Advanced biology最新文献

Anaesthetics temporarily inhibit neural activity by acting on voltage-gated sodium channels and GABA receptors. Although their neurological mechanisms are well-defined, their wider cellular effects, especially in non-neuronal systems, are inadequately understood. This study utilized Solanum lycopersicum plant's root apex cells as a transparent model to examine anaesthetic-induced subcellular alterations via live-cell fluorescence imaging, immunostaining, and super-resolution microscopy. These findings demonstrate the hierarchical cascade of organelle dysfunction, such as mitochondria, lysosomes, vesicle trafficking, and nuclear architectures under anaesthesia in plants. The nucleus is identified as the main controller of recovery potential and cellular fate. In a time dependent experiment, it is found that plant cells exposed to lidocaine for up to 4 h can still recover mitochondrial potential, lysosomal function, and nuclear integrity when anaesthesia is removed. However, beyond 4 h the damage, especially to the nucleus, is irreversible, and cells proceeded to cell death. The data further demonstrate that organelles can recover after brief exposure, but prolonged exposure stops recovery, resulting in the irreversible degradation of the nucleus leading to complete cell death. The results may help to uncover organelle-related dysfunction under anaesthetic toxicity and provide a clearer understanding for minimizing or reversing such damage.

Nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-driven malignancy with geographic prevalence in Asia, faces therapeutic challenges due to acquired resistance. Ferroptosis—an iron-dependent cell death pathway driven by lipid peroxidation—emerges as a critical regulator of NPC pathobiology. This review synthesizes how ferroptosis suppression promotes NPC tumor growth, metastasis, and therapy resistance. Key mechanisms include: 1. EBV-mediated activation of p62-Keap1-NRF2/GPX4 and GPX4-TAK1 axes conferring chemo/radioresistance; 2. Extracellular vesicle (EV)-mediated transfer of ITGB3 or SCARB1 reprogramming tumor-associated macrophages (TAMs) and inhibiting ferroptosis in circulating cells; 3. Metabolic rewiring (e.g., CAPRIN2/HMGCR, P4HA1/HMGCS1) enhancing metastasis. Additionally, ferroptosis induction via radiotherapy, natural compounds (solasodine, luteolin), repurposed drugs (disulfiram/copper), or nanotechnology synergizes with immunotherapy by promoting lipid peroxidation and reversing EBV-mediated immune evasion. Targeting ferroptosis regulators (SLC7A11, GPX4, FTO, CD38) overcomes resistance, positioning ferroptosis modulation as a transformative strategy for NPC management.

Type 1 Diabetes (T1D) is characterized by autoimmune destruction of pancreatic beta cells, resulting in insulin deficiency. Natural-based biomaterials like collagen offer promising avenues mimicking tissue microenvironments. However, limited research has been conducted on crosslinked collagen microgels with vascular endothelial growth factor (VEGF) and their effects on biomaterial stability and beta cell function. The aim is to synthesize functionalized-VEGF collagen microgels that mimic the pancreatic environment to sustain pancreatic beta cells for diabetes therapy. Physicochemical analysis confirms the incorporation of functional groups and structural stability over time. Mechanical testing shows adequate resistance to deformation. Metabolic activity increases after 48 h of incubation for the 1 and 3 ng mL⁻¹ VEGF concentrations, as demonstrated by enzymatic and microscopic assays. DNA quantification confirms enhanced cell proliferation at 72 h across all VEGF concentrations. Further analysis shows that VEGF microgels can maintain oxygen consumption and insulin secretion under glucose stimulation of pancreatic beta cells. These findings highlight the intrinsic advantages of collagen-based platforms for cell support and suggest their potential for translational applications. Future studies will focus on molecular-level interactions and in vivo validation, placing this strategy as a promising candidate for advanced diabetes therapy.

Macrophages are key modulators of immunity, tissue homeostasis and disease development. As our understanding of macrophage biology and their tissue-specific behaviors grows the necessity to model macrophages within a 3D biomimetic environment becomes increasingly apparent. Numerous hydrogels are developed and explored for this purpose, extracellular matrix (ECM) mimicking hydrogels gaining special interest. In this study, the use of such a hydrogel composed of collagen and hyaluronic acid (HA), two of the major ECM components, is presented for the 3D culture of macrophages to model their role in different tissues and diseases. The ability to tailor the mechanical properties of the hydrogel through formulation modulation is demonstrated. Human macrophages retain morphology, viability, and expression of key cell surface markers when 3D cultured within the hydrogel. Interestingly, it is demonstrate in this work, that independent of mechanical properties, by adjusting the composition of the hydrogel, specifically HA molecular weight, steers macrophage polarization toward either a pro-inflammatory or anti-inflammatory phenotype. This HA-dependent modulation of macrophage behavior is nullified if the HA is chemically crosslinked, shedding light on the impact of one of the most commonly used preparation methods for collagen-HA hydrogels on macrophage behavior.

Amide local anesthetics (LA) affect tumor burden in various preclinical studies, possibly via their anti-inflammatory properties. However, a translation into clinical evidence is still lacking. Here, effects of LA at clinically relevant concentrations are assessed using a human ex vivo tumor model of patient-derived tumor slice cultures from nine patients with non-small cell lung cancer. Tumors are cultivated for four days and treated with LA in absence/presence of cisplatin. Tumor cell proliferation and apoptosis as well as expression of intercellular adhesion molecule-1 and macrophage polarization are assessed using immunofluorescent imaging. Tumor specimens are considered to be “Responders”, when a change in proliferation and/or apoptosis by >50% compared to untreated slices occurred. Five of nine samples are “Responders”, in which the LA exerted effects comparable to cisplatin. Even at clinically relevant concentrations of LA, a strong anti-tumoral effect is observable in patient-derived tumor slice cultures with complex structures of the tumor microenvironment highlighting the LA effect on the tumor itself and its surroundings, without any interference by other leukocytes or neuronal stimulation. The diverse reaction to LA treatment also emphasizes the importance of biomarkers to determine the tumor phenotypes, which may benefit from LA treatment.

Qianlie Xiaozheng formula (QLXZF), a multi-herbal TCM prescription, has demonstrated clinical efficacy against prostate cancer (PCa), but its immunomodulatory mechanisms remain elusive. This study aims to explore the molecular mechanisms of QLXZF's inhibitory effects on PCa. Tumor-bearing mouse model and an RM-1 tumor cell model co-cultured with CD8T cells are treated with QLXZF. Mechanistic studies integrated in vivo imaging, IHC, WB, and genetic interventions (CHK1 overexpression). In the mouse model, QLXZF dose-dependently suppressed tumor growth (p<.01) without visceral toxicity. Immunofluorescence experiments showed QLXZF treatment has decreased the expression of CHK1, increased γH2AX foci formation. Western blot experiments confirmed an increase in pSTING/STING, pTBK1/TBK1, and pIRF3/IRF3 ratio. Additionally, the use of QLXZF increased the levels of CCL5 and CXCL10. In vitro cell experiments showed results consistent with those in the in vivo model. Further studies indicated that overexpression of CHK1 abolished the suppressive effects of QLXZF on prostate cancer cells. The study suggests that QLXZF may inhibit CHK1 expression, induce DNA image accumulation, and activate the STING/TBK1/IRF3 pathway to promote CD8⁺T cell recruitment. These findings provide a new mechanistic basis for the application of QLXZF in the treatment of PCa.

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.