搜索结果：Molecular Medicine

Photothermal therapy (PTT) holds transformative potential for precision cancer treatment, yet clinical translation remains constrained by the scarcity of molecularly defined, biocompatible, and efficiently NIR-absorbing photothermal agents (PTAs). Here we report a rational donor-acceptor-donor (D-A-D) framework that delivers ultrasmall organic PTAs with record photothermal conversion efficiencies (49.8%) and intrinsic immunogenic cell death (ICD) activity. The design exploits 6,7-diphenyl-[1,2,5]thiadiazolo[3,4-g]quinoxaline as a π-extended, multi-nitrogenated acceptor core flanked by trifluoromethyl groups to deepen the LUMO, while methoxylated triphenylamine donors intensify intramolecular charge-transfer and suppress radiative decay. Nanoprecipitation furnishes monodisperse nanoparticles that exhibit intense NIR-II absorption, exceptional photostability across five hyperthermic cycles, and lysosome-directed uptake. In vitro, single-dose FTPA NPs plus 808-nm laser irradiation trigger mitochondrial depolarization, G0/G1 arrest, and apoptosis in > 70% of 4T1 cells while releasing abundant ATP and surface calreticulin-canonical ICD signals. A prophylactic vaccination model corroborates these molecular cues: mice primed with FTPA-NP-treated tumor cells reject contralateral challenge, achieving > 90% long-term survival, expansion of cytotoxic CD8+ T cells (≈ 70% activation), and suppression of Tregs (≈ 3%). No systemic toxicity or off-target pathology is observed. This study establishes a chemically tunable, metal-free PTA platform that synergizes thermal ablation with systemic anti-tumor immunity, providing a versatile scaffold for next-generation precision immuno-photothermal medicine.

Eimeria necatrix, a member of the Apicomplexa phylum, is one of the most pathogenic parasites, causing high mortality in chickens. Microneme proteins (MICs) play essential roles in host cell recognition and invasion by apicomplexan parasites and are also attractive candidates for vaccine development. However, comprehensive studies on E. necatrix MICs remain limited. Eimeria necatrix MIC3 gene (EnMIC3) was amplified and expressed in Escherichia coli. The recombinant protein (rEnMIC3) was characterized via SDS-PAGE and Western blot. The antigenicity of rEnMIC3 and its localization in sporozoites (SZ) and second-generation merozoites (MZ-2) of E. necatrix were determined by Western blot and indirect immunofluorescence analyses (IFAs). The dynamic expression of EnMIC3 across different developmental stages and its impact on sporozoite invasion of host cells were analyzed. The immune protection provided by rEnMIC3 was evaluated in chickens using weight gain, lesion scores, oocyst production, anticoccidial index (ACI), and antibody levels. The open reading frame of EnMIC3 was 798 bp, encoding a 265-amino acid protein with a predicted molecular weight of 28.50 kDa. EnMIC3 contained a signal peptide and a single epidermal growth factor (EGF)-like domain. The rEnMIC3 with an approximate molecular weight of 36 kDa could be specifically recognized by convalescent sera from chickens infected with E. necatrix. The molecular mass of the native protein was approximately 35 kDa, and it localizes to the apical region in SZ but exhibits a cytoplasmic distribution in MZ-2. EnMIC3 mRNA was expressed at significantly higher levels in SZ than in MZ-2, whereas protein expression displayed an inverse pattern. Anti-rEnMIC3 polyclonal antibodies inhibited sporozoite invasion of DF-1 cells in a dose-dependent manner. Vaccination with rEnMIC3 conferred effective protection against E. necatrix challenge, with the high-dose group (200 µg) achieving the highest ACI value (171.32) and markedly elevated serum antibody levels. These findings not only offer a foundation for understanding the role of EnMIC3 protein in the host invasion of E. necatrix but also present a potential protective antigen of E. necatrix for the development of a subunit vaccine against avian coccidiosis.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, affecting nearly 0.3% of the global population. Its pathology is primarily linked to dopaminergic neuronal loss in the substantia nigra, leading to hallmark motor impairments such as tremor, rigidity, and bradykinesia. A defining molecular feature of PD is the aberrant aggregation of α-synuclein, alongside dysregulation of proteins such as MAO-B, COMT, and LRRK2, which collectively contribute to disease progression. Within the current research, these proteins were designated as docking targets to explore the enzyme-modulating activity and the therapeutic promise of steroidal alkaloid candidates from the genus Fritillaria, a taxon long recognized in traditional medicine for its neuroprotective properties. Docking analyses revealed that among 70 compounds analysed, compound 65 exhibited strong MAO-B inhibitory activity (binding energy - 11 kcal/mol), compound 5 demonstrated pronounced COMT inhibition (- 9 kcal/mol), and compound 42 emerged as a promising dual-acting agent capable of targeting both enzymes. Favorable physicochemical attributes, including optimal lipophilicity, low polar surface area, and blood-brain barrier permeability, further support their suitability. These findings identify preliminary computational leads that warrant further experimental validation for potential future development.

Reptiles often inhabit environments that are in close proximity to humans and livestock, creating opportunities for parasite transmission. They are common in areas where they find shelter, food and warmth. The Bengal monitor lizard (Varanus bengalensis), a member of the family Varanidae, represents one of the largest groups of extant poikilothermic predators. Monitor lizards are known to harbor several tick species that serve as vectors for a variety of pathogens. No prior information is available in the literature regarding ticks infesting V. bengalensis in Pakistan as well as regarding the occurrence of Toxoplasma gondii in these ticks. Therefore, we aimed to determine the molecular prevalence of T. gondii in Amblyomma gervaisi ticks (n = 93) collected from 24 V. bengalensis in Buner District, Khyber Pakhtunkhwa Province, Pakistan, between May and September 2023. Polymerase chain reaction (PCR) amplified a 300 bp fragment specific for the ITS-1 region of T. gondii in 10 of the 93 (11%) A. gervaisi ticks. DNA sequencing and BLAST analysis confirmed the presence of T. gondii. Phylogenetic analysis showed that these sequences clustered with the ITS-1 sequences of T. gondii detected in reptiles and mammals from Pakistan, Brazil, China, Tunisia and Portugal. The prevalence of T. gondii in A. gervaisi was not limited to a specific tick sex, feeding stage or month of sampling. However, among the tick developmental stages, nymphs had the highest rate of T. gondii infection. In conclusion, for the very first time from Pakistan, we are reporting the presence of T. gondii in A. gervaisi that were infesting monitor lizards. We recommend that similar and large scale studies should be conducted in all those areas of Pakistan that are unexplored for the presence of T. gondii in A. gervaisi ticks. Prevalence of this parasite should also be screened in all the animals harboring these as well as other tick species. This will help in better understanding of T. gondii transmission to new hosts that will lead toward its effective control.

The BK (big potassium, MaxiK) channel is a potassium channel of large conductance gated by calcium (Ca2+) and voltage. Formed by a homotetramer of alpha (slo1) subunits, this channel plays a major role in numerous physiological systems and processes. Consistently, BK channel expression and function are regulated by a variety of endogenous ligands. In particular, the activity of homotetrameric channels made of slo1 subunits is inhibited by cholesterol (CLR). However, it remains unknown whether BK channel inhibition involves direct chemical binding of CLR molecules to the slo1 protein, or results from allosteric coupling between slo1 and CLR binding elsewhere, such as the lipid bilayer. Here, we demonstrate by equilibrium dialysis that CLR binds slo1 proteins cloned from rat cerebral artery myocytes (cbv1) in both the absence and presence of activating Ca2+. This binding is saturable with a KD of 1.0-1.2 mM and requires the physical association between the cbv1 transmembrane core and its cytosolic tail domain (CTD). Moreover, F substitution of Y450, a CTD residue located nearby the membrane inner leaflet, abolishes CLR binding independent of Ca2+. Remarkably, cbv1Y450F protein intrinsic fluorescence is unaffected by Ca2+, suggesting that Y450 contributes to Ca2+ sensing by cbv1. In summary, the present study demonstrates for the first time direct binding of CLR to slo1 channels and underscores the critical role of Y450 in such binding and in Ca2+ sensing of slo1 channels.

Allexiviruses (family Alphaflexiviridae) are widespread pathogens of vegetatively propagated allium crops, but their occurrence has not previously been documented in Ukraine. We surveyed cultivated allium plants collected in eight Ukrainian regions (2022-2025) and screened their samples for garlic virus B (GarV-B), garlic virus C (GarV-C) and shallot virus X (ShVX) using enzyme-linked immunosorbent assay (ELISA). GarV-B, GarV-C and ShVX were detected in 39/108 (36.1%), 23/108 (21.3%) and 21/108 (19.4%) plants, respectively, with infections which were strongly host-associated: garlic (n = 63) had high frequencies of indicated viruses (GarV-B-61.9%; GarV-C-36.5%; ShVX-28.6%), whereas onion samples (n = 33) were largely negative (ShVX-3.0%; GarV-B and GarV-C-not detected). Co-occurrence analysis within garlic revealed a nested allexivirus module in which GarV-C and ShVX occurred only in GarV-B-positive plants. RT-PCR and Sanger sequencing generated 11 partial genomes representing GarV-B, GarV-C, ShVX, GarV-A and GarV-D. Maximum-likelihood phylogenies placed Ukrainian allexivirus isolates within established global diversity and indicated both European- and Asian-affiliated lineages. These findings provide the first evidence of allexiviruses in Ukrainian allium crops, and support their inclusion in plant health surveillance and planting-material certification.

The metabolic enzyme lactate dehydrogenase C4 (LDHC4) is aberrantly expressed in cancers and linked to poor prognosis. However, its role in lung adenocarcinoma (LUAD) and the molecular mechanisms beyond glycolysis remain unclear. This study investigates whether LDHC4 promotes LUAD by modulating protein lactylation, a lactate-derived post-translational modification, focusing on the tumor suppressor retinoblastoma protein (RB1). LDHC4 expression and its correlation with clinicopathological features and survival were analyzed using public databases (UALCAN, Kaplan-Meier Plotter, LOGpc) and validated in a cohort of 90 paired LUAD tissues via immunohistochemistry. The functional impact of LDHC4 on proliferation, migration, and invasion was assessed in A549 and PC-9 cells using gain- and loss-of-function models. The global lactylation profile was analyzed using DIA-based lactylation proteomics on the Astral platform. The interaction between RB1 and E2F1 (E2F transcription factor 1) was examined through molecular dynamics simulations, co-immunoprecipitation (Co-IP), and immunofluorescence. The functional consequences of site-specific RB1 lactylation at lysine 900 (RB1-K900lac) were determined using RB1-K900R mutant constructs and cell cycle analysis. LDHC4 was significantly overexpressed in LUAD tissues, correlating with poor patient survival, and was an independent prognostic risk factor. In vitro, LDHC4 promoted LUAD cell proliferation, migration, and invasion, and its tumor-promoting role was corroborated in an LUAD xenograft model, in which derived tumors exhibited increased volume and weight compared with mock-transfected controls. Mechanistically, LDHC4 overexpression elevated global protein lactylation levels and specifically increased lactylation of RB1. Bioinformatics and molecular dynamics simulations identified K900 as a key conserved residue for RB1-E2F1 binding; its lactylation destabilized the complex by increasing structural fluctuation and weakening intermolecular interactions. Cellular experiments confirmed that the lactylation-resistant RB1-K900R mutant bound E2F1 more strongly than wild-type RB1. Functionally, cells expressing RB1-K900R exhibited suppressed malignant phenotypes and G1/S cell cycle arrest, accompanied by downregulation of CDKs/cyclins and upregulation of P21. This study uncovers a novel LDHC4-driven oncogenic axis in LUAD. LDHC4 facilitates RB1 lactylation at the K900 residue, which disrupts the RB1-E2F1 tumor-suppressive complex, leading to cell cycle dysregulation and tumor progression. These findings may position the "LDHC4-RB1 lactylation" axis as a promising therapeutic target for LUAD.

Pancreatic ductal adenocarcinoma (PDAC) is frequently preceded by new-onset diabetes mellitus (NODM), yet differentiating PDAC-associated DM from type 2 diabetes (T2D) remains clinically challenging. We investigated whether plasma proteomic profiling combined with machine learning could discriminate these conditions. Plasma samples from individuals with PDAC (with and without DM), long-standing T2D, and controls were analyzed by MALDI-TOF mass spectrometry. Spectral features were processed through a nested cross-validation framework to prevent data leakage, and model interpretability was explored using SHAP values. In parallel, low-molecular-weight proteins were characterized by GeLC-MS followed by LC-MS/MS and differential abundance analysis. Machine learning models distinguished PDAC-associated DM from T2D with a balanced accuracy of 85%. Proteomic analyses identified distinct signatures in PDAC- associated DM, including downregulation of erythrocyte-related proteins and PPBP, and upregulation of acute-phase reactants such as FGA, CP, and SERPINA3. Treatment-naïve cases displayed increased circulating epithelial and keratin-associated proteins, which were attenuated after therapy, suggesting dynamic tumor-related remodeling. These findings demonstrate that integrating MALDI-TOF profiling with machine learning can capture plasma signatures associated with PDAC-associated DM. Although exploratory, this approach supports further validation in prospective cohorts aimed at improving PDAC risk stratification among individuals with NODM. SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a dismal 5-year survival rate, primarily due to late-stage diagnosis. The frequent occurrence of new-onset diabetes mellitus (NODM) as a paraneoplastic syndrome offers a critical window for early detection. However, the clinical challenge of distinguishing PDAC-associated diabetes (PDAC-DM) from type 2 diabetes mellitus (T2D) has hindered the implementation of effective screening strategies. This study addresses this significant clinical problem by leveraging a multi-faceted proteomics approach. We demonstrate that the integration of MALDI-TOF mass spectrometry peptide profiling with machine learning algorithms can accurately discriminate PDAC-DM from T2D with 85% accuracy. Furthermore, we used LC-MS/MS to identify specific low molecular weight proteins that are differentially regulated between these conditions, providing a molecular basis for the observed discrimination. Our work is significant as it presents a novel, high-throughput pipeline for biomarker discovery that combines the scalability of MALDI-TOF with the analytical power of LC-MS/MS and machine learning. The identified plasma signatures hold strong translational potential to improve risk stratification in patients with new-onset diabetes, ultimately enabling earlier diagnosis of PDAC and improving patient survival prospects. This research directly contributes to the field of clinical proteomics by providing a robust methodological framework and candidate biomarkers for the early detection of one of oncology's most challenging diseases.

Itch is a complex noxious sensation associated with many skin and systemic conditions, which varies in intensity and quality across different body regions. Despite its prevalence, the molecular and cellular mechanisms underlying regional itch differences remain poorly understood. Investigating the neural basis of regional itch differences, we identified a functional divergence in neuropeptide signaling and central circuit engagement between the trigeminal and spinal systems, which was independent of peripheral innervation density. Utilizing a combination of behavioral, pharmacological, genetic, and molecular assays, we identified a unique population of trigeminal (TG) neurons that facilitate specialized itch-pain coding. Our results indicate that while histamine receptors HRH1 and HRH3 are both involved in mediating mixed itch-and-pain sensations, the specific activity of Substance P (SP)- and Somatostatin (SST)-expressing neurons orchestrates this transition in the cheek. This behavioral shift is mediated by a central mechanism wherein sensory neurons activation recruits distinct nociceptive circuits within the brainstem. In brief, these findings provide insights into the molecular and cellular mechanisms underlying regional itch differences, highlighting the importance of considering anatomical location when developing targeted treatments.

Restless Legs Syndrome (RLS) is a sleep disorder characterized by the urge to move, primarily affecting the legs, especially during rest and at night, leading to difficulty or inability to initiate and maintain sleep. Exercise is a strategy that can improve symptoms; however, it remains underexplored. In this context, the aim of this study was to evaluate the effects of chronic aerobic exercise on sleep and on dopamine, adenosine, and glutamate systems in an iron-deficient animal model of Restless Legs Syndrome (RLS). Male Wistar rats were assigned to a control group (CTRL, standard diet), an iron-deficient group (ID, iron-restricted diet), an exercised control group (CTRLEX), and an exercised iron-deficient group (IDEX). After 9 weeks of diet, the exercise groups underwent treadmill running for four weeks, followed by sleep (electrocorticographic and electromyographic activity) and molecular (western blotting, PCR and ELISA) analyses. The ID group showed impairments in all expected sleep parameters associated with RLS, including reduced total sleep time and sleep efficiency, along with increased wakefulness, arousals, and limb movements compared with CTRL. In contrast, the IDEX group showed improvements in all these parameters compared with ID. Additionally, exercise increased dopamine transporter (DAT) and adenosine A1 receptor (A1R) levels, which may underlie the observed symptom improvements. These findings highlight the potential of physical exercise as a non-pharmacological treatment for sleep problems associated with RLS and provide insights into possible molecular pathways underlying these improvements.

Macrophages are central regulators of skeletal muscle regeneration, dynamically transitioning from pro-inflammatory (M1-like) to reparative (M2-like) phenotypes to coordinate debris clearance, inflammation modulation, satellite cell activation, and tissue remodeling. This review details the underlying molecular mechanisms, focusing on metabolic reprogramming, such as the shift to oxidative phosphorylation and key roles of AMPK, lactate, and glutamine metabolism. It further examines the transcriptional networks (e.g., PPARγ, Nfix) and multicellular crosstalk that shape the regenerative niche. We analyze macrophage dysfunction in pathological contexts: aging-related impairments in dynamics and metabolism that hinder repair, and in Duchenne Muscular Dystrophy (DMD), where sustained inflammation and trained immunity drive fibrosis. Current challenges include deciphering macrophage heterogeneity beyond the M1-like/M2-like paradigm and bridging translational gaps between models and human disease. The review outlines therapeutic strategies to reprogram macrophage function, spanning pharmacological agents (AMPK/PPARγ agonists, cytokine/chemokine modulation), nanotechnology, cell therapies (e.g., exosomes), and physical interventions. A key feature is the integration of molecular docking analyses, revealing structural interactions between compounds (e.g., AICAR, Cenicriviroc) and targets like AMPK, PPARγ, CCR2, and CCR5. This provides a structural pharmacology foundation for developing targeted immunometabolic therapies to restore muscle regeneration in injury and degenerative diseases.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive cytopenias, splenomegaly, and constitutional symptoms. The hallmark of MF pathophysiology is constitutive activation of JAK/STAT signaling, which, in the majority of cases, is associated with an acquired mutation in one of three driver mutations, JAK2, CALR, or MPL. Our growing understanding of the molecular biology of MPNs has resulted in regulatory approval of four JAK inhibitors (JAKi), which have demonstrated efficacy in improving symptom burden and reducing spleen size. Despite clear benefits of JAKi therapy, including evidence of improved survival, these therapeutic interventions have not established an ability to modify disease in terms of resolution of bone marrow fibrosis or molecular remissions. Therefore, recent emphasis has been on the development of novel therapies with informed targets outside of the JAK/STAT signaling pathway. Moreover, combination approaches utilizing JAK and non-JAK targeting agents underscore the potential for disease modification along with deeper and more durable clinical responses. Emerging combination strategies and their clinical development will be reviewed here, including investigations that pair JAKi therapy with BCL-2 family inhibitors, BET inhibitors, restored p53 cell death signals, telomerase inhibitors, PIM1 kinase inhibitors, and mutant CALR targeted therapies. While several combination clinical trials suggest improved spleen and symptom responses and the possibility of disease modification, toxicity profiles and optimal sequencing remain areas of active investigation.

To identify, characterize and determine the frequency of MED-12 exon 2 mutations in the uterine leiomyomas (ULs) of Nigerian women. MED-12 mutations are the most common molecular subtype of uterine leiomyomas and have been linked with ULs in Western populations. The frequency of MED-12 mutations among Nigerian women has not been established. Cross-sectional study. Nigerian women with uterine leiomyomas undergoing myomectomy. Fibroid weight and other characteristics such as age, weight, BMI, parity and age at menarche. Identification and frequency of MED-12 mutations. DNA was extracted from the fibroid and adjacent myometrial tissues, and the MED-12 gene (exon 2) was amplified by PCR, followed by Sanger sequencing. The sequencing data showed that 54.9% (56/102) of the fibroid tissues had MED-12 mutations compared with the adjacent myometrium. Of this percentage, 49.01% was found in codon 44, and c.131 G>A was the most frequent (24.51%), followed by c.130 G>C (5.88%). Other mutations were found in codons 43 (c.128 A>C) and 36 (c.107 T>G). Three samples had a mutation at intron 1 (c.100-8T>A). In summary, we identified 11 variants at four positions. Further computational prediction analysis showed that of the 11 variants, only 27.3% were tolerated, and all variants were either disease-causing, passenger mutations or probably damaging. However, there was no significant difference between the characteristics of the women whose ULs were MED-12 positive and negative. Our study represents the first comprehensive analysis of MED-12 mutations in ULs of Nigerian women. This study indicates that analyzing MED-12 mutations in ULs of Nigerian women is essential for clinical practice and informing precision medicine for Nigerian women with ULs.

Therapeutic plasma exchange (TPE) is being increasingly utilized in the clinical management of severe rheumatic immune diseases, providing an effective means for rapidly removing pathogenic autoantibodies and inflammatory mediators. However, the non-selective nature of this technique can also lead to the unintended clearance of concomitantly administered antirheumatic drugs, potentially compromising therapeutic efficacy and disease control. Therefore, effective management of potential drug removal process during TPE and the implementation of individualized risk assessment are crucial for optimizing treatment outcomes in patients undergoing TPE. The variability in the extent of drug removal during TPE is primarily determined by their distinct pharmacokinetic characteristics, necessitating the establishment of a systematic, evidence-based strategy for adjusting drug administration regimens in patients receiving TPE treatment. This review synthesizes current evidence from 65 studies on the removal of antirheumatic drugs during TPE, identifying key determinants influencing clearance rates, including volume of distribution, protein binding, molecular size, and elimination half-life. Our analysis reveals that the risk of drug removal exists as a continuous spectrum: large monoclonal antibodies (e.g., rituximab, natalizumab), characterized by a large molecule size, low volume of distribution, with which mostly confined to the vascular space, are cleared with high efficiency. This finding supports the clinical recommendation of administering such drugs after TPE. For drugs with limited direct evidence, we propose a predictive model based on fundamental pharmacokinetic parameters to estimate their removal risk and guide clinical decision-making. Based on this evidence, we have constructed a stratified clinical management framework. It aims to maintain effective therapeutic drug exposure levels during chronic TPE therapy and to provide a rationale for the judicious application of TPE in overdose scenarios. Implementing this pharmacokinetic-informed, risk-adapted individualized strategy is important for ensuring treatment continuity, enhancing patient safety, and advancing empiricism-based therapy towards precision medicine.

Lung cancer is one of the most common malignancies and the leading cause of cancer-related mortality worldwide, posing a major public health challenge. Flavonoids, a large and diverse group of plant metabolites, exhibit various anticancer properties, making them promising candidates for therapeutic applications. This study evaluated the anticancer efficacy of methoxy flavonoids and elucidated their underlying mechanisms of action in A549 lung cancer cells. A549 cells were treated with various flavonoids (AKC1-AKC5), and their effects were analyzed using an MTT assay, DAPI staining, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, colony formation, and wound scratch tests. Molecular docking was also performed to confirm the binding of AKC1 and AKC3 to EGFR, BCL-2, and CDK-2 proteins. AKC1 and AKC3 prevented the growth of A549 lung cancer cells with IC50 of 64.57 and 19.80 μM among 5 methoxy flavonoids. AKC1 and AKC3 triggered notable alterations in the shape and reduced the colony-forming potential of A549 cells. The DAPI staining experiment demonstrated that AKC1 and AKC3 impede the growth of cancer cells through activation of apoptotic cell death. Moreover, the anticancer properties of AKC1 and AKC3 were attributed to significant inhibition of MMP and a notable ROS enhancement in a dose-related pattern. The wound scratch assay demonstrated that AKC1 and AKC3 suppressed A549 lung cancer cell migration, suggesting their anti-metastatic properties. Molecular docking studies confirmed that AKC-1 and AKC-3 bind strongly to EGFR, BCL-2, and CDK2, suggesting a multi-target mechanism that underlies their anti-proliferative and pro-apoptotic effects in A549 cells. AKC1 and AKC3 exhibited significant anticancer activity against A549 cells and may serve as promising therapeutic drugs for lung cancer treatment.

Early life exposure to common pathogens and a high pathogen burden during childhood can have long-term effects on immune development and overall health. These infections can trigger molecular changes, including alterations in gene expression and DNA methylation (DNAm), which regulate immune and metabolic pathways. Our aim was to identify biological processes underlying differential patterns of DNAm and gene expression in whole blood by infection status in European children. In the Rhea (Greece) and INMA (Spain) cohorts, serum/plasma samples collected at mean ages of 4 and 8 years were analyzed by multiplex serology to measure IgG against 14 antigens from 9 pathogens, and blood collected at a mean age of 8 years was used for DNAm and gene expression profiling. Epigenome- and transcriptome-wide analyses were conducted to assess association with childhood infections. A total of 290 unique CpGs were significantly associated with pathogen outcomes: 265 with seropositivity, 111 with first exposure timing, and one with viral burden. Cytomegalovirus (CMV) exposure accounted for the largest number of both epigenetic (n = 325) and transcriptomic (n = 8) associations. A total of 89 CMV-related CpGs had been described before in adults, and among novel ones, 54 showed consistent effects in adults. CMV-related CpGs were enriched for SUZ12 targets linked to morphogenesis, oxidative stress, and cognition. A previously developed CMV episcore in adults predicted serologically assessed CMV infection at 4 and 8 years of age, with area under the curve values ranging from 0.74 to 0.78 (95% CI 0.68-0.83). We identified novel DNAm and gene expression signatures of common childhood infections, particularly CMV, implicating immune and morphogenesis pathways. A subset of CMV-related DNAm signals showed consistent associations with those reported previously in adults, suggesting similar molecular effects across ages.

Pain is a hallmark of inflammation and tissue injury, particularly following major surgical procedures. Despite its prevalence and clinical impact, pathological pain, defined as persistent pain that impairs function, remains a major unmet medical need. Human birth tissue, including the amniotic membrane and umbilical cord, has long been recognized for its regenerative properties and its ability to support wound healing. Recent studies have identified heavy chain 1 (HC)-hyaluronic acid (HA)/pentraxin 3 (HC-HA/PTX3) as a key matrix component within these tissues. This complex exhibits anti-inflammatory and anti-scarring activities and helps maintain stem cell quiescence. Emerging evidence, including our own findings, indicates that human birth tissue-derived products may also modulate pain responses in certain settings, such as post-surgical pain, potentially through mechanisms involving neuronal inhibition and regenerative healing. We summarize the molecular and cellular mechanisms by which human birth tissue-derived products and HC-HA/PTX3 may exert anti-inflammatory and analgesic effects. We then highlight preclinical and clinical studies evaluating their potential roles in wound healing and pathological pain. Finally, we discuss translational opportunities, current challenges, and future directions for advancing these biologics within the emerging field of regenerative pain medicine. This review outlines a framework for potential regenerative pain management using birth tissue-derived products, which may serve as a foundation for developing new therapies for certain pathological pain conditions.

Cyanuric chloride is a highly reactive, widely recognized compound in medicinal chemistry, enabling rapid and selective nucleophilic substitution reactions at its three chlorine positions. In the present study, explore the structural advantages of cyanuric chloride to develop a new DOTA-linked triazine-based scaffold for PSMA. Two scaffolds, abbreviated as PSMA-C1D and PSMA-C2D, were successfully synthesized with good yields and evaluated their properties through molecular docking, in vitro studies, radiolabelling, physicochemical properties, and internalization studies. The initial screening revealed that, the PSMA-C1D had greater potential as a PSMA-targeted imaging agent than PSMA-C2D. In vitro cytotoxicity assays further indicated good biocompatibility at imaging-relevant concentrations. The molecular docking demonstrated strong site-specific binding of PSMA-C1D to the PSMA active pocket (ΔG = - 10.2 kcal/mol), with interactions closely resembling the co-crystallized ligand. The radiolabelling of PSMA-C1D with Ga-68 shows high yield with > 95% radiochemical purity, excellent stability in multiple biological media, and high apparent molar activity (508 GBq/µmol). The tracer shows hydrophilicity (logD7.4 = - 2.76 ± 0.02), low %PPB (18 ± 5.4), and has a nanomolar affinity (Kd = 0.38 nM), with the percentage of bound internalization in LNCaP cells was 15 ± 2.9% incubation for 1 h. The study highlights the value of cyanuric chloride as a modular chemical hub for the design and linking of radiopharmaceuticals. It identifies [68Ga]Ga-PSMA-C1D as a promising, efficiently synthesizable, and highly PSMA-specific PET radiotracer for imaging prostate cancer.

This study examines the impact of a light-cycle shift regimen on corneal and conjunctival tissues in menopausal rats and evaluates the protective role of combined hormone therapy. Twenty-four menopausal female albino rats were randomly assigned to three groups (n&#x2009;=&#x2009;8) following a 10-day acclimatization period. Group 1 (Control+Saline) was maintained under a 12:12 light/dark cycle. Light-cycle shift regimen was induced in Groups 2 and 3 using a rotating 7-day light-exposure sequence repeated over 21 days; this protocol consisted of 24&#xa0;h of continuous light, 72&#xa0;h of inverted dark-light timing, and 72&#xa0;h of standard light-dark conditions. Groups 1 and 2 received saline, while Group 3 received 17&#x3b2;-Estradiol and drospirenone daily via oral gavage. After 31 days, eyes were enucleated for histological and immunohistochemical analyses of corneal, conjunctival, and palpebral tissues, including caspase-3 (Cas-3), tumor necrosis factor-alpha (TNF-&#x3b1;), and PERIOD-2 (PER2) expression. Light-cycle shift regimen (Group 2) significantly increased corneal thickness (p&#x2009;<&#x2009;0.001), conjunctival inflammation, and vascular congestion, with marked upregulation of Cas-3 and TNF-&#x3b1; and downregulation of PER2. Hormone therapy (Group 3) attenuated these effects, showing reduced corneal edema, diminished inflammatory infiltration, and partial normalization of molecular markers. Shifting light-dark cycles may aggravate inflammatory and apoptotic changes in the ocular surface during menopause. Estrogen-progestin therapy attenuates these alterations by modulating the expression of the circadian-associated protein PER2 and maintaining structural integrity. These findings suggest that hormone therapy may offer potential benefits for preserving ocular surface homeostasis in menopausal women experiencing sleep or circadian rhythm disturbances.