Xin Nie

Skin photoageing remains a topic of considerable concern. Retinol (RT) and retinyl palmitate (RP) have shown preliminary therapeutic efficacy; nevertheless, the high irritation associated with RT and the relatively modest efficacy of RP have constrained their broader application. Consequently, this study explored the effects and biosafety of RT and RP in repairing UV-induced skin ageing through a series of in vitro cell experiments, in vitro hemolysis assays, UV-irradiated mouse models, and molecular simulation techniques. The findings revealed that the interaction between RT and RP achieved complementary and enhanced therapeutic outcomes. Specifically, this combination improved the biosafety profile of retinoid formulations, accelerated cell migration rates, and facilitated the activation of the peroxisome proliferator-activated receptor α (PPARα) pathway. Moreover, the action of RT and RP further mitigated epidermal hyperplasia, mast cell infiltration, and the expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α), while stimulating the synthesis of type I collagen. Metabolomics and transcriptomics analyses indicated that RT and RP exerted complementary effects through metabolic pathways, significantly elevating the overall therapeutic efficacy. Network pharmacology and molecular docking studies unveiled that the structural similarity between RT and RP was one of the contributors to their enhancement. In conclusion, this study demonstrated that the combined application of RT and RP exhibited marked effects. Through their mutual action, they not only potentiated each other’s therapeutic effects but also achieved complementary and optimised therapeutic outcomes, thereby substantially enhancing the overall efficacy.

Background: It is been noted that the expression levels of numerous genes undergo changes as individuals age, and aging stands as a primary factor contributing to age-related diseases. Nevertheless, it remains uncertain whether there are common aging genes across organs or tissues, and whether these aging genes play a pivotal role in the development of age-related diseases.Methods: In this study, we screened for aging genes using RNAseq data of 32 human tissues from GTEx. RNAseq datasets from GEO were used to study whether aging genes drives age-related diseases, or whether anti-aging solutions could reverse aging gene expression.Results: Aging transcriptome alterations showed that brain aging differ significantly from the rest of the body, furthermore, brain tissues were divided into four group according to their aging transcriptome alterations. Numerous genes were downregulated during brain aging, with functions enriched in synaptic function, ubiquitination, mitochondrial translation and autophagy. Transcriptome analysis of age-related diseases and retarding aging solutions showed that downregulated aging genes in the hippocampus further downregulation in Alzheimer’s disease but were effectively reversed by high physical activity. Furthermore, the neuron loss observed during aging was reversed by high physical activity.Conclusion: The downregulation of many genes is a major contributor to brain aging and neurodegeneration. High levels of physical activity have been shown to effectively reactivate these genes, making it a promising strategy to slow brain aging.

Background and Aim: Gastric cancer (GC) is a common malignant neoplasm in the gastrointestinal tract, accounting for high mortality globally. Treacle ribosome biogenesis factor 1 (TCOF1) is a nucleolar protein, which has been reported to be implicated in the pathogenesis of Treacher Collins syndrome and the development of several types of human cancer. However, the role of TCOF1 in GC is not known.Methods: Immunohistochemistry was carried out to determine TCOF1 expression in GC tissues. Immunofluorescence, co‐IP, and DNA fiber assays were conducted to investigate the function of TCOF1 in GC‐derived BGC‐823 and SGC‐7901 cell lines.Results: TCOF1 expression was aberrantly increased in GC tissues compared with adjacent normal tissues. In addition, we found that TCOF1 left the nucleolus and localized to R‐loops (DNA/RNA hybrids) during S phase in GC cells. Furthermore, TCOF1 interacted with DDX5 and suppressed R‐loop levels. Knockdown of TCOF1 led to increased nucleoplasmic R‐loops specifically during S phase, which restrained DNA replication and cell proliferation. Overexpression of R‐loop eraser RNaseH1 rescued the DNA synthesis defects and decreased DNA damage caused by TCOF1 depletion.Conclusion: These findings demonstrate a novel role of TCOF1 in maintaining GC cell proliferation by alleviating R‐loop associated DNA replication stress.

Telomeres are transcribed into telomeric RNA termed as TERRA. However, the transcription itself and excessive TERRA may interfere with telomere replication during S phase. The mechanism that coordinates telomere transcription and replication is unknown. Here, we report that TCOF1 leaves the nucleolus and is recruited to telomeres specifically during S phase by interacting with TRF2. Therein, TCOF1 acts to suppress telomere transcription by binding and inhibiting Pol II. Thus, TERRA is limited to low levels in S phase. Depletion of TCOF1 leads to abnormally elevated TERRA and formation of DNA/RNA hybrids (R-loops) at telomeres, which induces replication fork stalling and fragile telomeres. Importantly, telomere replication defect induced by TCOF1 deficiency can be rescued by either masking TERRA or expressing an R-loop eraser RNase H1, demonstrating a critical role of TCOF1 in coordinating telomere transcription and replication. These findings link nucleolus to telomeres and uncover a novel function of TCOF1 on ensuring telomere integrity.

The immunocheckpoint protein PD-1/PD-L1 is considered a promising target for cancer immunotherapeutics. However, the objective response rate using antibodies that block the interaction between PD-1 and PD-L1 was less than 40%, and the mechanism underlying regulation of PD-1/PD-L1 expression is poorly understood. In this study, we identified the miRNA let-7 that posttranscriptionally suppresses PD-L1 expression. LIN28, an RNA binding protein upregulated in most cancer cells, inhibits the biogenesis of let-7, thus promoting PD-L1 expression. Therefore, inhibition of LIN28 may be a strategy to prevent immune evasion of cancer cells. We found that treatment with a LIN28 inhibitor, the small compound C1632, increases let-7 and suppresses PD-L1 expression, leading to reactivation of antitumor immunity in vitro and in vivo. In addition, C1632 also displayed the capacity to inhibit cancer cell proliferation and tumor growth in mice. Altogether, these findings identified LIN28/let-7 as a target for PD-L1–mediated immunotherapeutics and reveal the potential of C1632 and its derivatives as promising oncotherapeutic agents.

In approximately 15% of human cancers, telomere length is maintained independently of telomerase by the homologous recombination (HR)–mediated alternative lengthening of telomeres (ALT) pathway. Whether the ALT pathway can be exploited for therapeutic treatment remains unknown. The purpose of this study is to develop oncotherapeutic agent to target ALT cancers. Surface plasmon resonance assay, antibody to G-quadruplex, and fluorescence in situ hybridization (FISH) were used to discover Tetra-Pt(bpy), a cisplatin derivative that specifically targets telomeric G-quadruplex. We used immunofluorescence, FISH, C-circle assay, and chromosome orientation FISH to evaluate the inhibitory effect of Tetra-Pt(bpy) on ALT activity in human ALT cancers. The shortening of telomere length induced by Tetra-Pt(bpy) was determined by telomere restriction fragment or Q-FISH. Cell destination after Tetra-Pt(bpy) treatment was determined by β-gal staining or apoptosis assay. Nude mice (n = 4 per group) were injected with U2OS cells to evaluate the effects of Tetra-Pt(bpy) on tumor growth. All statistical tests were two-sided. Tetra-Pt(bpy) inhibits the strand invasion/annealing step of telomeric homologous recombination by selectively converting telomeric ssDNA to a G-quadruplex. ALT-cells treated with Tetra-Pt(bpy) show fewer ALT-associated promyelocytic leukemia bodies (untreated: mean±SD = 5.9±0.2 vs treated: mean±SD = 3.1±0.1, P < .001), fewer extrachromosomal C-circles (untreated: mean±SD = 100.5±1.6 vs treated: mean±SD = 18.0±1.7, P < .001), and reduced telomere sister chromatin exchanges (untreated: mean±SD = 25.2%±1.5% vs treated: mean±SD = 13.1%±1.9%, P < .001). Consequently, critically short telomeres accumulate after multiple population doublings (untreated: mean±SD = 18.9%±1.7% vs treated: mean±SD = 57.4%±2.2%, P < .001), resulting in cell death by apoptosis or senescence. In vivo, Tetra-Pt(bpy) severely inhibits the growth of ALT-cell xenograft tumors in mice (untreated: mean±SD = 57.1±3.7 mm³ vs treated: mean±SD = 19.0±3.2 mm³, P < .001). Importantly, Tetra-Pt(bpy) exhibits no adverse effects on proliferation, gene expression, or telomere metabolism in normal cells. These results reveal the potential of Tetra-Pt(bpy) as a novel oncotherapeutic agent for targeting ALT cancer cells.