This study provides systematic synthesis of therapeutic effects of magnolol (MN) in preclinical Alzheimer's disease (AD) models and integrates network pharmacology with molecular dynamics (MD) simulations to predict its core targets and binding stability. Systematic literature search was conducted in PubMed, CNKI, Wanfang, and Google Scholar up to January 1, 2026 following PRISMA guidelines. Network pharmacology, molecular docking, and 100 ns MD simulations were used to identify common targets, evaluate binding affinities, and assess complex stability. Fourteen studies (seven in vivo, five in vitro, two combined) were included. MN consistently ameliorated cognitive deficits and neuropathology through antioxidant, anti-inflammatory, anti-apoptotic, and anti-acetylcholinesterase activities, while preserving mitochondrial and synaptic function. Network pharmacology identified 60 common targets; Protein-Protein Interaction (PPI) analysis revealed five hub genes: AKT1, MMP9, MMP2, ERBB2, and EGFR. Molecular docking showed binding energies below -4.0 kcal/mol for all five targets, and MD simulations confirmed stable binding, with the ERBB2-MN complex exhibiting the lowest root mean square deviation (RMSD) (1.2 Å) and favorable free energy landscape. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations further confirmed that magnolol exhibited binding affinities comparable to the reference co‑crystal ligands. Unlike prior reviews, this study uniquely combines systematic evidence synthesis with computational predictions, identifying ERBB2 as a novel stable target of MN. MN exerts anti-AD effects via multi-pathway and multi-target regulation, with computational predictions aligning with experimental evidence, supporting MN as promising lead compound for AD drug development.
Panax ginseng C.A. Mey. is traditionally utilized to "tonify Qi and replenish Blood," particularly in managing anemia-like syndromes. Panaxadiol saponins (PND) represent a standardized bioactive fraction from ginseng that embodies these historical properties. While PND is currently in Phase II clinical trials for aplastic anemia (AA), its systemic pharmacological mechanisms remain to be fully elucidated. This study aimed to evaluate the therapeutic efficacy of PND against immune-mediated AA, and delineate its potential systemic regulatory mechanisms involving the NLRP3-related signaling and gut-bone marrow crosstalk. An immune-mediated AA mouse model was established. Network pharmacology, 4D-DIA quantitative proteomics and 16S rDNA sequencing were integrated to identify responsive molecular pathways and candidate targets. Predicted target interactions were characterized via molecular dynamics (MD) simulations and further validated by cellular thermal shift assay (CETSA). Functional validation was performed in an LPS-induced primary bone marrow nucleated cells (BMNC) injury model using the NLRP3-specific inhibitor MCC950, to investigate the functional involvement of the NLRP3 axis in PND-mediated cytoprotection. PND partially restored peripheral blood counts and ameliorated CD4+/CD8+ T-cell imbalances in AA mice. Integrative analysis identified the NOD-like receptor (NLR) signaling pathway as a candidate key responsive node, with MD simulations and CETSA characterizing potential biophysical interactions between ginsenosides and the chaperone HSP90AA1. Concurrently, PND treatment improved intestinal barrier integrity and enriched beneficial microbiota, changes that were associated with attenuated systemic endotoxemia. In vitro functional rescue assays further demonstrated that NLRP3 signaling axis is functionally involved in the anti-inflammatory and cytoprotective effects of PND on BMNCs. PND facilitates hematopoietic recovery, an effect associated with the suppression of the NOD/NLRP3 inflammatory axis and a reduced systemic inflammatory burden. These findings suggest that PND holds potential as an adjunctive supportive strategy for immune-related cytopenias.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by amyloid-beta (Aβ) accumulation, mitochondrial failure, and neuroinflammation. While probiotics show therapeutic potential via the gut brain axis, the molecular mechanisms remain poorly understood. This study investigated the neuroprotective potential of Leuconostoc mesenteroides lysate and its bioactive metabolites in an Aβ-induced SH-SY5Y neuroblastoma model. SH-SY5Y cells were challenged with Aβ and treated with L. mesenteroides lysate. Neuroprotective effects were evaluated via ROS accumulation, SOD1, APOE, NOS2, and mitochondrial dynamics (MFF, OPA1) using qPCR and WB. Potential mechanisms of action were explored computationally through integrated genome mining (antiSMASH 7.0), molecular docking (CB-Dock2), and systems pharmacology analysis (STRING/KEGG/R-studio) to identify candidate metabolites and host targets. L. mesenteroides lysate significantly attenuated Aβ-induced ROS levels and upregulated SOD1, enhancing antioxidant capacity. The lysate effectively downregulated APOE expression and restored mitochondrial homeostasis by reducing mitochondrial fission (MFF) and promoting fusion (OPA1). In silico analysis predected phytoene as a primary bioactive metabolite with significant theoretical binding affinity for APOE. Systems biology mapping revealed highly significant enrichment in PPAR signaling and cholesterol metabolism pathways (FDR < 10⁻⁵). Specifically, Cellular Component analysis highlighted robust interactions within protein-lipid complexes (FDR = 1.98e-16). L. mesenteroides lysate counteracts Aβ-induced neurotoxicity by modulating oxidative stress and restoring mitochondrial bioenergetics. Collectively, our findings suggest a theoretical Phytoene-PPAR-APOE signaling axis as a predictive framework for the observed cellular effects. We emphasize that phytoene represents a predicted candidate metabolite requiring future chemical characterization and biological validation.
Both therapeutic and nontherapeutic medications have a profound influence on sleep architecture, a vital component of overall health. Optimizing patient outcomes requires a clear understanding of how commonly prescribed drug classes affect the quality, duration, and structure of sleep. Clinicians should carefully consider these pharmacologic effects when selecting or modifying treatment regimens, particularly in patients with comorbidities or underlying sleep disorders. The widespread use of herbal and over-the-counter preparations further underscores the importance of comprehensive medication reviews and patient education. A thorough understanding of drug sleep interactions enables clinicians to deliver more informed, individualized, and safer patient care.
Coronopus didymus (Brassicaceae) is a medicinal herb valued for its anti-inflammatory and hyperlipidemic properties; however, its antidiabetic potential remains entirely unexplored. Furthermore, despite the known therapeutic benefits of Azadirachta indica and the bioflavonoid quercetin, their evaluation in combination with C. didymus has never been investigated. To address this knowledge gap, this study pioneers the evaluation of C. didymus, A. indica, and quercetin-individually and as a novel combined formulation for the management of type 2 diabetes mellitus (T2DM). We employed an integrated approach utilizing in silico network pharmacology and molecular docking (targeting NOS3, AKT1, and PPARG), in vitro bioassays (antioxidant, α-amylase inhibition, hemolytic, and anticancer), and in vivo evaluation in streptozotocin-nicotinamide (STZ-NA)-induced diabetic mice. Network screening identified 100 overlapping targets between the quercetin and T2DM, prioritizing 15 key hub targets via protein-protein interaction and KEGG pathway enrichment analyses. Molecular docking confirmed strong binding affinities of the lead compounds to NOS3, AKT1, and PPARG. In vitro assays validated robust antioxidant, α-amylase inhibitory, and anticancer activities, while maintaining a safe hemolytic profile. In vivo trials demonstrated that while individual treatments effectively lowered blood glucose, the combined formulation exhibited superior hepatoprotective efficacy, profoundly reducing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (p < 0.0001) toward baseline control levels compared to individual plant extracts, alongside enhancing serum antioxidants and ameliorating histopathological damage in hepatic and intestinal tissues. In conclusion, this study bridges a critical gap in ethnopharmacology by identifying the antidiabetic potential of C. didymus and demonstrating that its combination with A. indica and quercetin offers a potent, distinct hepatoprotective advantage, highlighting its potential as a targeted nutraceutical approach for managing T2DM and its associated hepatic complications.
Cerebral ischemia-reperfusion injury (CIRI) is a devastating neurological disorder involving autophagy, oxidative stress, and ferroptosis. Tetramethylpyrazine (TMP) has demonstrated potential pharmacological efficacy in antiplatelet aggregation, antithrombotic effects, vasodilation, and neuroprotection. This study aimed to determine the therapeutic efficacy of TMP in treating CIRI and to investigate whether TMP could improve CIRI by inhibiting ferroptosis through activation of the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1)/glutathione Peroxidase 4 (GPX4) pathway in rats. We established MCAO/R rat models and OGD/R-treated HT22 cell models to evaluate the neuroprotective effects of TMP, employed network pharmacology and metabolomics to predict key signaling pathways, and assessed ferroptosis-related changes via biochemical assays, Western blotting, and transmission electron microscopy. In vivo studies showed that TMP improved neurological scores, reduced infarct volume, and mitigated pathological features following MCAO/R. Network pharmacology and metabolomics revealed that TMP indirectly activated NRF2-mediated antioxidant responses while regulating glycerophospholipid metabolism and glycine/serine/threonine metabolism pathways. Mechanistically, TMP reduced oxidative stress markers, restored antioxidant capacity, and upregulated NRF2, HO-1, GPX4 and SLC7A11 expression, while the NRF2 inhibitor ML385 reversed these effects. These findings were further corroborated by in vitro experiments in OGD/R-exposed HT22 neurons, where TMP enhanced cell viability, attenuated lipid peroxidation and iron accumulation, and preserved mitochondrial ultrastructure, with ML385 partially reversing the protective effects. TMP exerts neuroprotective effects in mitigating CIRI, which is associated with the regulation of ferroptosis and involves activation of the NRF2/HO-1/GPX4 pathway.
Ulcerative colitis (UC) is a worldwide health issue with limited therapies. Traditional Chinese Medicine (TCM) shows potential, but lacks systematic efficacy evaluation and detailed mechanistic explanations. This study aims to evaluate the efficacy of TCM for active UC and explore its mechanisms. A meta-analysis of RCTs was conducted to assess TCM efficacy in active UC, and treatment efficacy was ranked. Core Chinese herbs were identified via association rule analysis. Network pharmacology and molecular docking predicted active components, targets, and pathways. Efficacy of the key component was validated in active UC mice. 17 studies (1,598 patients) showed TCM significantly improved active UC (SMD -1.73, 95%CI -2.21 to -1.25). Eight core Chinese herbs were identified. Network pharmacology revealed 76 overlapping targets. Isorhamnetin (Iso) showed strong binding to PTGS2 (binding energy: -9.34 kcal/mol) and Nrf2 (binding energy: -9.16 kcal/mol). In vivo, Iso dose-dependently alleviated disease symptoms, pathological damage, and spleen index in UC mice. TCM could ameliorate active UC. The key active component Iso shows therapeutic effects, with mechanisms potentially involving the Nrf2-PTGS2 axis and immune-inflammatory pathways. The findings offer some insight into the scientific basis of TCM in treating UC and predict that Iso may be a candidate for further mechanistic and clinical investigation.
Chronic pain conditions affect a large proportion of the global population and pain has tremendous personal and economic impact, affecting quality of life and ability to work while imposing a significant burden on families and health care systems. Neurological disorders and painful conditions are frequently accompanied by chronic pain, which is often jointly diagnosed with age-related neurodegenerative diseases, however, many patients do not receive adequate treatment. This review aims to create a working framework around the issue of under-recognized/undertreated chronic pain in Alzheimer disease by offering an in-depth overview of the mechanisms driving chronic pain and how we can leverage this knowledge to advance therapeutics approaches for these patients with an emphasis on the immune system. SIGNIFICANCE STATEMENT: Chronic pain conditions are prevalent among the aging population, and they positively associate with dementia. The incidence of chronic pain is associated with neuropsychiatric symptoms of dementia and pain management should aim for effective treatments regardless of cognitive status.
The introduction of immune checkpoint inhibitors targeting the programmed death-1 (PD-1) axis represented a major therapeutic advance, enabling long-term survival, and even cure, in a subset of patients, an outcome previously considered unattainable in metastatic disease. However, most patients do not yet derive sustained benefit. Despite extensive efforts to define biomarkers, identify mechanisms of sensitivity and resistance, and translate these insights into therapeutic strategies, attempts to intensify PD-1-based therapy have failed to improve long-term survival. Extending durable benefit and achieving cure in a broader population will require a deeper understanding of mechanisms of resistance, the development of novel immunotherapeutics, and more precise personalization of treatment strategies.
Hematopoietic cell transplantation (HCT) is a curative immunotherapy for hematologic malignancies such as acute myeloid leukemia, primarily through graft-versus-tumor (GVT) effects mediated by donor T cells. However, up to 60% of recipients develop graft-versus-host disease (GVHD), with intestinal involvement being a major contributor to morbidity and mortality. While CD8 T cells drive GVT, CD4 T helper (Th) cells are largely the key mediators of intestinal GVHD. Although IFN-γ-producing Th1 cells have been implicated in this process, recent evidence suggests a more complex role for Th cell subtypes. In our study, we identify the transcription factor GATA3, often associated with Th2 function, as a key regulator of Th cell proliferation, gut persistence, and cytokine production. Specifically, donor cell GATA3 was required for the early production of gut‑damaging granzyme A by intestinal Th cells and sustained granulocyte-macrophage colony-stimulating factor (GM‑CSF) production at later phases of the intestinal GVHD response. GATA3‑mediated maintenance of GM‑CSF expression during these later stages of disease was associated with increased intestinal eosinophil recruitment and activation, features that have been linked to GVHD severity in humans. Collectively, our findings demonstrate that GATA3‑expressing Th cells contribute to intestinal GVHD pathogenesis by sustaining GM-CSF-driven inflammatory circuits and promoting chronic eosinophilia. Targeting GATA3, or its downstream effector pathways, may therefore represent a novel therapeutic strategy to attenuate intestinal GVHD while preserving the overall efficacy of HCT.
The large effector arsenal of the bacterial pathogen Legionella pneumophila has been a rich source of biochemistry, highlighting the immense diversity of strategies deployed in host-pathogen conflict. Here, we redefine the purported translation inhibitor SidL as an adenylyltransferase that targets a glycolytic metabolite, discovering that it modifies 3-phosphoglycerate with adenosine monophosphate (AMP) to produce the previously unknown molecule 2-AMP-3-phosphoglycerate. When expressed alone in mammalian cells, SidL adenylates 3-phosphoglycerate, disrupts glycolysis, and blocks the nutrient-responsive translation regulator mTORC1, which we propose indirectly causes translation inhibition. Moreover, we observe SidL-dependent production of 2-AMP-3-phosphoglycerate in macrophages during L. pneumophila infection, the timing of which is consistent with a role for SidL in the early stages of the infection cycle. Thus, our study uncovers a mechanism by which an intracellular pathogen uses the chemical modification of a glycolytic intermediate to target central carbon metabolism in the host.
To synthesize the available evidence on the relationship between dietary glutamate or glutamatergic metabolism and glaucomatous neurodegeneration, with emphasis on biomarkers, retinal injury mechanisms, and nutritional, antioxidant, or pharmacological strategies with neuroprotective potential. This study was conducted as a systematic and bibliometric literature review following the PRISMA 2020 logic of identification, screening, eligibility, and inclusion. Searches were performed in Web of Science, Scopus, and PubMed for studies published in English between 2020 and 2025. The search strategy combined terms related to glaucoma or ocular neurodegeneration, the glutamatergic axis, and biomarkers, mechanisms, or interventions. After screening and full-text assessment, 39 studies were included in the systematic synthesis. Due to methodological heterogeneity, the evidence was synthesized narratively and comparatively, without meta-analysis. The included studies were organized into six thematic clusters: metabolomic, transcriptomic, and diagnostic biomarkers; pharmacological and neuroprotective interventions; nutritional, antioxidant, and natural-compound neuroprotection; oxidative stress, mitochondrial dysfunction, and regulated cell death; neuroinflammation and glia-mediated retinal injury; and glutamatergic excitotoxicity and neurotransmitter imbalance. The evidence indicates that glutamate-related mechanisms in glaucoma are mainly associated with endogenous glutamatergic metabolism, excitotoxicity, impaired glutamate clearance, glutamate-glutamine homeostasis, oxidative and nitrosative stress, mitochondrial dysfunction, ferroptosis, neuroinflammation, and retinal ganglion cell vulnerability. None of the 39 included studies directly evaluated dietary glutamate or monosodium glutamate as the main exposure. The available evidence does not support a direct conclusion that dietary glutamate or MSG intake contributes to glaucoma onset or progression. Instead, current findings mainly support an indirect mechanistic relationship between endogenous glutamatergic dysregulation and glaucomatous neurodegeneration. Pharmacological, antioxidant, metabolic, and natural-compound strategies show neuroprotective potential, particularly in experimental models, but clinical and translational studies are still needed to clarify the role of dietary exposure, glutamate-glutamine metabolism, and targeted neuroprotective interventions in glaucoma.
Optimal induction chemoimmunotherapy sequential concurrent chemoradiotherapy (cCRT) in locally advanced hypopharyngeal squamous cell carcinoma (HSCC) remains undefined. This study aimed to evaluate toripalimab plus chemotherapy sequential cCRT with nimotuzumab, followed by toripalimab maintenance in unresectable stage IVB HSCC. In this single-arm, open-label, phase 2 study, untreated patients received two 21-day cycles of induction toripalimab 240 mg (d1) plus nab-paclitaxel 230 mg/m2 (d1) and cisplatin/nedaplatin 40 mg/m2 (d1-2) sequential cCRT (helical tomotherapy; nab-paclitaxel 230 mg/m2 (d1, 22, 43)) with nimotuzumab 200 mg weekly for 7 weeks. Subsequently, toripalimab maintenance was administered for eight cycles. Primary endpoint was progression-free survival (PFS). From March 16, 2022 to April 24, 2024, 31 patients completed induction chemoimmunotherapy. With a median follow-up of 31 months, median PFS and overall survival (OS) were not reached; 2-year PFS and OS rates were 67.7% and 86.4%. The 2-year larynx preservation rate was 93.3%. 30 (96.8%) patients achieved the best objective response, with 28 (90.3%) complete responses and 2 (6.5%) partial responses. The most common grade 3-4 treatment-related adverse events (TRAEs) were radiation-induced oropharyngeal mucositis and decreased appetite (each 46.9%). No grade 5 and fatal TRAEs occurred. No difficulties in speech and swallowing functions were reported in 96.8% of patients. There was no significant association between PFS and PD-L1 combined positive score, epidermal growth factor receptor expression, tumor-infiltrating T-lymphocytes, tumor mutational burden, or genetic alterations. High baseline peripheral CD3+ and CD8+CD28+ T-cell levels were associated with favorable PFS. Exploratory biomarker analyses identified that patients without disease progression after maintenance exhibited significantly higher levels of CD8+CD28⁻ T cells with a memory phenotype and lower B-cell levels. This exploratory study demonstrated preliminary efficacy and larynx preservation with manageable toxicity, possibly supporting further evaluation of induction toripalimab plus chemotherapy sequential cCRT with nimotuzumab, followed by toripalimab maintenance in stage IVB HSCC. Peripheral lymphocytes may warrant further investigation as candidate biomarkers in locally advanced disease. NCT05860335; ChiCTR2300074672.
Candida spp. infections are an increasing challenge in high-complexity hospitals, yet epidemiological data remain scarce in underrepresented in Colombian regions such as Tolima. We conducted a retrospective observational study in a high-complexity hospital in Ibagué (Tolima, Colombia) from 2014 to 2024, integrating two institutional data sources: administrative/clinical records and the microbiology laboratory database (WHONET). Species identification relied on culture and VITEK, and antifungal susceptibility was interpreted using criteria from the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We summarized data using frequencies/proportions and medians (IQR), explored patterns with multiple correspondence analysis (MCA), and estimated associations with candidemia using penalized multivariable logistic regression due to low event frequency. We identified 987 candidiasis episodes and 776 fungal isolates, of which 314 were Candida (40.46%). Mucocutaneous disease predominated (vulvovaginal 50.7%; oropharyngeal 24.3%), while candidemia represented 2.0% of episodes. Among isolates, Candida albicans was most frequent (58.9%), followed by C. parapsilosis (16.6%), C. tropicalis (12.1%), and Nakaseomyces glabratus (6.4%); Candida auris was detected once. In exploratory clinical/administrative models, clinically recorded candidemia showed associations with invasive devices (OR 5.54, 95% CI 2.01-15.64), recent surgery (OR 7.11, 95% CI 1.20-30.88) and tumor (OR 19.88, 95% CI 3.14-97.51). Susceptibility data were available for 196/314 isolates (62.4%); echinocandin activity was high, whereas azole susceptibility was more variable. Candidiasis showed a sustained recorded burden and substantial non-albicans diversity, supporting local surveillance, species-level identification, and isolate-level susceptibility testing.
Malaria is a devastating disease that resulted in an estimated 610,000 deaths in 2024, the majority being children under the age of five. Here, we use KNX-115 to illustrate multistage antiparasitic activity upon targeting the cytoskeletal enzyme Plasmodium falciparum myosin A (PfMyoA). KNX-115 inhibits purified actin-activated ATPase with a potency in the low nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 traps PfMyoA in a state that binds weakly to actin. A 2.35 Å resolution structure of KNX-115 bound to PfMyoA reveals critical interactions contributing to its mechanism of action. Importantly, in vitro evolution data reveal that KNX-115 engages PfMyoA as a sole cellular target. Inhibiting PfMyoA blocks the development of the blood and liver stages of laboratory strains of P. falciparum, with no liver cell toxicity, sporozoite cell traversal and motility, and sporozoite development in the mosquito. Inhibiting PfMyoA completely kills parasites after 96 h of treatment. Furthermore, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials and shows inhibitory activity against P. falciparum circulating isolates from the Brazilian Amazon. Inhibiting PfMyoA with KNX-115 also blocks the blood stage of a laboratory strain of Plasmodium vivax. In line with the evolutionary identity of MyoA among various apicomplexan parasites, KNX-115 also inhibits Cryptosporidium and Eimeria MyoA in vitro and is an effective inhibitor of Cryptosporidium, Toxoplasma, and Eimeria cellular growth, with EC50s similar to those found for blood and liver stage Plasmodium.
Deltaretroviruses, particularly human T-cell leukemia virus type 1 (HTLV-1) and bovine leukemia virus (BLV), are oncogenic retroviruses responsible for severe lymphoproliferative and inflammatory diseases, including adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Despite decades of research, effective curative therapies remain limited, and disease progression is strongly influenced by host immune and metabolic factors. Accumulating evidence indicates that vitamins play critical roles in modulating viral pathogenesis, immune dysregulation, oxidative stress, and tissue damage in Deltaretrovirus infections. Clinical, experimental, and genetic studies demonstrate that deficiencies or altered signaling of vitamins D, C, and B complex are associated with increased disease susceptibility, inflammatory severity, and neurological or hematological complications in HTLV-1-infected individuals. Vitamin D signaling, in particular, has been linked to immune regulation, control of proviral load, and genetic susceptibility via vitamin D receptor polymorphisms. Antioxidant vitamins, such as vitamin C, exert pro-apoptotic effects in HTLV-1-transformed cells, while vitamin B derivatives improve neurological function and quality of life in HAM/TSP patients. Emerging data also suggest parallels in BLV infection, including vitamin-related metabolic alterations and potential zoonotic implications. This review synthesizes current evidence on the role of vitamins in Deltaretrovirus infection, highlights mechanistic and clinical insights, and identifies critical knowledge gaps. Understanding vitamin-dependent pathways may support the development of adjunctive, low-cost strategies to improve disease outcomes in HTLV-1- and BLV-associated disorders.
To identify pre/perioperative factors that predict graft failure after Descemet membrane endothelial keratoplasty (DMEK). This retrospective cohort study included consecutive eyes that underwent DMEK in 2015-2023 in a regional referral hospital and were followed for at least 12 months. DMEK-graft failure was defined as need for regrafting during follow-up. Univariable analysis of graft-failure associations with 20 covariates was performed. Hierarchical multivariable analysis was conducted for DMEK-graft failure with covariates whose univariable-analysis p-values were ≤0.15. Posthoc univariable analyses were performed to elucidate the mechanisms by which covariates promoted DMEK-graft failure. 171 eyes (129 patients) with mostly Fuchs endothelial corneal dystrophy (94%) were included. Median (range) follow-up was 24 (12-29) months, during which 15 grafts (9%) failed. On univariable analyses, graft failure associated with eight variables, including long (≥25 mm) preoperative axial length (AXL): 40% of graft-failure eyes had AXL ≥ 25 mm vs. 13% for graft-success eyes (p = 0.01). On multivariable analysis, graft failure was predicted by AXL ≥ 25 mm (OR=5.70; 95%CI = 1.27-25.68; p = 0.02), younger graft-donor age (OR=0.93; 95%CI = 0.88-0.99; p = 0.02), graft-unscrolling/positioning difficulties (OR=6.93; 95%CI = 1.58-30.48; p = 0.01), and major graft detachment (OR=6.28; 95%CI = 1.36-28.96; p = 0.02). The model accounted for 14% of total graft-failure variance. Posthoc univariable analysis showed that eyes with AXL ≥ 25 experienced graft-unscrolling/positioning difficulties more often than shorter eyes (27% vs. 10%, p = 0.0497). Eyes with long AXL (≥25 mm) may be more prone to DMEK-graft failure than shorter eyes. This may reflect the deep anterior chamber, which can complicate graft unscrolling and/or graft positioning. The additional graft handling may induce endothelial-cell loss and subsequent graft failure. Younger donor age weakly predicted DMEK-graft failure, possibly due to tighter scrolling of younger grafts. Major graft detachment strongly predicted DMEK-graft failure. This could reflect surgical and/or rebubbling-induced endothelial damage and/or pre-existing graft weakness.
A biocatalytic approach was applied to synthesizing esters and amides derived from 2-(1H-indol-3-yl)acetic (IAA), 3-(1H-indol-3-yl)propionic (IPA), and 4-(1H-indol-3-yl)butanoic (IBA) acids. Thirty-seven derivatives were obtained through lipase catalysis in mild reaction conditions with good to excellent yields and a reduced environmental impact. The scope of the reaction was explored in terms of enzyme source, solvent, temperature, substrate-to-nucleophile and enzyme-to-substrate ratios, and substrate versatility. Ten representative derivatives were evaluated as potential anti-Alzheimer's disease (AD) agents using Caenorhabditis elegans models. Among them, octyl 3-(1H-indol-3-yl)propanoate (6e), N-butyl-3-(1H-indol-3-yl)propanamide (10a), and (S)-N-(2-hydroxypropyl)-3-(1H-indol-3-yl)propanamide (13c) emerged as the most promising candidates, demonstrating significant improvements in AD pathology, including enhanced locomotion and mitochondrial function. In addition, the obtained compounds showed no toxicity in Vero cells, making them potential lead drug candidates.
Bone metastases are a major cause of morbidity in advanced prostate cancer (PCa), where tumor cells adapt to a hypoxic and osteoblast-rich microenvironment. Here, we investigated how endosteal niche conditions regulate GJA1-20k expression and mitochondrial dynamics in metastatic PCa cells. We demonstrate that osteoblastic-conditioned medium (ObCM) combined with hypoxia preferentially increase GJA1-20k expression over full-length Cx43, without changes in GJA1 mRNA levels. This result correlates with a redistribution of mitochondria from perinuclear to peripheral regions. Interestingly, by co-immunoprecipitation experiments, we show that GJA1-20k interacts with mitochondria. Finally, stable overexpression of GJA1-20k in PCa cells was sufficient to reproduce this mitochondrial remodeling. These findings identify GJA1-20k as a stress-adaptive effector that links translational reprogramming to metabolic plasticity within the bone metastatic niche, highlighting new therapeutic opportunities to target PCa dormancy and progression.
Cutaneous melanoma remains the most lethal skin cancer due to profound tumor heterogeneity and the frequent development of resistance to current therapies. Here, we identify the cysteinyl leukotriene receptor 1 (CysLT1R) as a previously unrecognized driver of melanoma progression. Analysis of bulk RNA-sequencing datasets from The Cancer Genome Atlas (TCGA) revealed significantly elevated CysLT1R transcript in metastatic tumors compared to primary tumors. Functional studies in murine and human melanoma cells demonstrated that leukotriene D4 (LTD4)-mediated activation of CysLT1R promotes melanoma cell proliferation and invasion through the parallel engagement of YAP and ERK signaling pathways. Notably, melanoma cells express LTC4 synthase and secrete cysteinyl leukotrienes, establishing a constitutive autocrine signaling loop that sustains CysLT1R activity independently of the host niche. Genetic ablation or pharmacological inhibition of CysLT1R with MK571 significantly attenuated tumor growth in vivo and was associated with inhibition of the YAP-LOXL-2 signaling axis. In addition, studies using Cysltr1-/- mice reveal that host-derived CysLT1R signaling within the tumor microenvironment also contributes to melanoma progression. Together, these findings uncover a previously unrecognized pro-tumorigenic CysLT1R-ERK/YAP,LOXL-2 signaling circuit that promotes cutaneous melanoma progression and highlight CysLT1R as a potential therapeutic target for melanoma.