Advanced biology最新文献

Glaucocalyxin A (GLA), a bioactive diterpenoid from the medicinal plant Rabdosia japonica, demonstrates potent antitumor activity, yet its molecular mechanisms in renal cell carcinoma (RCC) remain elusive. Here, GLA is reported to trigger cytotoxicity in RCC cells through reactive oxygen species (ROS) overaccumulation. Mechanistically, ROS surge activates autophagy, and pharmacological or genetic autophagy inhibition significantly rescues GLA-induced cell death, indicating autophagy acts as a pro-death effector in this context. Employing activity-based protein profiling (ABPP) coupled with proteomic analysis, peroxiredoxins PRDX1/2 are identified as direct covalent targets of GLA. Functional validation reveals that PRDX1/2 overexpression mitigates GLA-mediated apoptosis, establishing their role as critical redox sensors governing cell fate. The findings delineate a ROS-autophagy-apoptosis axis driven by PRDX1/2 targeting, positioning GLA as a novel therapeutic scaffold for RCC treatment.

Small nucleolar RNAs (snoRNAs)—60–300 nucleotide non-coding RNAs are associated with adverse clinical outcomes in cancer patients. However, information on the role of snoRNAs and associated small nuclear ribonucleoprotein (snoRNPs) in prostate cancer (PCa) remains scarce. Here, the contribution of the snoRNP U3 snoRNA-interacting protein 2 (RRP9) in PCa pathogenesis is investigated. A combination of three different shRNAs is employed to knockdown RRP9 in the PCa cell lines DU-145 and PC-3. Cell proliferation is evaluated by seeding cells into a 96-well plates and monitoring daily. Cell migration is evaluated by scratch and Transwell assays. FLAG-RRP9 pull-down, MALDI-TOF/TOF, and co-immunoprecipitation assays are conducted to identify RRP9 binding partners in DU-145 cells. In vitro cell proliferation and migration, as well as in vivo tumor growth, are suppressed following RRP9 knockdown. Pull-down and MALDI-TOF/TOF analyses identified five putative RRP9 binding partners, and co-immunoprecipitation validated that RRP9 interacts with the scaffolding hub protein Sequestome-1 (SQSTM1, p62). Interestingly, SQSTM1 overexpression rescued the anti-growth/migration effects of RRP9 knockdown. This study unveiled a novel oncogenic role for the RRP9-SQSTM1 axis in PCa cells. RRP9 is a snoRNP that binds to SQSTM1, thereby promoting PCa cell proliferation and migration. Targeting the RRP9-SQSTM1 axis may be a viable therapeutic strategy for PCa.

Brown adipose tissue (BAT) is crucial for maintaining whole-body metabolic homeostasis and combating obesity and metabolic disorders. SOX4 collaborates with EBF2 to promote the expression of thermogenic genes in BAT, but it is unclear whether there are mechanisms independent of this regulation. However, it is found that SOX4 can directly interact with the promoter regions of thermogenic genes, thereby activating their expression. Simultaneously, early B cell factor 2 (EBF2) and peroxisome proliferator-activated receptor-γ (PPARγ) can independently interact with SOX4, forming two distinct complexes that promote the expression of thermogenic genes. Phenotypically, the deletion of SOX4 in BAT of mice (Ucp1^Cre+-Sox4^f/f (Sox4-BKO)) leads to the downregulation of thermogenic and oxidative phosphorylation genes, as well as a reduction in mitochondrial numbers. Furthermore, Sox4-BKO mice are more susceptible to obesity, glucose intolerance, and insulin resistance when subjected to a high-fat diet (HFD). Consistently, the loss of SOX4 results in increased cellular triglyceride content and reduced expression levels of thermogenic genes in vitro. Together, a novel mechanism by which SOX4 regulates thermogenesis in BAT is elucidated, offering a promising strategy to address obesity and metabolic disorders.

Transgender individuals experience profound health disparities across the life course, shaped by developmental, social, and environmental stressors that accumulate over time. As they age, these disparities manifest in poorer physical and mental health, increased disability, and heightened risks of multimorbidity compared to cisgender peers. This editorial examines the scientific value of integrating life course frameworks, minority stress models, and exposome research to understand the biological and psychosocial mechanisms underlying these disparities. The importance of investigating resilience is highlighted —both physiological and psychosocial—as a key factor in promoting healthy aging, alongside the need to study intersectionality, particularly how race, ethnicity, immigration status, and socioeconomic context interact to influence health outcomes. Additionally, research opportunities are outlined to evaluate the long-term impact of gender-affirming care, advocacy efforts, and macro-level social stressors on health trajectories. It is emphasized how insights gained from transgender-focused research can inform broader health science, including comparative investigations in other high-stress populations, such as military veterans. Together, these lines of inquiry can advance precision health strategies, foster inclusive and person-centered healthcare models, and ultimately improve health equity across diverse aging populations.

Physiological aging is accompanied by structural and molecular changes in the brain, with varying degrees in different brain areas, and is considered one of the major risk factors for neurodegenerative diseases. Thus, the present study focuses on elucidating age-related changes in the substantia nigra pars compacta (SNpc), a brain region particularly vulnerable in Parkinson's disease. Here, the aim is to gain a spatially resolved view of aging-dependent alterations to conclude early processes potentially involved in neurodegeneration. Neuromelanin granules and SNpc tissue are isolated from tissue samples of young and elderly individuals via laser microdissection and measured by mass spectrometry to ascertain changes in protein expression in response to age. The findings include the identification of reduced levels of proteins involved in dopaminergic neurotransmission, either suggesting a specific loss of dopaminergic neurons or a reduction in metabolic activity. Furthermore, increased neuroinflammation is observed in elderly individuals and alterations in vesicular trafficking as well as mitochondrial proteins. Consequently, this exploratory study suggests that alterations causing known pathomechanisms of Parkinson's disease are already occurring in the physiological aging process. Since aging is still the most important risk factor for neurodegenerative diseases, these findings strengthen the necessity for studying age-related changes.

Signal Transducer and Activator of Transcription 3 (Stat3) acts as a central transcriptional modulator coordinating cellular proliferation, survival, apoptosis, vascularization, immune regulation, and migratory processes. Human Stat3 deficiency triggers Hyper-IgE syndrome, associated with immune dysregulation, osseous defects, and dental malformations. This study employs genetically engineered murine models to dissect Stat3's mechanistic role within mesenchymal progenitor cells during molar root formation and periodontal tissue maturation. Conditional Stat3 knockout mice (Prx1-Cre; Stat3^f/f) are generated. Comparative assessments of mandibular first molar root development between Stat3 CKO and wild-type cohorts are performed through histomorphometric evaluation, micro-computed tomography, cellular proliferation assays (Ki67/BrdU), and transcriptome sequencing. Stat3 ablation causes marked morphological defects in first molars, featuring reduced root length and elevated crown-root proportion. The periodontal ligament (PDL) at the distal root exhibits diminished width in mutants. Alveolar bone displays suppressed expression of osteogenic markers (Runx2, Col1a1, Ocn), accompanied by decreased Ki67⁺ and BrdU⁺ cell populations in the PDL. Stat3 critically regulates mandibular first molar and alveolar bone morphogenesis. Conditional ablation of Stat3 disrupts the osteogenic capacity of Prx1⁺ mesenchymal progenitors, as evidenced across in vivo and in vitro models.

Esophageal cancer is a major disease that seriously threatens human health. Ribosomal RNA biogenesis is implicated in tumorigenesis, while the small nucleolar RNAs (snoRNAs) are responsible for post-transcriptional modifications of ribosomal RNAs during biogenesis, which are identified as potential markers of various cancers. The clinical significance, biological behavior, and potential molecular mechanism of the nucleolar small nuclear ribonucleoprotein RRP9 in esophageal squamous cell carcinoma (ESCC), which is a major pathological type of esophageal cancer, are investigated in this study. It is found that RRP9 is abnormally highly expressed in ESCC tissues and is closely associated with poor prognosis. Furthermore, it is found that RRP9 could regulate the cell cycle protein-dependent kinase CDK1 to promote ESCC progression in vitro and in vivo. Mechanistically, RRP9 promotes ESCC progression through enhancing the E2F1-mediated transcriptional regulation of CDK1. Collectively, the results defined RRP9 as an important tumor driver in ESCC that acted by activating oncogenic signaling by the E2F1-CDK1 pathway, and suggested RRP9 as a candidate therapeutic target for ESCC.

The mechanisms underlying leaf unfolding remain largely speculative and are often inferred from mathematical models. Peltate leaves, unlike typical foliage leaves, frequently emerge in a “rolled-up” state. This study investigates mechanisms related to the unrolling process in the peltate species Syngonium podophyllum by analyzing anatomical and morphological changes and quantifying forces that arise during unrolling. Leaf unrolling in S. podophyllum appears to be primarily driven by cell expansion, particularly in the upper epidermis, with cell turgor playing an important role in leaf development and unrolling. Considering leaf properties such as cell dimensions and leaf radius of curvature, this work proposes a mathematical model to further characterize the unrolling process. The model provides satisfactory predictions of curvature variations, highlighting its potential for other plant movements involving dynamic curvature changes.

Growth factors play a crucial role in regulating cellular processes such as proliferation, differentiation, and survival. Their activities are tightly modulated to ensure proper physiological functioning, with dysregulation often contributing to disease pathogenesis. Among these, the insulin-like growth factor (IGF) system that encompasses IGF-1 and IGF-receptor binding proteins is pivotal in maintaining overall cellular health by regulating growth, repair, and metabolic regulation. Capitalizing on its pro-mitogenic effects, translational studies have focused efforts on developing therapeutics based on IGF-1 for age-related muscle loss, metabolic disorders, or cardiovascular diseases. Mimetic peptide design has emerged as an innovative approach to overcoming limitations of direct IGF-1 therapy, focusing on structural optimization to enhance bioavailability, stability, and receptor specificity. Herein, the development of IGF-1 mimics and their potential clinical applications are reviewed. Their design and molecular properties, including structural considerations and mechanisms of action, are described. In vitro and in vivo approaches analyzed to provide insights into their pharmacokinetics, therapeutic efficacy, and safety profiles in animal models will be delved into. These preclinical studies shed light on the advantages of IGF-1 mimics, such as bioavailability, stability, and delivery, as well as the limitations, including potential immunogenicity.

Antimicrobial Photodynamic Therapy (aPDT) has become a potential alternative for treating multidrug-resistant bacterial skin infections, such as those caused by methicillin-resistant Staphylococcus aureus (MRSA), which are at high risk in aging individuals. One of the main components of aPDT is an agent known as a photosensitizer (PS). Some plants with high flavonoid content are reported as PS. In the genus Passiflora, flavonoids are predominant, but their photosensitizing activity has yet to be described. This study investigates the photosensitizing potential of extracts from Passiflora edulis, Passiflora alata, and Passiflora cincinnata. The butanolic fraction of P. cincinnata undergoes in vivo evaluation against intradermal MRSA infection in a senescent murine model (C57BL/6). In vitro assays determine the photoactivatable concentrations and their cytotoxicity. In vivo, MRSA-infected mice are divided into control, P. cincinnata-treated, and aPDT-treated groups. Subsequent assessments include cytokine levels, bacterial load, and cellular infiltrate in the ear. The P. cincinnata-treated group exhibits improved bacterial control, reduced leukocyte infiltration, and less weight loss. The aPDT group demonstrates a unique cytokine correlation profile, featuring more negative correlations among pro-inflammatory cytokines and interleukin-10. P. cincinnata emerges as an effective photosensitizer for aPDT in a senescent model and highlights the potential of underexplored plant-derived photosensitizers.