Archives of biochemistry and biophysics最新文献

Background: Prostate cancer (PC) remains a major public health challenge, with emerging evidence suggesting that microRNA-93-5p (miR-93-5p) plays a critical role in cancer progression.

Aim: This study investigated how exosomal miR-93-5p derived from PC cells modulates tumor-associated macrophage (TAM) polarization and influences PC progression, while elucidating the underlying molecular mechanisms.

Methods: We analyzed miR-93-5p expression levels in PC tissues and serum samples, followed by detailed characterization of PC cell-derived exosomes. Subsequently, we evaluated the capacity of these exosomes to induce macrophage polarization, examined the regulatory relationship between miR-93-5p and suppressor of cytokine signaling 6 (SOCS6), and assessed the activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway.

Results: Elevated miR-93-5p levels in PC tissues and serum were significantly associated with metastatic features. We demonstrated that PC cell-derived exosomes enriched with miR-93-5p effectively reprogram macrophages toward an immunosuppressive M2 phenotype. Mechanistically, this polarization was mediated through miR-93-5p-induced downregulation of SOCS6, a negative regulator of cytokine signaling, leading to subsequent activation of the JAK2/STAT3 pathway, which enhances PC cell motility and invasiveness. Importantly, xenograft experiments confirmed that miR-93-5p-enriched macrophages substantially accelerated tumor growth in vivo.

Conclusion: Our findings reveal that exosomal miR-93-5p from PC cells drives M2 macrophage polarization and disease progression through SOCS6 suppression and JAK2/STAT3 pathway activation. These results identify exosomal miR-93-5p as a promising therapeutic target and provide new avenues for developing innovative treatment strategies against PC.

Background: Retinopathy of prematurity (ROP) is a major cause of childhood blindness, driven by hypoxia-induced VEGF overproduction. Anti-VEGF therapy has limitations including recurrence and potential side effects, highlighting the need for upstream interventions. M2 macrophages contribute to ROP pathogenesis, but the regulatory mechanisms controlling their polarization remain unclear.

Methods: We explored the regulatory interplay among lncRNA KCNQ1OT1, miR-142-3p, and TRIM24 in RAW264.7 and THP-1 macrophages, human retinal microvascular endothelial cells (HRMECs), and an oxygen-induced retinopathy (OIR) mouse model. Interactions were validated via dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Effects on macrophage polarization and endothelial function were assessed using flow cytometry, immunofluorescence, and proliferation, migration, and tube formation assays. OIR mice received AAV-mediated KCNQ1OT1 delivery, followed by retinal histology, immunostaining, cytokine measurements, TUNEL assays, RT-qPCR, and Western blot analyses.

Results: KCNQ1OT1 acted as a competitive endogenous RNA to sequester miR-142-3p, partially relieving suppression of TRIM24 and attenuating STAT6-mediated M2 polarization. In macrophages, KCNQ1OT1 overexpression reduced M2 markers and VEGFA expression, diminishing pro-angiogenic effects on HRMECs. In OIR mice, AAV-KCNQ1OT1 delivery was associated with reduced retinal neovascularization, decreased M2 macrophage infiltration, and lower VEGFA and inflammatory cytokine levels.

Conclusions: The KCNQ1OT1/miR-142-3p/TRIM24 axis influences macrophage polarization and angiogenic signaling in ROP. While preliminary, these findings suggest that targeting this upstream regulatory network may complement existing VEGF-targeted therapies.

Diabetic foot ulcers (DFUs), characterized by impaired angiogenesis and a chronic inflammatory milieu, represent a severe complication of diabetes. This study investigates the therapeutic potential of exosomes derived from HISLA-overexpressing adipose-derived stem cells (HISLA-ex) in enhancing DFU healing. In vitro, under high glucose conditions, HISLA-ex significantly elevated HISLA expression by approximately 3-fold in endothelial cells, markedly improving cell viability at 24-72 h in HMEC-1 cells, reducing pro-inflammatory cytokines IL-1 and IL-6, and enhancing tube formation capacity as evidenced by increased branching points and total tube length. Subsequently, a DFU rat model was established by inducing diabetes with streptozotocin followed by creation of a full-thickness cutaneous wound on the foot dorsum. HISLA-ex application substantially accelerated wound closure and modulated key angiogenic factors: upregulating VEGFA and Ang-1 while suppressing TSP-1. Furthermore, HISLA-ex shifted the helper T (Th)1/Th2 balance by inhibiting T-bet and pro-inflammatory cytokines (IFN-γ and TNF-α) and promoting GATA3 and anti-inflammatory cytokines (IL-4 and IL-13) in vivo and in vitro. Mechanistically, these effects were mediated through activation of the HIF-1α pathway, confirmed by both gain- and loss-of-function experiments, and abolished upon HIF-1α inhibition. Collectively, our results demonstrate that HISLA-ex synchronously promotes angiogenesis and corrects Th immune dysfunction, offering a novel RNA-based exosomal therapeutic strategy for the treatment of DFUs.

Hypoxia-inducible factor 1 alpha antisense RNA 2 (HIF1A-AS2) and microRNA-590-3p (miR-590-3p) have been linked to inflammation and preeclampsia. In HTR-8/SVneo cells, HIF1A-AS2 was overexpressed and miR-590-3p mimic was introduced, and proliferation, migration/invasion and apoptosis were assessed by proliferation assays, wound-healing and Matrigel invasion assays, and flow cytometry, while molecular alterations were analyzed by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence. HIF1A-AS2 overexpression enhanced proliferation and motility and reduced apoptosis, increased insulin-like growth factor 2 messenger RNA-binding protein 1 (IGF2BP1), and decreased NLR family pyrin domain containing 3 (NLRP3), gasdermin D (GSDMD) and cleaved caspase-1. Conversely, miR-590-3p suppressed IGF2BP1 and partially reversed HIF1A-AS2-associated phenotypes. Together, these data defined a HIF1A-AS2-miR-590-3p-IGF2BP1 axis linking trophoblast behaviour to inflammatory effector signalling.