International Journal of Molecular Sciences最新文献

Hyperlipidemia (HLP) is a metabolic dysfunction marked by dysregulated lipid metabolism, which jeopardizes cardiovascular health. The function of autophagy modulated by the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in HLP pathogenesis has not been fully elucidated. Thus, this study centered on the impacts of different feeding durations on HLP models. ICR mice were given a high-fat diet (HFD) to induce the model, with durations set at 3, 6, 9, 12, and 15 weeks. Body weight, liver and adipose organ indices, serum and hepatic lipid levels, and pathological changes (assessed by Oil Red O and HE staining) were measured. Related pathway markers were detected via immunofluorescence, quantitative real-time PCR (qPCR), and Western blotting. At week 9, the relative protein expression ratios of P-AMPK/AMPK, P-mTOR/mTOR, and P-ULK1/ULK1 were markedly reduced, while the expression levels of LC3Ⅱ/LC3Ⅰ and P62 proteins were notably elevated, exhibiting transient dysregulation characteristics and suggesting a potential optimal modeling time point. It clarifies the temporal pattern, core molecular mechanism, and critical turning point of abdominal adipose metabolic disorder induced by a high-fat diet (HFD) in ICR mice. This study offers a credible basis for the optimal duration of HLP modeling and in vivo animal experimental design.

Aging profoundly reshapes the immune system, leading to increased susceptibility to infection, impaired vaccine responses, chronic inflammation, and age-associated inflammatory diseases. While immune aging has traditionally been attributed to defects in immune cell development, signaling, and metabolism, emerging evidence highlights dysregulation of programmed cell death as a central and unifying mechanism. Apoptosis, necroptosis, pyroptosis, and ferroptosis are increasingly recognized not only as terminal cellular events but also as active regulators of immune homeostasis and inflammatory signaling. In aged immune cells, coordination among these death pathways is disrupted, weakening apoptotic resolution and favoring inflammatory forms of cell death that amplify tissue damage and sustain inflammaging. In this review, we summarize current evidence on how aging remodels programmed cell death pathways in the immune system, discuss the molecular mechanisms underlying this network-level shift, and consider potential strategies for restoring immune function by modulating cell death decisions.

The uterus is a dynamic organ in which the endometrium undergoes cyclic processes of proliferation, shedding, and regeneration under the influence of estrogen and progesterone. In particular, estrogen regulates the proliferation and differentiation of the endometrium and plays an important role in the development of gynecological diseases such as endometrial cancer. Farnesyl diphosphate synthase (FDPS) is a key enzyme involved in the mevalonate pathway, catalyzing the synthesis of farnesyl pyrophosphate (FPP), which plays an essential role in cholesterol biosynthesis and protein prenylation. In this study, we demonstrated using an in vivo mouse model that the expression of FDPS is regulated by estrogen. FDPS expression was specifically elevated during the proestrus stage of the estrous cycle and subsequently decreased. In ovariectomized (OVX) mice, FDPS expression was significantly increased 24 h after estrogen treatment, whereas this response was suppressed by treatment with the estrogen receptor alpha (ERα) antagonist, ICI 182,780. Although FDPS expression has been reported in various cancers, its role in endometrial cancer remains unclear. Histological and cellular analyses revealed that FDPS is highly expressed in human endometrial cancer tissues and in the endometrial cancer cell line Ishikawa, where it contributes to cell proliferation. These findings suggest that FDPS may play a role in the survival and growth of endometrial cancer cells. This study provides new insights into the potential function of FDPS in the uterus and suggests that targeting FDPS may represent a promising therapeutic strategy for endometrial cancer.

Flavonoids exert antioxidant activity by scavenging free radicals, chelating metals, and modulating antioxidant enzymes. The root extract of Glycine tomentella Hayata (GTE), a traditional Chinese medicinal herb contains flavonoids, particularly, isoflavones. However, its neuroprotective effects against anxiety remain unclear. In this study, the effects of GTE on anxiety-like behavior and oxidative stress in male Balb/c mice were investigated. The mice were administered GTE orally once daily for 14 d and subsequently, the anxiolytic-like effects of the extract were observed via elevated plus maze and open field tests. Oxidative stress levels in the treated mice were also measured. The results obtained identified daidzein (9.19 mg/g dry extract) and daidzin (2.95 mg/g dry extract) as the key isoflavones in GTE. Furthermore, free radical scavenging assays confirmed that GTE shows strong antioxidant activity, with an IC50 value of 8.82 μg/mL. It also showed pronounced anxiolytic effects, attenuating reactive oxygen species production in a dose-dependent manner. Mechanistic studies attributed these effects to the estrogenic activity of daidzein, which possibly modulates emotional state via estrogen receptor activation and systemic oxidative stress mitigation. These findings suggest that isoflavone-enriched GTE is a natural resource with potential for use as an antioxidant for mitigating anxiety.

Tumor angiogenesis is a critical driver of cancer progression; however, current anti-angiogenic therapies remain limited by resistance and toxicity. Hypoxia within the tumor microenvironment induces hypoxia-inducible factor-1α (HIF-1α), which promotes aberrant angiogenesis by upregulating vascular endothelial growth factor (VEGF) and, subsequently, delta-like ligand 4 (DLL4) in endothelial cells. A systematic screening of flavanone derivatives was performed to identify compounds capable of dual inhibition of HIF-1α and DLL4. Among 16 natural compounds evaluated, isoxanthohumol (IXN), a prenylated flavanone, emerged as the most potent, suppressing both hypoxia-induced HIF-1α accumulation in tumor cells and VEGF-induced DLL4 expression in endothelial cells. IXN markedly inhibited endothelial proliferation, migration, and tube formation in vitro. In a Lewis lung carcinoma (LLC) mouse syngeneic model, IXN monotherapy reduced tumor growth and vessel density. Notably, combination treatment with IXN and anti-PD-1 immunotherapy produced greater anti-tumor effects than either monotherapy. This combination enhanced cytotoxic T cell infiltration into the tumor core, increased granzyme B expression, and induced widespread tumor cell apoptosis, consistent with improved vascular normalization. These findings identify IXN as a promising dual-targeting agent that inhibits both HIF-1α and DLL4 and demonstrate its potential to enhance immune checkpoint blockade. Simultaneous targeting of hypoxia-driven and VEGF-DLL4-mediated angiogenic pathways represents a compelling therapeutic strategy to overcome the limitations of current anti-angiogenic and immunotherapeutic approaches.

We present a family case study of Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene, in which two of three siblings were clinically diagnosed with PMS. Sanger sequencing identified a novel heterozygous deletion in exon 20 of SHANK3 (c.3679del, p.Ala1227Profs*168), predicted to introduce a premature stop codon and truncate the protein; this variant was absent in the unaffected sibling. Auditory steady-state responses (ASSRs) were recorded at 16, 27, and 40 Hz. The 40 Hz ASSR was markedly reduced in both affected siblings, reaching statistical significance in the younger child and remaining non-significant in the older sibling, while it was preserved in the unaffected sibling. These findings suggest that the 40 Hz ASSR is particularly sensitive to SHANK3-related cortical inhibitory dysfunction during childhood and adolescence, with reduced sensitivity in early adulthood. The results highlight the potential of the 40 Hz ASSR as an electrophysiological biomarker in PMS and underscore the need for age-stratified normative control datasets to enable robust individual-level interpretation and support its use in biomarker development, clinical trial stratification, and monitoring of treatment response.

The persistence of latent HIV-1 reservoirs in individuals on antiretroviral therapy (ART) remains a major barrier to cure, necessitating strategies such as "shock and kill" using latency-reversing agents (LRAs). However, current LRAs show limited clinical efficacy, highlighting the need for novel interventions. This study evaluated the in vitro latency-reversing potential of Product Nkabinde (PN) and Gnidia sericocephala using J-Lat A2 (subtype B) and J-Lat C clones T66 and T17 (subtype C) cells. Cell viability was assessed using flow cytometry with Live/Dead dye. Reactivation potential was further tested in combination with established LRAs: panobinostat, SAHA, and TNF-α. G. sericocephala induced dose-dependent latency reversal, with 26.1% of J-Lat A2 and 15.8% of J-Lat T66 cells GFP-positive at 106 µg/mL (p = 0.0001). Co-treatment with LRAs enhanced reactivation-34.6% with SAHA and 87.2% with TNF-α in J-Lat A2 cells, and 56.9% with SAHA and 65.4% with TNF-α in J-Lat T66 cells (p = 0.0001)-while maintaining cell viability above 90%. PN showed minimal activity (≤1.3% GFP-positive) and no effect in combination assays. Fractional inhibitory concentration index analysis revealed no synergistic interactions. Ex vivo, PN and G. sericocephala induced limited increases in HIV-1 gag RNA without substantial cytotoxicity. These findings demonstrate that G. sericocephala effectively reverses HIV-1 latency and potentiates TNF-α-induced reactivation, supporting its potential as a plant-derived LRA for future "shock and kill" HIV-1 cure strategies.

Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents, and outcomes for metastatic disease have remained poor, highlighting the need for molecular biomarkers. We integrated three Gene Expression Omnibus (GEO) mRNA expression datasets (GSE12865, GSE14359, and GSE246405) to identify differentially expressed genes (DEGs) between OS and non-malignant bone-related controls. Overlapping DEGs were used to build a protein-protein interaction network, and hub genes were prioritized using multiple network topology algorithms. Prognostic associations were evaluated using the R2 Genomics Platform. Putative upstream miRNAs targeting the top candidate were obtained from prediction databases and intersected with dysregulated circulating miRNAs from GSE65071 (localized OS plasma vs. healthy controls). Functional enrichment analyses (Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and cancer hallmarks) were performed to contextualize the candidate signature. We identified 107 overlapping DEGs and prioritized eight hub genes. CD81 was significantly associated with overall survival (Bonferroni-adjusted p = 0.043) and showed reduced expression in OS tissues and cell line models. hsa-miR-582-5p was nominated as a candidate miRNA predicted to target CD81 and was upregulated in OS plasma. Enrichment results linked the signature to angiogenesis, extracellular matrix remodeling, focal adhesion, and metastasis-associated signatures. These findings support CD81 as a candidate prognostic biomarker and nominate a putative hsa-miR-582-5p-CD81 relationship for future validation.

This article presents the concept of using a functionalised siloxane compound HOL9 with amphiphilic properties as a coating for cement composites to enhance their antifouling properties against algae. The biological properties of the compound were assessed based on its ability to inhibit chlorophyll fluorescence intensity, which is used as an indicator of photosynthetic activity and biofilm development. The greatest decrease in algal photosynthetic activity was observed for a 10% aqueous solution of HOL9 applied by painting. In these conditions, the maximum ^chlFI value decreased by 97.6%. In addition, the impact of the protective coating containing HOL9 on the fundamental physical and mechanical characteristics of the cement composite, along with its resilience to frost cycling, was thoroughly investigated. The coating applied by immersion demonstrated a 50.7% strength loss after 150 freeze-thaw cycles, while the coating applied by painting exhibited a 43.8% loss. In comparison, the control samples experienced a 42.8% strength reduction. It has been demonstrated that the method of application, the modifier concentration, and the type of solvent can have a substantial impact on the protective properties of concrete. The most marked inhibition of algae photosynthetic activity was observed with a 10% aqueous solution applied by painting.

Neurodegenerative diseases (NDs) are among the leading causes of disability and mortality worldwide and are characterized by multifactorial pathogenesis involving interconnected mechanisms, such as oxidative stress, protein misfolding and aggregation, neuroinflammation, and mitochondrial dysfunction. Dysregulation of transcription factors, governing cellular defense responses, particularly nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and proteostatic pathways, plays a critical role in neurodegenerative processes. Currently, available pharmacological treatments for NDs are largely symptomatic, as no disease-modifying therapies exist. Natural bioactive compounds have emerged as promising multi-target agents, demonstrating antioxidant, anti-aggregative, and anti-apoptotic properties, frequently mediated through activation of the Nrf2 signaling pathways. These compounds may represent valuable supportive strategies alongside conventional drug treatments, potentially contributing to the modulation of multiple pathogenic mechanisms. This review summarizes key oxidative stress- and protein aggregation-driven mechanisms underlying Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. It further examines the neuroprotective potential of plant-, fungi-, and marine-derived natural compounds, with particular emphasis on Nrf2 activation. Beyond redox regulation, the broader role of Nrf2 in maintaining proteostasis is discussed. Overall, the review highlights Nrf2-inducing nutraceuticals as promising complementary, multi-target approaches for neuroprotection in NDs.