Mutations in SLC26A4, which encodes the anion transporter pendrin, represent one of the most common genetic causes of hereditary hearing loss, including Pendred syndrome and DFNB4. Pendrin plays a critical role in maintaining ion homeostasis within the inner ear, particularly in the endolymphatic sac (ES), making it an important therapeutic target for gene replacement strategies. However, efficient delivery of therapeutic genes to relevant inner ear structures remains a major challenge for clinical translation. In this study, we evaluated the inner ear transduction profile of AAV8BP2, an engineered AAV8-derived capsid, in comparison with AAV2.7m8 and AAV8 in mice. Neonatal mice received posterior semicircular canal (PSCC) injections at postnatal day 0 (P0), and viral transduction in the cochlea and ES was assessed at P7. To examine age-dependent differences in viral transduction, additional experiments were performed in adult mice injected at P21 and analyzed at P28. We also compared three surgical delivery routes for inner ear gene transfer: PSCC injection, round window membrane (RWM) injection, and RWM injection combined with PSCC fenestration. AAV8BP2 effectively transduced the ES in both neonatal and adult mice and showed greater GFP expression in the spiral prominence than AAV8 following neonatal administration. Among the three delivery routes evaluated in adult mice, PSCC injection achieved the highest ES transduction while maintaining cochlear hair cell transduction comparable to that achieved with RWM-based approaches. Together, these findings define the relative transduction profiles of the tested AAV capsids and delivery routes and provide a basis for selecting vector-delivery route combinations for SLC26A4-targeted inner ear gene therapy.
Direct human evidence linking Scrophularia ningpoensis to asthma is limited, and database-derived herb–target records do not establish constituent exposure or target engagement. We used an evidence-audited molecular-informatics workflow to prioritize asthma airway-brushing-associated genes overlapping a frozen HERB export. GSE63142 was the discovery set, GSE67472 the independent airway-epithelial replication set, GSE137268 an induced-sputum cross-biospecimen transfer set, and GSE43696 a descriptive same-cohort reference because 105 of 108 identifiers overlapped GSE63142. Of 1266 measurable HERB-annotated targets, an 81-gene FDR-defined overlap did not exceed an expression-matched null (p = 0.0972), whereas a 19-gene strict overlap showed 2.27-fold enrichment (empirical p = 3.00 × 10−4) and 12 genes met the prespecified replication criterion in GSE67472. Provenance sensitivity retained two genes after database-mining-only edges were excluded and none under a direct-target-engagement requirement. Nested classifiers transferred to GSE67472, but not to sputum. Out-of-fold SHAP identified model-specific contributors, with moderate cross-cohort rank stability for LASSO (Spearman ρ = 0.563) and random forest (ρ = 0.693); SHAP was not interpreted as causal or herbal-target importance. These findings support computational prioritization and transferability assessment, not chemical presence, exposure, target binding, mechanism, or efficacy.
Bioactive polyphenols have emerged as multi-target regulators of cellular processes involved in the pathogenesis of skin diseases. Skin disorders, including inflammatory conditions, photoaging, and skin cancers, are characterized by complex pathogenic mechanisms associated with oxidative stress, mitochondrial dysfunction, dysregulated signaling pathways, and metabolic imbalance. Excessive production of reactive oxygen species (ROS) and persistent inflammatory signaling contribute to disease progression and cellular adaptation under stress conditions. Unlike conventional agents that typically target a single pathway, polyphenols act on interconnected signaling and metabolic networks. These compounds regulate key signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), AMP-activated protein kinase (AMPK), nuclear factor-κB (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby regulating cell survival, proliferation, inflammatory responses, antioxidant defense, and metabolic adaptation. Polyphenols also influence mitochondrial function by maintaining redox homeostasis, regulating energy metabolism, and affecting apoptosis-related signaling pathways. This review provides a mechanistic overview of the effects of polyphenols on oxidative stress, mitochondrial function, and cell survival signaling in skin diseases. In addition, the therapeutic implications and current limitations of polyphenol-based approaches are discussed, with particular emphasis on the translational gap between experimental findings and physiological relevance. Factors such as concentration, bioavailability, and cellular microenvironment are highlighted as major determinants of polyphenol activity and key challenges for clinical translation. Finally, the need for further in vivo and clinical investigations is emphasized to support the development of effective polyphenol-based therapeutic strategies for skin diseases.
Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy because of recurrence, treatment resistance, and limited therapeutic efficacy in advanced disease. This study investigated the anticancer effects and molecular mechanisms of jaceidin (JAC), a naturally occurring flavonoid derivative, in human OSCC cells. SCC-1 and SCC-47 cells were treated with JAC, and cell viability, colony formation, cell cycle distribution, apoptosis, and apoptosis-related signaling pathways were examined. JAC reduced OSCC cell viability and colony formation in a dose- and time-dependent manner. It also induced G2/M cell cycle accumulation and decreased the expression of cyclin D1, cyclin E1, phosphorylated cdc2, and CDK2/4/6. Apoptosis analyses showed that JAC promoted caspase-dependent apoptotic signaling, as evidenced by increased cleavage of caspase-3, caspase-8, caspase-9, and PARP. JAC modulated death receptor-associated signaling, characterized by increased Fas, TRADD, and DR5 expression and caspase-8 cleavage, while the decoy receptors DcR2 and DcR3 were also upregulated. JAC also promoted mitochondrial apoptotic signaling by increasing Bax, Bak, and Bim expression while decreasing Mcl-1. In addition, JAC attenuated AKT and ERK1/2 phosphorylation, and pharmacological inhibition with LY294002 or U0126 further enhanced JAC-induced apoptotic signaling. Furthermore, JAC reduced survivin expression and attenuated survivin-mediated apoptotic resistance. These findings suggest that JAC suppresses OSCC cell survival in association with modulation of AKT/ERK–survivin signaling and caspase-dependent apoptosis.
Non-small-cell lung cancer (NSCLC) treatment is hampered by its complex pathogenesis and high heterogeneity. N6-methyladenosine (m6A) represents the most common post-transcriptional modification regulating RNA stability and function in eukaryotes. This methylation is catalyzed by methyltransferase complexes, with METTL14 being the core catalytic subunit. Abnormal expression of lncRNA MSTRG.292666.16 is related to poor prognosis of NSCLC. However, the mechanism by which it regulates NSCLC progression through m6A modification remains unclear. We employed cell function experiments, molecular mechanism analysis, RNA interaction experiments, and a nude mouse tumor model to explore the roles of METTL14-mediated MSTRG.292666.16 m6A modification in NSCLC and the potential MAPK signaling pathway involved. METTL14 was significantly upregulated in NSCLC cell lines and promoted m6A modification of MSTRG.292666.16 by forming a stable association with it. METTL14 knockdown significantly inhibited the viability, migration and invasion of A549 cells and promoted apoptosis, whereas MSTRG.292666.16 overexpression reversed these effects. Mechanistically, METTL14 upregulated the expression of MSTRG.292666.16 through m6A modification, thereby activating the MAPK pathway (manifested as elevated levels of MAPK8IP3 and p-ERK1/2). The use of a selective p38 MAPK inhibitor SB203580 stimulated the tumor-suppressive effect of METTL14 knockdown, whereas the activator U-46619 reversed it. In vivo experiments confirmed that METTL14 knockdown significantly inhibited tumor growth, whereas MSTRG.292666.16 overexpression partially restored the malignant phenotype of the tumor, which was associated with MAPK pathway activation. This study revealed that METTL14-dependent m6A modification of MSTRG.292666.16 may act as an upstream driver to activate the MAPK cascade and facilitate NSCLC progression. These findings clarify a key epitranscriptomic regulatory mechanism driving NSCLC development and offer preliminary molecular clues for exploring potential therapeutic targets in subsequent clinical NSCLC research.
Plant growth-promoting bacteria (PGPB) are increasingly deployed as biofertilizers, yet the link between an inoculant’s genomic potential and its realized effect on the plant is rarely assessed within an integrative framework that jointly captures the rhizosphere microbiome, plant phenotype, and strain genome. Two Bacillus strains—B. halotolerans 1453 and B. pumilus 630—were applied to wheat and soybean in a factorial pot experiment (2 strains × 2 application methods × 3 frequencies + control, 3–4 replicates). Rhizosphere samples (n = 67 after filtering) were profiled by 16S rRNA sequencing with PICRUSt2 functional prediction and compositional validation (Aitchison PERMANOVA, ALDEx2, ANCOM-BC2). The PGPB gene repertoire was characterized by genome mining (481 marker genes, 14 categories). Wheat phenotype (six traits) and soybean height were analyzed with models appropriate for count data (Negative Binomial and binomial GLMs) for treatment-vs.-control comparisons, and with factorial ANOVA for decomposition into main effects and interactions. Crop identity was the dominant factor shaping both microbiome structure and function (PERMANOVA R2 = 14.7% taxonomically and R2 = 7.8% functionally, both p < 0.001), with biologically meaningful taxonomic differences between wheat and soybean; strain, application count and method had no significant effect on community composition (R2 < 4% each), and co-occurrence networks showed no reliable differences between crops once read depth and sample size were controlled for. Despite this neutrality at the microbiome level, inoculation significantly increased wheat spike count (NB-GLM, all 12 treatments vs. control, padj 0.0002–0.031), ear weight, and stem count, with application count the strongest source of variability and a pronounced strain × application count. Strain 1453 outperformed 630 in spike count (+23.1%, p = 0.012) and ear weight (+20.4%, p = 0.023); we hypothesize that this may be related to its more complete DNRA pathway (narGHI + nirB-nirD) and biocontrol genes (bacE, srfAA). Strain 630 produced a less pronounced effect than strain 1453 but was subject to smaller fluctuations across replicates (CV ≈ 16–21% vs. ≈24–26% for 1453), which may reflect better resilience to environmental fluctuations, possibly due to its confirmed rsbV/rsbW stress-tolerance regulon. Rhizosphere microbiome composition differed clearly by crop (wheat vs. soybean) but showed no detectable response to strain, application method, or application count. Despite this lack of a microbiome signal, inoculation significantly increased wheat spike count and ear weight, with the magnitude and stability of this effect differing by strain. We hypothesize that this strain-dependent difference relates to underlying genomic differences—particularly in nitrogen metabolism (DNRA pathway) and stress-tolerance genes—though this link has not been tested directly and remains a hypothesis for future work.
Intravitreal inhibition of vascular endothelial growth factor (VEGF) has transformed the management of neovascular age-related macular degeneration, diabetic macular oedema and macular oedema secondary to retinal vein occlusion, but frequent monitoring and retreatment remain major burdens. Ocular half-life is often used as shorthand for durability, although the clinical interval is produced by a wider molecular and biological system. This narrative review examines how dose, molecular format, hydrodynamic size, binding affinity, valency, ligand spectrum, target turnover, tissue distribution and delivery architecture determine the time for which an eye remains controlled. Human ocular pharmacokinetic and pharmacodynamic evidence is interpreted according to compartment, assay and model provenance, with particular attention to the distinction between drug elimination, free-ligand suppression, anatomical control and protocol-assigned treatment interval. Trial evidence for ranibizumab, aflibercept, conbercept, brolucizumab and faricimab shows that extended dosing can arise from greater starting exposure, altered binding architecture or pathway expansion without a proportionate change in intrinsic ocular half-life. Patient phenotype and retreatment rules further modify the observed interval. Refillable reservoirs, biodegradable depots and ocular gene therapy change the governing kinetics from bolus elimination to controlled release or sustained local production, thereby increasing the importance of reversibility and cumulative safety. We propose that durability be defined as a time-to-threshold phenotype integrating active target-site exposure, biological demand, anatomical recurrence, all treatment-related procedures and safety. Standardised estimands, longitudinal human ocular sampling, spatial exposure methods and externally validated mechanism-informed models are needed to make molecular durability comparable and clinically actionable.
1,2-Benzothiazine derivatives have attracted attention as structurally versatile scaffolds for antiviral drug discovery. Their sulfur-containing heterocyclic core supports diverse substitution patterns, allowing modulation of physicochemical properties and biological activity through medicinal chemistry optimization. This review summarizes published studies on 1,2-benzothiazine-based derivatives as potential inhibitors of human immunodeficiency virus (HIV) and hepatitis C virus (HCV), with particular emphasis on structure–activity relationships (SAR). Comprehensive SAR analyses indicate that substitutions at the N-1 and C-3 positions play a pivotal role in modulating antiviral potency and selectivity. Among the reported compounds, the most selective anti-HIV agent was a pyrazole-substituted 1,2-benzothiazine (9h) bearing a 2-amino-4-methylthiazolehydrazidoacetyl moiety, which exhibited an EC50 value of 3.8 μM against HIV-1 in primary human peripheral blood mononuclear cells. For HCV, the most promising derivative was a pyrazolebenzothiazine (5b) containing a 4-chloro substituent in the N-1 phenyl ring and a p-methanesulfonamidophenyl group at the C-3 position, demonstrating an IC50 value of 7.9 μM in the NS5B polymerase assay. Despite showing antiviral activity against both HIV and HCV, all tested compounds, including the most active derivatives, were considerably less potent than the corresponding reference drugs. Further optimization is therefore needed to improve their antiviral potency.
Glioblastoma (GBM) is the most aggressive primary brain tumor with limited therapeutic options and extremely poor prognosis. Aberrant activation of the receptor tyrosine kinase MET drives tumor progression, therapeutic resistance, and reduced survival, particularly in the mesenchymal GBM subtype. Given its crucial role in GBM recurrence and progression, we investigated the mechanisms of resistance to MET inhibition using patient-derived glioma-initiating cells (GICs) and orthotopic xenograft mouse models. GICs were treated with the MET inhibitor crizotinib to elucidate the mechanism of adaptive resistance. Prolonged MET inhibition induced a senescent-like phenotype in GICs, associated with downregulation of BNIP3, a mitochondrial protein regulating mitophagy. We showed that BNIP3 downregulation led to activation of mTOR signaling, promoting cellular survival and adaptive resistance. Combining crizotinib with the mTOR inhibitor everolimus effectively suppressed mTOR activity, reduced cell viability, and induced mitochondrial alterations, apoptosis, and necroptosis. In orthotopic GBM xenograft models, combined MET and mTOR inhibition significantly prolonged survival compared with single-agent treatments. Notably, sequential treatment—crizotinib followed by everolimus—further enhanced therapeutic efficacy. These effects were achieved without significant weight loss, supporting tolerability of the treatment regimen. Our findings identify the BNIP3-mTOR axis as a critical mediator of resistance to MET inhibition and demonstrate that combined inhibition of MET and mTOR exhibits significant synergy against GBM.
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by excessive extracellular matrix remodeling and limited therapeutic options. Matrix metalloproteinase-2 is involved in extracellular matrix degradation and tissue remodeling, making it a relevant target for antifibrotic drug discovery. In this study, an MMP2-focused ligand-based pharmacophore model was developed and was applied to screen a curated FDA-approved drug library, leading to the identification of 83 pharmacophore-matching compounds. These compounds were subsequently prioritized through molecular docking against the catalytic site of MMP2, and the five best candidates were further evaluated by molecular dynamics (MD) simulations. Because of the biological relevance of MMP3 in pulmonary fibrosis, these five selected compounds were also profiled against MMP3 as a secondary target. Among them, Regorafenib (S1178) and Capmatinib (S2788) showed the most favorable cross-target profiles and were further supported by MD analysis. From these findings, S1178 and S2788 were proposed as promising MMP2-prioritized compounds with potential MMP3 cross-activity, warranting further experimental validation as candidate antifibrotic MMP modulators.
Resting antioxidant enzyme activity in youth athletes may reflect stable individual redox characteristics and developmentally modulated plasticity. This 12-month longitudinal analysis from the MuCAYAplus study examined the tracking of superoxide dismutase (SOD) and glutathione peroxidase (GPX) in 69 trained athletes aged 10–17 years. Participants underwent repeated assessments of antioxidant enzyme activity, training exposure, body composition, and hematological parameters. Longitudinal tracking was evaluated using Pearson correlation and intraclass correlation coefficients, while change-score regression models tested whether changes in training exposure, growth-related variables, sex interactions, and hematological parameters predicted changes in SOD or GPX. In exploratory analyses, cluster-based redox phenotype stability was assessed using agreement statistics. Over 12 months, SOD decreased whereas GPX increased. GPX showed substantial tracking (r = 0.714, p < 0.001; ICC = 0.683), while SOD showed no meaningful tracking (r = 0.057, p = 0.644; ICC = 0.053). No statistically supported associations were detected between changes in training-exposure or growth-related measures and enzyme changes. Exploratory erythrocyte-related associations were observed for SOD, whereas leukocyte and platelet changes were unrelated. Cluster-based SOD/GPX phenotype analyses were not robust. These findings are compatible with a comparatively stronger trait-like component for GPX and greater state-like variability for SOD.
CYB5R3 (NADH–cytochrome b5 reductase 3) and mARC1, the product of MTARC1, draw on the same cytochrome-b5 electron relay, so they are usually treated as two ends of one redox axis. Whether they behave as a unit across the continuum from metabolic dysfunction–associated steatotic liver disease (MASLD) to hepatocellular carcinoma (HCC) has not been established. In TCGA-LIHC, higher CYB5R3 expression was associated with shorter overall survival in a continuous multivariable Cox model adjusted for age, sex, and stage (n = 339, 114 deaths; HR 1.23 per SD, 95% CI 1.01–1.48, p = 0.035), although it added essentially nothing to a clinical model containing age, sex, and stage (change in Harrell C-index 0.005, 95% CI −0.015 to +0.037). The direction was reproduced in the only independent cohort examined, GSE14520 (n = 242, 96 deaths; unadjusted HR 1.42 per SD, 95% CI 1.14–1.76, p = 0.0015), in which higher MTARC1 was associated with longer survival (unadjusted HR 0.73 per SD, 95% CI 0.60–0.89, p = 0.0017); both single-gene estimates fall below conventional significance after adjustment for age, sex, and TNM stage (HR 1.24, 95% CI 0.99–1.56, p = 0.058 and HR 0.89, 95% CI 0.72–1.10, p = 0.29; n = 225, 86 deaths), although CYB5R3 remains nominally significant in an adjusted model containing both genes (HR 1.27, 95% CI 1.01–1.59, p = 0.039), so that cohort replicates direction rather than independent prognostic value. Across the primary tumors of the analysis set, no correlation between the two transcripts was detectable (Spearman rs = −0.03, 95% CI −0.13 to +0.08, p = 0.62; n = 339), so the axis is not demonstrably a unit at the expression level. In three human liver-biopsy cohorts spanning the MASLD histological spectrum (393 biopsies with fibrosis staging), CYB5R3 gave estimates that differed in sign between cohorts and were uninformative when pooled (fibrosis stage, random-effects rs = +0.01, 95% CI −0.24 to +0.26, q = 0.95, I2 = 83%). MTARC1 behaved differently, falling with fibrosis stage in all three cohorts (pooled rs = −0.22, 95% CI −0.32 to −0.13, q = 3 × 10−5, I2 = 0%), as did PARP16 (−0.17, I2 = 0%), while SCD rose in all three (+0.13, I2 = 0%). This is consistent with the inconsistency being specific to CYB5R3 rather than a property of the cohorts, although the fibrogenic positive controls were themselves heterogeneous (I2 = 53–62%), I2 is estimated from only three cohorts, and the difference between the CYB5R3 and MTARC1 coefficients was not formally tested. These observations are associative and hypothesis-generating. They provide no support for the widely assumed corollary that hepatic CYB5R3 becomes deficient as steatotic liver disease advances, so a therapeutic strategy predicated on that corollary currently rests on mouse gain-of-function data alone, without corroboration from human tissue. What they do support is narrower: within a single physically coupled electron-transfer axis, the two members behave differently before malignancy—MTARC1 tracks fibrosis stage reproducibly while CYB5R3 shows no reproducible relationship—and carry opposite prognostic directions after malignancy, significant for MTARC1 only before covariate adjustment.
OX40 (TNFRSF4) is a costimulatory T-cell receptor and OX40 agonists are in clinical development, yet its role in small cell lung cancer (SCLC) is still to be characterised. We analysed the discovery cohort (n = 77, 48 events), GSE60052 (n = 79 tumours; 48 with survival), GDSC1+GDSC2 (61 SCLC cell lines, 542 drugs) and human SCLC single-cell atlas (77,143 cells from primary and metastatic sites, 20 donors), using Cox models, FDR-controlled correlation, nested-model comparison and deconvolution. High TNFRSF4 showed a non-significant protective trend (pooled HR = 0.86 per SD, 0.68–1.10, p = 0.23); a nominal cutpoint did not survive correction for cutpoint search (p = 0.25). No drug reached FDR < 0.05 among 658 tests, including platinum agents and etoposide. TNFRSF4 tracked immune infiltration (13-gene score ρ = 0.76, p = 3 × 10−16) and was detected in 17.6% of T cells versus 1.03% of malignant cells in all 20 donors. OX40 was enriched in the POU2F3/SCLC-P subtype (p = 0.033), persisting after immune adjustment (β = 1.32, p = 0.011) but not replicating independently (p = 0.10). Adding TNFRSF4 to clinical-plus-immune models provided no meaningful discrimination gain (ΔC-index ≤ 0.005). Power was limited to HR ≥ 1.50 harmful or HR ≤ 0.67 protective, so the observed trend is undetectable at this size. Bulk OX40 therefore primarily reflects immune infiltration, and its SCLC-P association is a hypothesis for prospective testing.
Coronary artery disease (CAD) and non-obstructive azoospermia (NOA) have distinct aetiologies. We examined whether separately analysed public transcriptomic cohorts contained overlapping exploratory candidate signals without assuming a shared causal mechanism. We re-analysed five Gene Expression Omnibus datasets using differential-expression screening, weighted gene co-expression network analysis (WGCNA), an archived neural-network candidate ranking, xCell enrichment scoring, and single-cell transcriptomic mapping. Nominal differential-expression screening identified 978 CAD-associated and 2562 NOA-associated candidate transcripts. WGCNA showed a moderate correlation between the MElightyellow module and NOA status (r = 0.58, p = 0.007) in GSE45887, a small, imbalanced, non-independent subset of GSE45885. An archived neural-network (NNET) ranking prioritised HSPA1B, PLCL2, ISLR2, STRN, and AQP7 for descriptive analyses; the ranking was generated from the same 20 specimens and is treated as heuristic. xCell produced marker-gene enrichment scores rather than direct measurements of cell abundance or function. Single-cell mapping was descriptive because GSE149512 combined heterogeneous NOA aetiologies with paediatric and adult comparator tissues. The analyses generate hypotheses from separate CAD and NOA cohorts. They do not establish a shared causal pathway, a sex- or age-independent association, temporal sequence, clinical diagnostic utility, or direct correspondence between testicular and coronary cell states.
Seawater electrolysis is emerging as a key alternative strategy for sustainable hydrogen production in water-scarce regions such as the Atacama Desert; however, the high concentration of chloride ions poses significant challenges related to material stability, selectivity, and corrosion resistance. In this context, Prussian Blue Analogues (PBAs) have recently gained attention as multifunctional materials capable of operating in highly saline environments such as seawater. This review provides a critical analysis of PBAs as electrocatalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in seawater and brine systems, with a particular emphasis on nickel hexacyanoferrate (NiHCF), cobalt hexacyanoferrate (CoHCF), and copper hexacyanoferrate (CuHCF). In addition, a comparative analysis across different electrochemical applications is presented, highlighting the limited number of studies conducted under real seawater conditions. Furthermore, the limitations of current electrochemical evaluation protocols are discussed, and a framework for realistic benchmarking under saline conditions is proposed. Finally, emerging opportunities in hybrid materials and high-entropy PBAs are addressed, positioning PBAs as a promising platform for next-generation electrochemical technologies for sustainable solar hydrogen production from seawater or highly chloride-concentrated brines.
An efficient approach to unsymmetrical 1,10-phenanthroline-2,9-dicarboxamides based on the bifunctional reactivity of 4-oxo-7-haloderivatives is reported. These substrates exhibit orthogonal reactivity, enabling selective nucleophilic aromatic substitution at the C7 position alongside electrophilic functionalization of the 4-oxo group under mild conditions. Reactions with a broad range of C-, N-, and O-nucleophiles afford 4-oxo-7-functionalized products in high yields, while subsequent transformations of azido- and hydroxy-substituted derivatives further demonstrate the synthetic versatility of this platform. The observed chemoselectivity is reflected in the highly selective O-functionalization of the 4-oxogroup, with alkylation proceeding under mild conditions. The developed strategy provides a general route to structurally diverse unsymmetrical derivatives and highlights the potential of 4-oxo-7-halo-systems as bifunctional building blocks.
Non-small cell lung cancer is one of the leading causes of cancer-related mortality. The effectiveness of treatment is limited by several factors, including significant tumoral heterogeneity, rapid development of drug resistance, high metastatic potential, and a complex tumor microenvironment. In recent years, natural products have emerged as valuable resources for the discovery of novel antitumor strategies against non-small cell lung cancer. These compounds possess diverse chemical properties, target multiple pathways, are abundant in nature, and exhibit relatively low toxicity. The utilization of existing medications with established pharmacokinetic profiles and safety records, combined with shorter development timelines, shows promise for advancing lung cancer treatment research. A growing body of evidence indicates that both naturally occurring compounds and commercially available drugs exert effects that extend beyond traditional cytotoxic mechanisms. These agents influence processes such as ferroptosis, oxidative stress, metabolic reprogramming, autophagy, apoptosis, epithelial–mesenchymal transition (EMT), tumor immune microenvironments, and epigenetic networks, suggesting that their activities can be leveraged for a robust multi-target antitumor strategy. Accordingly, this review summarizes research advances on natural products and repurposed marketed drugs for non-small cell lung cancer; outlines their potential for combination with chemotherapy, targeted therapy, radiotherapy and immunotherapy; and discusses future directions for clinical translation.
The jujube tree fruit remains a primary fruit in northern China, yet its geographical distribution and yield are significantly constrained by freezing stress during winter. Numerous studies have highlighted the pivotal regulatory function of microRNAs (miRNAs) in plant responses to low-temperature stress. Nevertheless, the specific miRNAs involved in the response to low temperatures and their associated gene networks in Ziziphus jujuba Mill are not well understood. In this investigation, we utilized high-throughput sequencing to analyze small RNA libraries from branches subjected to temperatures of 4 °C and −30 °C. Our analysis identified a total of 342 miRNAs, comprising 123 known miRNAs and 219 novel miRNAs. The differential expression analysis revealed that under low-temperature conditions, 177 miRNAs underwent significant changes. Among them, specific upregulation of miR319 in the less cold-resistant variety and miR6483 in sensitive variety was observed. By employing degradome sequencing, we identified a total of 1551 target genes corresponding to 3059 unique miRNA target interaction pairs involving 299 miRNAs. Functional analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways indicated that these target genes are primarily associated with transcriptional regulation, metabolic pathways, and genetic information processing. Through a comprehensive analysis, we pinpointed 11 genes corresponding to 9 miRNAs that are implicated in jujube tree cold stress, and 7 target genes of 7 miRNAs were confirmed by 5′-RACE analysis. These miRNAs are likely to exert crucial regulatory functions in the context of jujube tree cold stress. This study is the first to systematically identify miRNAs and their target genes in the response of Ziziphus jujuba Mill to low-temperature stress, which provides important resources for in-depth analysis of the molecular mechanism of jujube tree cold resistance and for cold-resistant breeding.
Type 2 diabetes mellitus (T2D) is a major and growing global health burden that is associated with substantial cardiovascular, renal, and metabolic complications and is increasingly recognized as a systemic disorder involving multiple organs, particularly the liver. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than half of individuals with T2D, and the two conditions have a bidirectional relationship: T2D promotes the development and progression of MASLD, including advanced fibrosis and increased liver-related mortality, while MASLD worsens insulin resistance and metabolic control, favoring the onset of T2D. In this context, the liver is increasingly viewed not only as a metabolic organ but also as an endocrine one, secreting hepatokines that act on distant tissues to regulate insulin sensitivity, inflammation, glucose metabolism, and lipid homeostasis. Through these actions, hepatokines are thought to represent one of the mechanistic links between MASLD and T2D. This narrative review summarizes current evidence on several of the most extensively studied hepatokines, including fibroblast growth factor 21, fetuin-A, fetuin-B, leukocyte cell-derived chemotaxin-2, selenoprotein P, angiopoietin-like proteins, and retinol-binding protein 4. As a distinctive feature, the review also discusses emerging pharmacological strategies targeting hepatokine pathways and evaluates how commonly used antidiabetic therapies may modulate hepatokine secretion.
Genetic testing plays an important role in the diagnosing of liver diseases, but its diagnostic performance varies across patient populations. By analyzing diagnostic yield across patient subgroups, this study aims at defining age-tailored diagnostic workflows for a more effective integration of genetic testing into clinical practice. We retrospectively analyzed 203 patients (145 children, 58 adults) with acute or subacute liver disorders of suspected genetic origin who underwent next-generation sequencing, categorized them by clinical diagnosis, and evaluated diagnostic yields to develop age-tailored testing workflows. The median age was 8 years; 65.5% were male, 84.7% White, and 27.6% had undergone liver transplantation. Cholestatic liver disorders (30%) and unexplained liver dysfunction (20.2%) were the most common indications for testing. Overall, genetic testing achieved a definitive diagnosis in 35.5% of patients, with a higher yield in children than adults (41.4% vs. 20.7%). Metabolic disorders had the highest diagnostic yield (83.3%), while PFIC/BRIC and Alagille syndrome were the most frequent genetic diagnoses. Age-specific diagnostic workflows retrospectively enriched the overall diagnostic rate by approximately 11% across age and disease categories. These findings demonstrate that tailoring genetic testing strategies to patient age and clinical presentation can improve diagnostic efficiency and support a standardized integration of genetic testing into hepatology practice.
