Mingxiong Guo

Exposure to ultraviolet (UV), particularly UVA radiation, is a primary driver of photoaging due to its deep dermal penetration, which triggers DNA damage, collagen degradation, and immune suppression. Chebulinic acid (CA), a polyphenolic compound from Terminalia chebula, exhibits potent antioxidant and anti-inflammatory properties against UVB-induced skin damage. However, its large molecular weight hinders transdermal delivery and the TAT_47–57 peptide (core of HIV-1 TAT) enables rapid transmembrane transport. Large particles with double-layer membrane structure and a diameter exceeding 1000 nm were obtained during the separation of plant-derived exosome-like nanoparticles (PELNs), which are not considered as PELNs (50–500 nm), after a mixture with TAT anchored to the surface of engineered artificial vesicles (EAVs) and extrusion causes membrane fusion, employed as novel nanocarriers to overcome the difficulty in skin penetration by leveraging their lipid bilayer structure and surface membrane-anchored TAT for efficient epidermal fusion and intercellular penetration. Furthermore, CA-loaded TAT-ePELNs demonstrate significant efficacy in mitigating UVA-induced photoaging. Collectively, this study expands the anti-UVR damage application spectrum of CA from UVB to UVA exposure and establishes a green, efficient, and biosafe strategy for transdermal drug delivery by utilization of non-PELNs generated during the preparation process of PELNs.

The tumor microenvironment (TME) is a crucial mediator of tumor progression and treatment response. Here, we compare the immune microenvironments of HBV and non-HBV hepatocellular carcinoma (HCC) and investigate the reason for the persistence of HBV infection in the liver. We combine the Viral-Track method with scRNA sequencing and profile the transcriptomes of 70,056 cells from HBV and non-HBV-HCC patients. In addition to hepatocytes and macrophages, HBV transcripts were also detected in T and B cells using the Viral-Track method, confirming the lymphotropic nature of HBV in scRNA-sequencing data for the first time, to the best of our knowledge. HBV-HCC tumors have reduced levels of NK cells, macrophages, DCs, and increased malignant hepatocytes compared with those in non-HBV HCC. Notably, we report the enrichment of metallothioneins (MTs), particularly MT1G, in HBV-related HCC TAMs, which is associated with a worse prognosis. HBV-tumor-infiltrated CD8⁺ T cells exhibit a dysfunctional cytotoxic phenotype, characterized by upregulated MDK and CTLA4 expression and reduced IFN-γ production, unlike the non-HBV-HCC. Additionally, HBV-HCC exhibits immunosuppressive ligand-receptor interactions, whereas non-HBV-HCC exhibits antitumor ligand-receptor interactions. Our deeper understanding of the HBV-HCC ecosystem using Viral-Track integrated scRNA sequencing provides insights into immune evasion mechanisms and HBV lymphotropism associated with viral persistence.

Introduction: Against the backdrop of global biodiversity decline, the role of gut microbiota in endangered species conservation remains underexplored. Endemic fish species in Xizang are critical to plateau ecosystems, yet many face severe survival threats. This study investigates the association between gut microbiota composition and conservation status in five endemic fish species, including the nationally protected Oxygymnocypris stewarti, Schizothorax waltoni, and Schizothorax macropogon.Methods: Using 16S rRNA sequencing, we systematically analyzed gut microbiota community structures across the five fish species. We compared microbial diversity, dominant bacterial phyla, and the influence of dietary habits on microbiota composition.Results: Dominant Bacterial Phyla: Fusobacteria, Proteobacteria, and Verrucomicrobia were common across species, while Tenericutes was uniquely dominant in endangered fish. Diversity Trends: Gut microbiota diversity followed the order: Ptychobarbus dipogon > S. waltoni > Schizothorax o-connori > S. macropogon > O. stewarti. Conservation Status Correlation: Species with higher endangerment levels exhibited significantly lower diversity: Least Concern (LC) > Near Threatened (NT) > Vulnerable (VU) > Endangered (EN). Dietary Influence: Phytophagous (PHY) fish had higher microbial diversity than omnivorous (OMN) and sarcophagous (SAR) fish, confirming diet as a key factor shaping gut microbiota.Discussion: This study provides the first evidence linking gut microbiota composition to the conservation status of endemic Tibetan fish. The reduced microbial diversity in endangered species suggests potential microbiome-related health vulnerabilities. Additionally, dietary differences significantly influence microbiota structure, highlighting the need for habitat and dietary conservation strategies. These findings open new avenues for microbiome-based conservation approaches in endangered species management.

Viral infection activates the transcription factors IRF3 and NF-κB, which induce type I interferon (IFN) and antiviral innate immune responses. Here, we identify dual-specific tyrosine phosphorylation-regulated kinase 4 (DYRK4) as an important regulator of virus-triggered IFN-β induction and antiviral innate immunity. Overexpression of DYRK4 enhances virus-triggered activation of IRF3 and type I IFN induction, whereas knockdown or knockout of DYRK4 impairs virus-induced activation of IRF3 and NF-κB. Moreover, Dyrk4 -knockout mice are more susceptible to viral infection. The underlying mechanism involves DYRK4 acting as a scaffold protein to recruit TRIM71 and LUBAC to IRF3, increasing IRF3 linear ubiquitination, maintaining IRF3 stability and activation during viral infection, and promoting the IRF3-mediated antiviral response. Our findings provide new insights into the molecular mechanisms underlying viral infection-triggered IRF3 stabilization and activation.

Cellular prion protein (PrP^C) has been implicated in carcinogenic through the activation of various signal pathways, however, the precise mechanisms remain elusive. In vitro studies have shown that PrP^C is prone to undergo liquid-liquid phase separation (LLPS). However, it remains unknown whether PrP^C contributes to LLPS-inducing cancer development. Herein, we observed an upregulation of PrP^C expression in hepatitis B virus-positive hepatocellular carcinoma (HCC). Subsequent investigation revealed that HBx of HBV enhances PrP^C expression in a dose-dependent manner by binding to CREB1. Furthermore, we demonstrated that PrP^C undergoes LLPS and recruits TRAF2/6, TAB2/3, and TAK1 protein, thereby activating the NF-κB signaling pathway and promoting tumor progression. Notably, although unable to undergo LLPS itself, the α3 helix of PrP^C is essential for its activation of the NF-κB signaling pathway during the LLPS process. Further analysis unveiled that disulfide bond formation within the C-terminal domain of PrP^C is necessary for its LLPS and subsequent activation of the NF-κB signaling pathway. Additionally, our findings indicate that NF-κB activation by PrP^C condensates leads to increased IL-8 expression which further promotes tumor development.

A viral infection activates the transcription factors IRF3 and NF-κB, which synergistically induces type I interferons (IFNs). Here, we identify the E3 ubiquitin ligase RNF138 as an important negative regulator of virus-triggered IRF3 activation and IFN-β induction. The overexpression of RNF138 inhibited the virus-induced activation of IRF3 and the transcription of the IFNB1 gene, whereas the knockout of RNF138 promoted the virus-induced activation of IRF3 and transcription of the IFNB1 gene. We further found that RNF138 promotes the ubiquitination of PTEN and subsequently inhibits PTEN interactions with IRF3, which is essential for the PTEN-mediated nuclear translocation of IRF3, thereby inhibiting IRF3 import into the nucleus. Our findings suggest that RNF138 negatively regulates virus-triggered signaling by inhibiting the interaction of PTEN with IRF3, and these data provide new insights into the molecular mechanisms of cellular antiviral responses.

Viral infection activates the transcription factors IRF3 and NF-κB, which synergistically induce type I interferons (IFNs). Here, we identify the E3 ubiquitin ligase RNF138 as an important negative regulator of virus-triggered IRF3 activation and IFN-β induction. Overexpression of RNF138 inhibited virus-induced activation of IRF3 and transcription of the IFNB1 gene, whereas knockout of RNF138 promoted virus-induced activation of IRF3, and transcription of the IFNB1 gene. We further found that RNF138 promotes ubiquitination of PTEN and subsequently inhibits PTEN interactions with IRF3, which is essential for PTEN-mediated nuclear translocation of IRF3, thereby inhibiting IRF3 import into the nucleus. Our findings suggest that RNF138 negatively regulates virus-triggered signaling by inhibiting the interaction of PTEN with IRF3, and these data provide new insights into the molecular mechanisms of cellular antiviral responses.

Glioblastoma multiforme (GBM) treatment is hindered by complex pathologies and the need to cross the blood–brain barrier (BBB) during drug delivery. Although exosomes have great potential for GBM treatment, these alone cannot fully meet the therapeutic requirements, owing to their limitations in targeting and delivery. Herein, engineered artificial vesicles (EAVs), ANG‐TRP‐PK1@EAVs, which are constructed using a liposome extruder from HEK293T cells expressing ANG‐TRP‐PK1 peptides, is developed. ANG‐TRP‐PK1 is a fusion peptide of Angiopep‐2 fused to the N‐terminus of TRP‐PK1, to present Angiopep‐2 on the EAVs. ANG‐TRP‐PK1@EAVs have similar characteristics to the secreted exosomes, but a much higher yield. ANG‐TRP‐PK1@EAVs have efficient BBB‐penetration and GBM‐targeting abilities in a mock BBB model in in vitro and orthotopic GBM mouse models in vivo. Doxorubicin loading EAVs (ANG‐TRP‐PK1@DOX) do not alter the characteristics of the EAVs, which can cross the BBB, reach the GBM, and kill tumor cells in orthotopic GBM mouse models. These engineered drug‐loaded artificial vesicles show better therapeutic effects on GBM than temozolomide in mice, with very few side effects. In conclusion, EAVs can be inserted into different targeting ligands and packed into different drugs, and they may serve as unique and efficient nanoplatforms for drug delivery and tumor promise therapy.