Choroidal neovascularization (CNV) is a devastating pathology of numerous ocular diseases, such as wet agerelated macular degeneration (wAMD), which causes irreversible vision loss. Although anti-vascular endothelial growth factor (VEGF) therapy has been widely used, poor response or no response still exists in some cases, suggesting that there are other components involved in the angiogenic process. Therefore, the underlying mechanism needs to be clarified and new target of anti-angiogenic therapy is urgently needed. It has been demonstrated that damaged retinal pigment epithelium (RPE) cells can activate inflammasome, driving a degenerative tissue environment and an enhanced pro-angiogenic response, which implies that RPE dysfunction may be a hallmark of the pathogenesis. Previously, we have shown that DNA damage can induce RPE dysfunction, triggering senescence-associated secretory phenotype (SASP) and local inflammation. In this study, we identify that chrysin can reduce DNA damage, especially telomere erosion in vitro, thus compromise the dysfunction of RPE and the decreased expression of SASP factor. Importantly, we find that DNA damage of RPE cells is remarkable in laser-induced CNV lesion, resulting in inflammatory response, which can be ameliorated by chrysin, mainly through IL-17 signaling pathway and its downstream signal transducer and activator of transcription 3 (STAT3) activities. In summary, our results indicate the interplay between DNA damage, perturbed RPE homeostasis, inflammatory response and angiogenesis in laser-induced CNV, and more importantly, chrysin may be an effective therapeutic supplement for CNV.

Allergic rhinitis is a highly prevalent chronic inflammatory disorder of the nasal mucosa that poses a significant burden on patients' health and quality of life. Current therapies for allergic rhinitis are unable to reinstate immune homeostasis or are restricted by specific allergens. Potential therapeutic strategies for allergic rhinitis are urgently needed. Mesenchymal stem cells (MSCs) are immune-privileged, have strong immunomodulatory effects, and can be easily isolated from various sources. Thus, MSC-based therapies demonstrate potential for treating inflammatory diseases. Recently, numerous studies have investigated the therapeutic effects of MSCs in animal models of allergic rhinitis. Here, we review the immunomodulatory effects and mechanisms of MSCs on allergic airway inflammation, especially allergic rhinitis, highlight the recent research regarding MSCs in the modulation of immune cells, and discuss the clinical potential of MSC-based therapy for allergic rhinitis.

Aims: Oral squamous cell carcinoma (OSCC) is considered as the sixth most common cancer worldwide char-acterized by high invasiveness, high metastasis rate and high mortality. It is urgent to explore novel therapeutic strategies to overcome this feature. Metformin is currently a strong candidate anti-tumor drug in multiple cancers. However, whether metformin could inhibit cancer progression by regulating RNA alternative splicing remains largely unknown.Main methods: Cell proliferation and growth ability of CAL-27 and UM-SCC6 were analyzed by CCK8 and colony formation assays. Cell migration was judged by wound healing assay. Mechanistically, RNA-seq was applied to systematically identify genes that are regulated by metformin. The expression of metformin-regulated genes was determined by real-time quantitative PCR (RT-qPCR). Metformin-regulated alternative splicing events were confirmed by RT-PCR.Key findings: We demonstrated that metformin could significantly inhibit the proliferation and migration of oral squamous cell carcinoma cells. Mechanistically, in addition to transcriptional regulation, metformin induces a wide range of alternative splicing alteration, including genes involved in centrosome, cellular response to DNA damage stimulus, GTPase binding, histone modification, catalytic activity, regulation of cell cycle process and ATPase complex. Notably, metformin specifically modulates the splicing of NUBP2, a component of the cytosolic iron-sulfur (Fe/S) protein assembly (CIA). Briefly, metformin favors the production of NUBP2-L, the long splicing isoform of NUBP2, thereby inhibiting cancer cell proliferation.Significance: Our findings provide mechanistic insights of metformin on RNA alternative splicing regulation, thus to offer a potential novel route for metformin to inhibit cancer progression.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. The destruction of the intestinal epithelial barrier is one of the major pathological processes in IBD pathology. Growing evidence indicated that epithelial cell ferroptosis is linked to IBD and is considered a target process. Methods: RAS-selective lethal 3 (RSL3) was used to induce ferroptosis in intestinal epithelial cell line No. 6 (IEC-6) cells, and cell ferroptosis and the effects of tanshinone IIA (Tan IIA) were determined by cell counting kit-8 (CCK-8), reactive oxygen species (ROS) staining, Giemsa staining and transmission electron microscope (TEM). The cell viability of natural product library compounds was determined by CCK-8. The expression of ferroptosis-related genes were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Results: Treatment of IEC-6 cells results in the accumulation of ROS and typical morphological characteristics of ferroptosis. RSL3 treatment caused rapid cellular cytotoxicity which could be reversed by ferrostatin-1 (Fer-1) in IEC-6 cells. Natural product library screening revealed that Tan IIA is a potent inhibitor of IEC-6 cell ferroptosis. Tan IIA could significantly protect the RSL3-induced ferroptosis of IEC-6 cells. Furthermore, the ferroptosis suppressors, glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and miR-17-92 were found to be early response genes in RSL3-treated cells. Treatment of IEC-6 cells with Tan IIA resulted in upregulation of GPX4, SLC7A11, and miR-17-92. Conclusion: Our study demonstrated that Tan IIA protects IEC-6 cells from ferroptosis through the upregulation of GPX4, SLC7A11, and miR-17-92. The findings might provide a theoretical grounding for the future application of Tan IIA to treat or prevent IBD.

Background: Several studies have shown that MSCs can significantly improve the survival of sepsis animals. CD146+ mesenchymal stem cells (MSCs) correlate with high therapeutic potency. However, their therapeutic effect on sepsis and detail mechanisms have not been explored. Methods: The effect of CD146 +/- MSCs on differentiation of Treg, Th1, Th17 subsets was evaluated by flow cytometry. The effects of CD146 +/- MSCs on RAW264.7 phagocytosis and LPS-stimulated polarization were studied using a co-culture protocol. Luminex bead array and RNA sequencing were employed to determine the mechanisms of MSCs on LPS-stimulated RAW264.7. The Arg1 protein was detected by Western blot. CD146 +/- MSCs were injected into LPS-induced sepsis mice by tail vein. The therapeutic effect was assessed by organ HE staining, T-cell subsets, cytokine in plasma, peritoneal macrophages, infiltrating monocytes subpopulations. Results: In vitro, CD146+MSCs could significantly increase the proportion of Treg cells. Co-culture with CD146+MSCs increase the phagocytic rate of RAW264.7. CD146+MSCs regulate M2-type macrophages production more rapidly. The transcript profile differences between the CD146+MSCs and CD146-MSCs groups were clustered in arginine metabolism pathways. CD146+MSCs decreased NO production and increased ARG1 expression. CD146+MSCs secreted higher level of IL15,IFN gamma, VEGF and lower level of IL1 beta, IL8 under LPS stimuli. In vivo, The level of IL10 at 24h and CXCL1, IFN gamma at 12h in CD146+MSCs group was the highest. CD146+MSCs treatment enhances the phagocytic capacity of peritoneal macrophages. CD146+MSCs also increases the ratios of CD11b+Ly6Clo reparative monocytes and CD11b+Ly6Chi inflammatory monocytes until 24h. Conclusion: Compared with CD146-MSCs, CD146+MSCs can accelerate the end of the inflammatory response and have robust anti-inflammatory effects, by increasing the Treg cells, promoting macrophage phagocytosis, enhancing the reparative macrophage,

Purpose: Mesenchymal stem cells (MSCs) have become novel therapeutic agents for the treatment of inflammatory bowel diseases (IBDs). However, the precise cellular and molecular mechanisms by which MSCs restore intestinal tissue homeostasis and repair the epithelial barrier have not been well elucidated. This study aimed to investigate the therapeutic effects and possible mechanisms of human MSCs in the treatment of experimental colitis.Methods: We performed an integrative transcriptomic, proteomic, untargeted metabolomics, and gut microbiota analyses in a dextran sulfate sodium (DSS)-induced IBD mouse model. The cell viability of IEC-6 cells was determined by Cell Counting Kit-8 (CCK-8) assay. The expression of MUC-1 and ferroptosis-related genes were determined by immunohistochemical staining, Western blot, and real-time quantitative polymerase chain reaction (RT-qPCR).Results: Mice treated with MSCs showed notable amelioration in the severity of DSS-induced colitis, which was associated with reduced levels of proinflammatory cytokines and restoration of the lymphocyte subpopulation balance. Treatment with MSC restored the gut microbiota and altered their metabolites in DSS-induced IBD mice. The 16s rDNA sequencing showed that treatment with MSC modulated the composition of probiotics, including the upregulation of the contents ofFirmicutes, Lactobacillus, Blautia, Clostridia, and Helicobacter bacteria in mouse colons. Protein proteomics and transcriptome analyses revealed that pathways related to cell immune responses, including inflammatory cytokines, were suppressed in the MSC group. The ferroptosis-related gene, MUC-1, was significantly upregulated in the MSC-treated group. MUC-1-inhibition experiments indicated that MUC-1 was essential for epithelial cell growth. Through overexpression of MUC-1, it showed that upregulation of SLC7A11 and GPX4, and downregulation of ACSL4 in erastin and RSL3-treated IEC-6 cells, respectively.Conclusion: This study described a mechanism by which treatment with MSCs ameliorated the severity of DSS-induced colitis by modulating the gut microbiota, immune response, and the MUC-1 pathway.

BACKGROUND: Cataract is the primary cause of blindness globally, and surgery offers the only method by which to remove cataracts. We aimed to examine whether previous cataract surgery is associated with cognitive function.; METHODS: Our study included 13,824 participants. Data from the baseline of the China Health and Retirement Longitudinal Study (CHARLS) were used. The participants were categorized into two groups: with and without previous cataract surgery. Weighted multiple linear regression was used to obtain the beta and 95% confidence intervals (CI).; RESULTS: The participants who had previous cataract surgery (n=261) scored lower in cognition, including both memory and mental state, than those without previous cataract surgery. After adjusting for socioeconomic factors and metabolic measures, a negative association was evident between previous cataract surgery and cognition (beta = -0.647, 95% CI: -1.244, -0.049). Furthermore, the participants who were older and female demonstrated a decline in cognition, while living in cities and having higher levels education were associated with higher cognition.; CONCLUSIONS: Better cognitive function was associated with less previous cataract surgery or cataract occurrence. This suggests that a period of vision loss due to cataract leads to cognitive decline, however further studies are need to dissect the impact of vision loss and cataract surgery on cognitive decline. © 2023. The Author(s).

Amyloid-beta (A beta) is thought to be a critical pathologic factor of retinal pigment epithelium (RPE) degeneration in age-related macular degeneration (AMD). A beta induces inflammatory responses in RPE cells and recent studies demonstrate the N6-methyladenosine (m6A) regulatory role in RPE cell inflammation. m6A is a reversible epigenetic posttranslational modification, but its relationship with A beta-induced RPE degeneration is yet to be thoroughly investigated. The present study explored the role and mechanism of m6A in A beta-induced RPE degeneration model. This model was induced via intravitreally injecting oligomeric A beta and the morphology of its retina was analyzed. One of m6A demethylases, the fat mass and obesity-associated (FTO) gene expression, was assessed. An m6A-messenger RNA (mRNA) epitranscriptomic microarray was employed for further bioinformatic analyses. It was confirmed that A beta induced FTO upregulation within the RPE. Hypopigmentation alterations and structural disorganization were observed in A beta-treated eyes, and inhibition of FTO exacerbated retinal degeneration and RPE impairment. Moreover, the m6A-mRNA epitranscriptomic microarray suggested that protein kinase A (PKA) was a target of FTO, and the PKA/cyclic AMP-responsive element binding (CREB) signaling pathway was involved in A beta-induced RPE degeneration. m6A-RNA binding protein immunoprecipitation confirmed that FTO demethylated PKA within the RPE cells of A beta-treated eyes. Altered expression of PKA and its downstream targets (CREB and brain-derived neurotrophic factor) was confirmed by quantitative reverse-transcription polymerase chain reaction and Western blot analyses. Hence, this study's findings shed light on FTO-mediated m6A modification in A beta-induced RPE degeneration and indicate potential therapeutic targets for AMD.

Diabetic macular edema (DME) is the complication of diabetic retinopathy, the leading cause of vision loss among diabetic patients. Metformin is the main antidiabetic treatment. It is preferable for its great anti-angiogenic and anti-inflammatory effects. Anti-vascular endothelial growth factor (VEGF) therapy is the preferable treatment for DME despite its lack of convincing results in some patients. To assess whether the combination of metformin and anti-VEGF drugs may decrease the risk of anti-VEGF resistance among DME patients. We included DME patients with a central retinal thickness (CRT) >= 250 mu m who consecutively underwent at least 3 anti-VEGF therapies from January 1, 2020, to December 30, 2021. Anti-VEGF resistance was defined as persistent macular edema with decreased CRT <= 25% after 3 anti-VEGF injections. 109 patients were considered for this research, of whom 65 (59.6%) were resistant to anti-VEGF therapy. The mean CRT of the non-metformin group decreased from 344.88 +/- 129.48 to 318.29 +/- 123.23 (20.85%) and from 415.64 +/- 144.26 to 277.11 +/- 99.25 (31.51%) (P = .031) in the metformin group. Moreover, the metformin group had fewer resistant patients than the non-metformin, 24 (45.3%) versus 41 (73.2%). Furthermore, a considerable gain in visual acuity was observed in both groups, with a BCVA gain of 40.41% in the metformin group and 39.9% in the non-metformin group. Metformin may be combined with an anti-VEGF drug to minimize the risk of anti-VEGF resistance among DME patients. Moreover, it can serve to design effective therapeutic deliveries.