximized on-tumor efficacy while minimizing off-target toxicity. In vivo studies confirmed that, LHRH-RBC/Ce6-NG/HCPT achieved potent synergistic effects in both PDT/chemotherapy and SDT/chemotherapy, demonstrating its potential as an effective and safe treatment strategy for prostate cancer.
In August 2025, an updated International Multidisciplinary Classification of Interstitial Pneumonias was released by the European Respiratory Society (ERS) and American Thoracic Society (ATS). For the first time, the "idiopathic-only" paradigm has been transcended through the integration of secondary interstitial lung diseases (ILD) into a unified framework. Grounded in recent advances in ILD research, major changes have been introduced to disease patterns, diagnostic terminology, subcategories, and diagnostic approach. Actual histopathologic findings are more accurately represented by the new schema, and clearer, more actionable guidance for patient management is provided to clinicians. The pathological dimensions of the update are highlighted herein, with key innovations outlined, newly introduced subcategories, terminologies, and categorization systems elucidated, and a systematic overview of the histological characteristics of major patterns offered. Additionally, the opportunities and challenges that the new classification presents to pathologists are discussed. 2025年8月，欧洲呼吸学会（European Respiratory Society，ERS）/美国胸科学会（American Thoracic Society，ATS）发布新版《间质性肺炎国际多学科分类》更新，首次突破“特发性”框架，将继发性间质性肺病纳入统一体系，并依据近年来间质性肺病的相关研究进展对疾病模式、诊断术语、亚类分组、诊断方法等作出重大调整。新分类更加贴近疾病实际病理学表现，也为临床治疗管理提供了更强的指导价值。本文将聚焦其中的病理相关内容，梳理核心变革，解读新增亚类、术语与分组设置，系统描述主要模式的组织学特征，并探讨更新给病理医师带来的机遇与挑战。.
Aerosolized or vaporized glycols have been proposed as a safe and low-cost measure for air sanitization, but limited information is available on their efficacy in real-world conditions. We evaluated 2 commercial glycol products, including a dipropylene glycol aerosol spray air sanitizer containing 30% to 60% ethanol and a triethylene glycol product released as a vapor over up to 48 hours. In a simulated patient room with 8 air changes per hour, we tested the efficacy of both products in reducing aerosolized bacteriophages Phi6 and MS2 in air and settling on disks, and the triethylene glycol vapor in reducing the viruses and bacterial pathogens and Candidozyma auris on steel disks. Both products significantly reduced recovery of the bacteriophages in air and significantly reduced recovery of bacteriophage Phi6, but not bacteriophage MS2, on settle disks. After 16 or 48 hours, the triethylene glycol vapor reduced recovery of Phi6, Acinetobacter baumanii, and C. auris by >1 log10, and reduced methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and Klebsiella pneumoniae by ~0.5 log10. The glycol products could be an effective adjunctive method to reduce airborne viruses, and with prolonged exposure might have a modest impact on surface contamination with bacteria and fungi.
Effective communication in health care is critical for treatment outcomes and adherence. With patient-provider exchanges shifting to secure messaging, analyzing electronic patient-communication (EPPC) data is both essential and challenging. We introduce EPPCMinerBen, a benchmark for evaluating LLMs in detecting communication patterns and extracting insights from electronic patient-provider messages. EPPCMinerBen includes three sub-tasks: Code Classification, Subcode Classification, and Evidence Extraction. Using 1933 expert-annotated sentences from 752 secure messages of the patient portal at Yale New Haven Hospital, it evaluates LLMs on identifying communicative intent and supporting text. Benchmarks span various LLMs under zero-shot and few-shot settings, with data to be released via the NCI Cancer Data Service. Model performance varied across tasks and settings. Llama-3.1-70B led in evidence extraction (F1: 82.84%) and performed well in classification. Llama-3.3-70b-Instruct outperformed all models in code classification (F1: 67.03%). DeepSeek-R1-Distill-Qwen-32B excelled in subcode classification (F1: 48.25%), while sdoh-llama-3-70B showed consistent performance. Smaller models underperformed, especially in subcode classification (>30% F1). Few-shot prompting improved most tasks. Our results indicate that large, instruction-tuned models tend to achieve higher performance in EPPCMinerBen tasks, particularly evidence extraction while smaller models struggle with fine-grained reasoning. EPPCMinerBen provides a benchmark for discourse-level understanding of patient-provider communication, supporting future work on structured communication analysis and model evaluation.
Cognitive deficits associated with chronic pain pose a significant burden on a patient's quality of life. Emerging evidence indicates that Toll-like receptor 4 (TLR4), a pattern recognition receptor implicated in neuroinflammatory signaling that can disrupt synaptic plasticity and memory processes. However, the specific involvement of TLR4 in the development of neuropathic pain-related cognitive deficits has not been fully elucidated. In this investigation, we observed an upregulation of TLR4 expression within hippocampal neurons in male mice subjected to chronic constriction injury (CCI) relative to sham group. Notably, in separate experimental cohorts, TLR4-knockout and neuron-specific TLR4-knockdown mice exhibited improved cognitive function compared to wild-type controls, alongside attenuated neuroinflammatory responses, reduced neuronal apoptosis, and enhanced preservation of hippocampal neuroplasticity. Concurrently, elevated concentrations of high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, were detected in the sciatic nerve, serum, and hippocampal tissues following CCI. Furthermore, increased co-localization of HMGB1 with TLR4 was evident in the hippocampus. Exogenous administration of HMGB1 augmented HMGB1 and TLR4 levels in the hippocampus and worsened memory functions that depend on hippocampal integrity. Conversely, inhibition of HMGB1 with glycyrrhizin, which subsequently attenuates TLR4 activation, ameliorated cognitive impairments induced by CCI. Collectively, these results support a model in which HMGB1, elevated during chronic neuropathic pain, contributes to cognitive deficits via a TLR4-dependent mechanism, triggering downstream inflammatory and apoptotic cascades and impairing synaptic plasticity.Significance Statement Chronic neuropathic pain is frequently accompanied by debilitating cognitive deficits, yet the underlying mechanisms linking peripheral nerve injury to central nervous system dysfunction remain poorly understood, hindering the development of targeted therapies. This study identifies the HMGB1/ TLR4 signaling axis as a critical mediator driving these cognitive impairments. We demonstrate that HMGB1, released after nerve injury, activates hippocampal TLR4, triggering neuroinflammation, neuronal apoptosis, and synaptic deficits. Importantly, genetic deletion or neuronal-specific knockdown of TLR4, as well as pharmacological inhibition of the HMGB1/TLR4 interaction, rescues cognitive function. These findings elucidate a precise molecular pathway connecting peripheral neuropathic pain to cognitive decline and establish the HMGB1/TLR4 axis as a promising therapeutic target for preventing or treating pain-associated cognitive dysfunction.
Astrocytic Ca2+ activity is crucial for maintaining normal brain function. However, the pathophysiological role of astrocytes in the context of addictive drugs remains largely unknown. Taking advantage of two-photon Ca2+ imaging in awake mice, we show that a physiologically relevant level of cocaine induces synchronized and hyperactive Ca2+ signals in frontal cortical astrocytes. Mechanistically, this process occurs primarily through the volume release of norepinephrine from locus coeruleus innervation, followed by the activation of Gq-coupled α1 adrenergic receptors in the prefrontal cortex and the subsequent IP3R2-dependent store Ca2+ release, thus causing hyperactive Ca2+ fluctuations in astrocytes. Importantly, interrupting the hyperactive astrocytic Ca2+ signals either by blocking store Ca2+ release or by conditionally knocking out the astrocytic α1AR rescued FrA neuronal activity and aggravated cocaine-induced locomotor sensitization. These findings revealed that, in addition to neurons, astrocytes can be super-activated by cocaine through the crosstalk between norepinephrine nerves and glia, providing a new perspective for the understanding and clinical treatment of cocaine addiction.
Low-level laser therapy (LLLT) is being increasingly applied in regenerative medicine due to its ability to modulate cellular metabolism and support repair processes. However, the effect of various exposure parameters on fibroblast activity still does not remain fully understood. The study aim was to evaluate the effect of selected LLLT parameters (808 nm, 100 and 200 mW, 2 and 10 J/cm², pulsed beam) on the biological activity of fibroblasts in vitro. Fibroblasts were exposed to the established exposure parameters, and then the number of adherent and metabolically active cells, their migration, adenylate kinase (AK) as well as nitric oxide (NO) levels, cytokine secretion, metalloproteinase (MMP-2, MMP-9) activity, and oxidative-antioxidant potential were assessed. The most favourable effects were achieved with 200 mW; 2 J/cm² and 100 m; 10 J/cm² exposure parameters. In these conditions, increased number of adherent and metabolically active cells, and elevated migration were observed. Moreover, in this condition decreased AK release and NO secretion were found. Furthermore, LLLT reduced in fibroblasts interleukin 6 (IL-6) and interleukin 8 (IL-8) secretion as well as affected the activity of metalloproteinases, what corresponded with subsequent wound healing process. Additionally, a beneficial effect on maintaining the oxidative-antioxidant balance in fibroblasts was noted. In summary, the effects of LLLT on fibroblasts depend on the applied irradiation parameters, and appropriately selected LLLT treatment (200 mW; 2 J/cm² and 100 mW; 10 J/cm²,) stabilise fibroblast metabolism, limits their proinflammatory response and promotes extracellular matrix remodelling (ECM). These results confirm the potential of LLLT as an effective method supporting regenerative processes in the treatment of tissue damage.
Alzheimer's disease (AD) is a neurodegenerative condition marked by amyloid β (Aβ) plaque accumulation, contributing to cognitive decline. Epigallocatechin (EGC) has shown potential in preventing Aβ aggregation and disrupting fibrils, but its low bioavailability and poor blood-brain barrier (BBB) penetration limit its therapeutic use. To address these challenges, this study introduces the first functionalized nanosystem developed for the EGC delivery. Liposomal EGC was optimized and conjugated with transferrin (Tf), given literature evidence supporting its potential role in BBB-targeting strategies. The optimal formulation exhibited a mean diameter of 127 ± 14 nm, a polydispersity index of 0.20 ± 0.02, a zeta potential of -0.9 ± 0.3 mV, and an encapsulation efficiency of 20 ± 3%, properties that were maintained after 1 month of storage at 4 °C. Moreover, the nanosystem exhibited a controlled and sustained release, achieving 77 ± 11% release over 9 days. In terms of therapeutic activity, the nanoformulation showed an antioxidant capacity of 53 ± 6%, demonstrating its potential to neutralize free radicals, a key factor in AD progression. Furthermore, targeted liposomal EGC completely inhibited Aβ fibrillation, as demonstrated by thioflavin T assays. Data revealed a reduction in parallel β-sheet content from 44 ± 4% to 33 ± 5% and an increase in α-helices from 31 ± 5 to 45 ± 4%, suggesting inhibition of fibril formation. Additionally, Tf conjugation enhanced liposome uptake by endothelial cells without inducing cytotoxicity. These findings support the potential of this nanosystem as a promising platform for further investigation in AD.
Myocardial infarction (MI) often leads to adverse ventricular remodeling, a major precursor to heart failure, while current clinical approaches remain limited in effectively promoting myocardial regeneration and suppressing fibrosis. To address these challenges, we developed an injectable, smart-responsive hydrogel integrated with catalytic nanozyme and conductive components for synergistic MI repair. The hydrogel is constructed using phenylboronic acid-modified oxidized hyaluronic acid (OHA-PBA) and dopamine-grafted gelatin (GelDA) as the backbone, cross-linked via dynamic Schiff base and boronate ester bonds, conferring rapid self-healing and specific MI microenvironment-responsive properties. This biomimetic network not only replicates the structure and function of the native extracellular matrix but also responds specifically to the acidic and highly reactive oxygen species (ROS) microenvironment within the infarcted zone, enabling on-demand drug release. Incorporated into the hydrogel are black phosphorus nanosheets (BP Ns) to restore electrical conductivity, and puerarin-loaded honeycomb-like manganese dioxide nanozymes (PHMP NPs) that act as both ROS scavengers and in situ oxygen generators. Together, these components work synergistically to promote angiogenesis, alleviate local hypoxia, and reestablish blood and oxygen supply to the ischemic tissue. This integrated platform thus concurrently delivers mechanical support, restores electrical signaling, alleviates hypoxia, and combines antioxidant, anti-inflammatory, pro-angiogenic, and anti-fibrotic capabilities, offering a comprehensive multi-target therapeutic strategy for MI. Both in vitro and in vivo evaluations demonstrate that the developed hydrogel can effectively inhibit pathological ventricular remodeling, enhance vascularization, and modulate inflammatory responses, with histopathological and transcriptomic analyses further confirming these therapeutic effects, thereby significantly promoting the recovery of cardiac functions and offering a promising and advanced therapeutic strategy for MI treatment. STATEMENT OF SIGNIFICANCE: This work presents an injectable hydrogel platform that uniquely integrates electrical conductivity, catalytic oxygen generation, and smart microenvironment responsiveness for myocardial infarction (MI) therapy. Its significance lies in overcoming the limitation of current single-target approaches by enabling a synergistic multi-functional therapy. The system simultaneously restores electrical conduction, scavenges reactive oxygen species, alleviates hypoxia, and inhibits fibrosis within the infarcted heart. This integrated biomaterial strategy establishes a new paradigm for addressing the complex pathophysiology of MI, offering broad interest to researchers in biomaterials science, cardiac tissue engineering, and regenerative medicine.
Growth factors selectively activate calcium signaling pathways in the cell nucleus, which in turn regulate gene transcription and other intranuclear events, but the specific way this is accomplished is not entirely understood. Growth factors increase inositol 1,4,5-trisphosphate (IP3) in the nucleus, which in turn releases calcium from intranuclear IP3 receptors (ITPRs), and the present study shows that this leads to transient assembly of an actin nucleoskeleton that associates with intranuclear non-muscle myosin 2A (MYH9). Mass spectrometry suggests that much of the MYH9 cargo consists of components of the gene transcription machinery, and chromatin immunoprecipitation identified a number of specific genes that associate with the myosin in response to stimulation with growth factors. Together, these findings suggest that growth factors initiate gene transcription by transiently assembling an actin nucleoskeleton that works with MYH9 to bring specific genes to the transcription machinery.
Ferroptosis is a form of regulated cell death characterized by dysregulated iron metabolism and accumulation of lipid peroxides, which is closely associated with various pathological conditions. Hypoxia-inducible factor 1α (HIF-1α), as the principal subunit of the hypoxia-inducible transcription factor complex, controls the balance between iron homeostasis and antioxidant defense system within the hypoxic microenvironment. In oncology, PI3K/AKT signaling pathway of some tumor cells is amplified to activate HIF-1α. Then HIF-1α upregulate the SLC7A11/GPX4 axis to evade cell death. Restoration of ferroptosis signaling through pharmacological or genetic approaches, triggers iron accumulation and the production of lipid reactive oxygen species (ROS). However, this will lead to immunogenic cell death and subsequent tumor regression. In neurodegenerative disorders, excessive iron deposition in neurons occurs and coupled with compromised antioxidant defenses. As a result, ferroptosis becomes a key pathogenic mechanism in neurodegenerative disorders. In renal pathology: activation of HIF-1α suppresses GPX4 activity to mitigate lipid ROS during acute kidney injury, thereby exerting protective effects. Under conditions of chronic diabetic hypoxia, upregulation of heme oxygenase-1 (HO-1) promotes iron release, exacerbating tubular ferroptosis and accelerating fibrotic progression. Context-specific manifestations of ferroptosis are found in various systemic diseases, where its biological outcomes are determined by the dynamic equilibrium between iron homeostasis and antioxidant mechanisms. Despite compounds targeting HIF-1α have demonstrated therapeutic potential in ferroptosis-related diseases, specialized treatment strategies still depend on the underlying pathological context. Therefore, a systematic summary of the existing molecular mechanisms and discovering new mechanisms of HIF-1α regulates ferroptosis will greatly enhance our understanding of ferroptosis-related diseases, providing novel insights for precise therapeutic approaches.
Platinum (Pt)-based chemotherapy has served for decades as the foundation of ovarian cancer therapy. Yet, its gains are always undermined by severe toxic side effects and drug resistance. Although a new generation of therapy - including anti-angiogenic drugs, PARP inhibitors, ADCs, and immune checkpoint inhibitors- has emerged, issues of costs and patient stratification have limited their use as first line treatment. Hence, platinum-based drugs won't be easily surpassed by newer modalities in the immediate future, thus providing a window of opportunities to make them work more efficiently. This review re-evaluates the future of platinum therapies by exploring key strategies to counteract resistance mediated by intracellular mechanisms and the complex tumour microenvironment. One approach includes converting non-specific and reactive FDA-approved Pt(II) agents into the next-generation Pt(IV) prodrugs, which are stable, single/dual/multi-action or stimuli-triggered agents that become activated only inside target cells, releasing their original Pt(II) counterparts and two additional axial ligands. A second approach includes the development of advanced nanoscale delivery systems to enhance the amount of chemotherapeutic reaching the tumour site while minimizing off target effects. These nanotechnology platforms span from liposomes to virus-like particles and can be engineered to bypass biological obstacles while avoiding premature elimination from the body, even though they are associated with immunogenic reactions. By uniting advances in platinum chemistry with the precision offered by modern nanotechnology, a new therapeutic paradigm emerges-one that can enhance efficacy, reduce systemic toxicity, and offer a more accessible alternative to costly biologics, thereby securing a renewed and enduring role for platinum in ovarian cancer treatment.
Sepsis-induced acute respiratory distress syndrome (ARDS) is characterized by uncontrolled pulmonary inflammation and neutrophil-driven pathology. Neutrophil extracellular traps (NETs) have been implicated in ARDS progression, but the role of interleukin-36 (IL-36) in this process remains unclear. This study aimed to investigate the regulatory mechanism of IL-36 via NETs and its impact on NF-κB activation in a murine model of LPS-induced ARDS. A lipopolysaccharide (LPS)-induced ARDS model was established in C57BL/6 mice. Animals were divided into Control, ARDS, ARDS + IL-36, and ARDS + IL-36Ra groups. Pulmonary edema was assessed via wet/dry weight ratio, inflammatory cytokines were measured by ELISA, and histopathological changes were evaluated through H&E staining. NETs formation was analyzed using immunofluorescence and Western blot. NF-κB activation was detected via phosphorylation of p65. IL-36 administration exacerbated pulmonary edema, inflammatory cytokine levels (IL-10,TNF-α,MPO) and histopathological injury. Conversely, IL-36 receptor antagonist (IL-36Ra) attenuated these effects. IL-36 promoted NETs formation, as indicated by elevated citrullinated histone H3 (CitH3) and neutrophil elastase (NE) expression. NETs further enhanced IL-36-induced proinflammatory cytokine release and NF-κB activation in bronchial epithelial cells. IL-36Ra partially reversed NET-mediated NF-κB phosphorylation and inflammatory responses. IL-36 exacerbates LPS-induced ARDS by enhancing NETs formation and activating the NF-κB pathway, leading to amplified pulmonary inflammation and injury. Targeting IL-36 signaling may represent a potential therapeutic strategy to mitigate LPS-induced ARDS progression.
Bovine tuberculosis (bTB), caused by Mycobacterium bovis, is a zoonosis that threatens public health and causes substantial economic losses in livestock. The suboptimal Escherichia coli-expressed recombinant proteins limit the diagnostic performance of current bTB serological tests. To overcome this limitation, we evaluated Mycolicibacterium smegmatis as an expression host capable of producing recombinant antigens with post-translational modifications comparable to those of M. bovis. Ten antigen candidates were individually expressed in E. coli using the pET-26b( +) vector and in M. smegmatis using the pSOΔBam vector. Their diagnostic performance was evaluated using an enzyme-linked immunosorbent assay (ELISA) with plasma samples from interferon-gamma release assay (IGRA)-negative (n = 30) and -positive (n = 46) cattle in South Korea, followed by receiver operating characteristic (ROC) curve analysis. Among the single antigens, LprA expressed in M. smegmatis demonstrated diagnostic performance comparable to that of the well-established antigen MPB70 (sensitivity: 50.0%, specificity: 96.6%, AUC: 0.791). In addition, several M. smegmatis-derived antigens showed higher concordance with the IGRA results, as assessed by Cohen's kappa and Fisher's exact tests, and a stronger association between age and antigen-specific antibody responses was observed among IGRA-positive cattle. Moreover, a multiple logistic regression model incorporating eight antigens, including those derived from both hosts, achieved high predictive accuracy for IGRA results (sensitivity: 87.0%, specificity: 100%, AUC: 0.991). These findings suggest that M. smegmatis is a promising host for identifying novel antigens and that a multi-host strategy may improve bTB serodiagnosis.