Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance.

Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.

Retraction Notice to: Decreased Lung Tumor Development in SwAPP Mice through the Downregulation of CHI3L1 and STAT 3 Activity via the Upregulation of miRNA342-3p.

[This retracts the article DOI: 10.1016/j.omtn.2019.02.007.].

Phase 1/2 trials of human bone marrow-derived clonal mesenchymal stem cells for treatment of adults with moderate to severe atopic dermatitis.

BACKGROUND: Mesenchymal stem cells (MSCs) play important roles in therapeutic applications by regulating immune responses. OBJECTIVE: We investigated the safety and efficacy of allogenic human bone marrow-derived clonal MSCs (hcMSCs) in subjects with moderate to severe atopic dermatitis (AD). METHODS: The study included a phase 1 open-label trial followed by a phase 2 randomized, double-blind, placebo-controlled trial that involved 72 subjects with moderate to severe AD. RESULTS: In phase 1, intravenous administration of hcMSCs at 2 doses (1 × 106 and 5 × 105 cells/kg) was safe and well tolerated in 20 subjects. Because there was no difference between the 2 dosage groups (P = .9), it was decided to administer low-dose hcMSCs only for phase 2. In phase 2, subjects receiving 3 weekly intravenous infusions of hcMSCs at 5 × 105 cells/kg showed a higher proportion of an Eczema Area and Severity Index (EASI)-50 response at week 12 compared to the placebo group (P = .038). The differences between groups in the Dermatology Life Quality Index and pruritus numeric rating scale scores were not statistically significant. Most adverse events were mild or moderate and resolved by the end of the study period. CONCLUSIONS: The hcMSC treatment resulted in a significantly higher rate of EASI-50 at 12 weeks compared to the control group in subjects with moderate to severe AD. The safety profile of hcMSC treatment was acceptable. Further larger-scale studies are necessary to confirm these preliminary findings.

Neuronal Cell Differentiation of iPSCs for the Clinical Treatment of Neurological Diseases.

Current chemical treatments for cerebrovascular disease and neurological disorders have limited efficacy in tissue repair and functional restoration. Induced pluripotent stem cells (iPSCs) present a promising avenue in regenerative medicine for addressing neurological conditions. iPSCs, which are capable of reprogramming adult cells to regain pluripotency, offer the potential for patient-specific, personalized therapies. The modulation of molecular mechanisms through specific growth factor inhibition and signaling pathways can direct iPSCs' differentiation into neural stem cells (NSCs). These include employing bone morphogenetic protein-4 (BMP-4), transforming growth factor-beta (TGFß), and Sma-and Mad-related protein (SMAD) signaling. iPSC-derived NSCs can subsequently differentiate into various neuron types, each performing distinct functions. Cell transplantation underscores the potential of iPSC-derived NSCs to treat neurodegenerative diseases such as Parkinson's disease and points to future research directions for optimizing differentiation protocols and enhancing clinical applications.

Hispidin Increases Cell Apoptosis and Ferroptosis in Prostate Cancer Cells Through Phosphatidylinositol-3-Kinase and Mitogen-activated Protein Kinase Signaling Pathway.

BACKGROUND/AIM: Chemotherapy is mainly used in the clinical treatment of prostate cancer. Different anticancer mechanisms can induce cell death in various cancers. Reactive oxygen species (ROS) play crucial roles in cell proliferation, differentiation, apoptosis, and signal transduction. It is widely accepted that ROS accumulation is closely related to chemical drug-induced cancer cell death. MATERIALS AND METHODS: We utilized the MTT assay to detect changes in cell proliferation. Additionally, colony formation and wound healing assay were conducted to investigate the effect of hispidin on cell colony formation and migration ability. Fluorescence microscopy was used to detect intracellular and mitochondrial ROS levels, while western blot was used for detection of cell apoptosis. RESULTS: Hispidin treatment significantly decreased viability of PC3 and DU145 cancer cells but exhibited no cytotoxicity in WPMY-1 cells. Furthermore, hispidin treatment inhibited cell migration and colony formation and triggered cellular and mitochondrial ROS accumulation, leading to mitochondrial dysfunction and mitochondrion-dependent apoptosis. Moreover, hispidin treatment induced ferroptosis in PC3 cells. Scavenging of ROS with N-acetyl cysteine significantly inhibited hispidin-induced apoptosis by altering the expression of apoptosis-related proteins, such as cleaved caspase-3, 9, Bax, and Bcl2. Furthermore, hispidin treatment dramatically up-regulated MAPK (involving p38, ERK, and JNK proteins) and NF-kB signaling pathways while down-regulating AKT phosphorylation. Hispidin treatment also inhibited ferroptosis signaling pathways (involving P53, Nrf-2, and HO-1 proteins) in PC3 cells. In addition, inhibiting these signaling pathways via treatment with specific inhibitors significantly reversed hispidin-induced apoptosis, cellular ROS levels, mitochondrial dysfunction, and ferroptosis. CONCLUSION: Hispidin may represent a potential candidate for treating prostate cancer.

The protective roles of integrin α4ß7 and Amphiregulin-expressing innate lymphoid cells in lupus nephritis.

Type 2 innate lymphoid cells (ILC2s) have emerged as key regulators of the immune response in renal inflammatory diseases such as lupus nephritis. However, the mechanisms underlying ILC2 adhesion and migration in the kidney remain poorly understood. Here, we revealed the critical role of integrin α4ß7 in mediating renal ILC2 adhesion and function. We found that integrin α4ß7 enables the retention of ILC2s in the kidney by binding to VCAM-1, E-cadherin, or fibronectin on structural cells. Moreover, integrin α4ß7 knockdown reduced the production of the reparative cytokine amphiregulin (Areg) by ILC2s. In lupus nephritis, TLR7/9 signaling within the kidney microenvironment downregulates integrin α4ß7 expression, leading to decreased Areg production and promoting the egress of ILC2s. Notably, IL-33 treatment upregulated integrin α4ß7 and Areg expression in ILC2s, thereby enhancing survival and reducing inflammation in lupus nephritis. Together, these findings highlight the potential of targeting ILC2 adhesion as a therapeutic strategy for autoimmune kidney diseases.

Antiviral activity of adenoviral vector expressing human interferon lambda-4 against influenza virus.

Interferon lambda (IFNλ), classified as a type III IFN, is a representative cytokine that plays an important role in innate immunity along with type I IFN. IFNλ can elicit antiviral states by inducing peculiar sets of IFN-stimulated genes (ISGs). In this study, an adenoviral vector expression system with a tetracycline operator system was used to express human IFNλ4 in cells and mice. The formation of recombinant adenovirus (rAd-huIFNλ4) was confirmed using immunohistochemistry assays and transmission electron microscopy. Its purity was verified by quantifying host cell DNA and host cell proteins, as well as by confirming the absence of the replication-competent adenovirus. The transduction of rAd-huIFNλ4 induced ISGs and inhibited four subtypes of the influenza virus in both mouse-derived (LA-4) and human-derived cells (A549). The antiviral state was confirmed in BALB/c mice following intranasal inoculation with 109 PFU of rAd-huIFNλ4, which led to the inhibition of four subtypes of the influenza virus in mouse lungs, with reduced inflammatory lesions. These results imply that human IFNλ4 could induce antiviral status by modulating ISG expression in mice.

Cisplatin Induces Kidney Cell Death via ROS-dependent MAPK Signaling Pathways by Targeting Peroxiredoxin I and II in African Green Monkey (Chlorocebus aethiops sabaeus) Kidney Cells.

BACKGROUND/AIM: Cisplatin [cis-diamminedichloroplatinum(II), CDDP] is a widely used and effective antitumor drug in clinical settings, notorious for its nephrotoxic side effects. This study investigated the mechanisms of CDDP-induced damage in African green monkey kidney (Vero) cells, with a focus on the role of Peroxiredoxin I (Prx I) and Peroxiredoxin II (Prx II) of the peroxiredoxin (Prx) family, which scavenge reactive oxygen species (ROS). MATERIALS AND METHODS: We utilized the Vero cell line derived from African green monkey kidneys and exposed these cells to various concentrations of CDDP. Cell viability, apoptosis, ROS levels, and mitochondrial membrane potential were assessed. RESULTS: CDDP significantly compromised Vero cell viability by elevating both cellular and mitochondrial ROS, which led to increased apoptosis. Pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) effectively reduced CDDP-induced ROS accumulation and subsequent cell apoptosis. Furthermore, CDDP reduced Prx I and Prx II levels in a dose- and time-dependent manner. The inhibition of Prx I and II exacerbated cell death, implicating their role in CDDP-induced accumulation of cellular ROS. Additionally, CDDP enhanced the phosphorylation of MAPKs (p38, ERK, and JNK) without affecting AKT. The inhibition of these pathways significantly attenuated CDDP-induced apoptosis. CONCLUSION: The study highlights the involvement of Prx proteins in CDDP-induced nephrotoxicity and emphasizes the central role of ROS in cell death mediation. These insights offer promising avenues for developing clinical interventions to mitigate the nephrotoxic effects of CDDP.

Inhibitory Effects of Latilactobacillus curvatus BYB3 Cell-Free Extract on Human Melanoma B16F10 Cells and Tumorigenic Mice.

Latilactobacillus curvatus BYB3 (BYB3) is a species of lactic acid bacteria, formerly named Lactobacillus curvatus, which is isolated from kimchi. In this study, the effect of BYB3, Lactobacillus rhamnosus GG, and Lactobacillus acidophilus GP1B strain extracts at various concentrations was examined on B16F10, a mouse melanoma cell line. Cell viability was examined via MTT assay, and the results indicated that compared to the other two probiotics, BYB3 significantly decreased the total percentages of viable cells. The effects of BYB3 on cell migration and proliferation in B16F10 cells were evaluated using wound healing mobility and proliferation assays, respectively; the results indicated that BYB3 inhibits cell migration and proliferation in a concentration-dependent manner. Using human dermal fibroblast cells to investigate BYB3 extract in vivo had no effect on skin-related cells. Nonetheless, the BYB3 extract inhibited tumor growth in a mouse model, as demonstrated by liver slices. Therefore, this suggests that using BYB3 extract to inhibit melanoma may be a novel approach.

Fucosylation deficiency enhances imiquimod-induced psoriasis-like skin inflammation by promoting CXCL1 expression.

Psoriasis is a multifaceted chronic inflammatory skin disease; however, its underlying molecular mechanisms remain unclear. In this study, we explored the role of fucosylation in psoriasis using an imiquimod-induced psoriasis-like mouse model. ABH antigen and fucosyltransferase 1 (Fut1) expression was reduced in the granular layer of lesional skin of patients with psoriasis. In particular, the blood group H antigen type 2 (H2 antigen)-a precursor of blood group A and B antigens-and FUT1 were highly expressed throughout the spinous layer in both patients with psoriasis and the skin of imiquimod-treated mice. Upon the application of imiquimod, Fut1-deficient mice, which lacked the H2 antigen, exhibited higher clinical scores based on erythema, induration, and scaling than those of wild-type mice. Imiquimod-treated Fut1-deficient mice displayed increased skin thickness, trans-epidermal water loss, and Gr-1+ cell infiltration compared with wild-type mice. Notably, the levels of CXCL1 protein and mRNA were significantly higher in Fut1-deficient mice than those in wild-type mice; however, there were no significant differences in other psoriasis-related markers, such as IL-1ß, IL-6, IL-17A, and IL-23. Fut1-deficient primary keratinocytes treated with IL-17A also showed a significant increase in both mRNA and protein levels of CXCL1 compared with IL-17A-treated wild-type primary keratinocytes. Further mechanistic studies revealed that this increased Cxcl1 mRNA in Fut1-deficient keratinocytes was caused by enhanced Cxcl1 mRNA stabilization. In summary, our findings indicated that fucosylation, which is essential for ABH antigen synthesis in humans, plays a protective role in psoriasis-like skin inflammation and is a potential therapeutic target for psoriasis.

Tomato and lemon extracts synergistically improve cognitive function by increasing brain-derived neurotrophic factor levels in aged mice.

Brain ageing, the primary risk factor for cognitive impairment, occurs because of the accumulation of age-related neuropathologies. Identifying effective nutrients that increase cognitive function may help maintain brain health. Tomatoes and lemons have various bioactive functions and exert protective effects against oxidative stress, ageing and cancer. Moreover, they have been shown to enhance cognitive function. In the present study, we aimed to investigate the effects of tomato and lemon ethanolic extracts (TEE and LEE, respectively) and their possible synergistic effects on the enhancement of cognitive function and neurogenesis in aged mice. The molecular mechanisms underlying the synergistic effect of TEE and LEE were investigated. For the in vivo experiment, TEE, LEE or their mixture was orally administered to 12-month-old mice for 9 weeks. A single administration of either TEE or LEE improved cognitive function and neurogenesis in aged mice to some extent, as determined using the novel object recognition test and doublecortin immunohistochemical staining, respectively. However, a significant enhancement of cognitive function and neurogenesis in aged mice was observed after the administration of the TEE + LEE mixture, which had a synergistic effect. N-methyl-d-aspartate receptor 2B, postsynaptic density protein 95, and brain-derived neurotrophic factor (BDNF) levels and tropomyosin receptor kinase B (TrkB)/extracellular signal-regulated kinase (ERK) phosphorylation also synergistically increased after the administration of the mixture compared with those in the individual treatments. In conclusion, compared with their separate treatments, treatment with the TEE + LEE mixture synergistically improved the cognitive function, neurogenesis and synaptic plasticity in aged mice via the BDNF/TrkB/ERK signalling pathway.

Not all (cells) who wander are lost: Upstream migration as a pervasive mode of amoeboid cell motility.

Leukocytes possess the ability to migrate upstream-against the direction of flow-on surfaces of specific chemistry. Upstream migration was first characterized in vitro for T-cells on surfaces comprised of intracellular adhesion molecule-1 (ICAM-1). Upstream migration occurs when the integrin receptor αLß2 (also known as lymphocyte function-associated antigen-1, or LFA-1) binds to ICAM-1. LFA-1/ICAM-1 interactions are ubiquitous and are widely found in leukocyte trafficking. Upstream migration would be employed after cells come to arrest on the apical surface of the endothelium and might confer an advantage for both trans-endothelial migration and tissue surveillance. It has now been shown that several other motile amoeboid cells which have the responsibility of trafficking from blood vessels into tissues, such as Marginal zone B cells, hematopoietic stem cells, and neutrophils (when macrophage-1 antigen, Mac-1, is blocked), can also migrate upstream on ICAM-1 surfaces. This review will summarize what is known about the basic mechanisms of upstream migration, which cells have displayed this phenomenon, and the possible role of upstream migration in physiology and tissue homeostasis.

Impact of ultraviolet radiation on cardiovascular and metabolic disorders: The role of nitric oxide and vitamin D.

BACKGROUND/PURPOSE: Ultraviolet (UV) radiation has both harmful and beneficial effects on human skin and health. It causes skin damage, aging, and cancer; however, it is also a primary source of vitamin D. Additionally, UV radiation can impact energy metabolism and has protective effects on several cardiovascular and metabolic disorders in mice and humans. However, the mechanisms of UV protection against these diseases have not been clearly identified. METHODS: This review summarizes the systemic effects of UV radiation on hypertension and several metabolic diseases such as obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) in mice, and we also consider the mechanisms of action of the related regulators nitric oxide (NO) and vitamin D. RESULTS: UV exposure can lower blood pressure and prevent the development of cardiovascular diseases and metabolic disorders, such as metabolic syndrome, obesity, and type 2 diabetes, primarily through mechanisms that depend on UV-induced NO. UV radiation may also effectively delay the onset of type 1 diabetes through mechanisms that rely on UV-induced vitamin D. UV-induced NO and vitamin D play roles in preventing and slowing the progression of NAFLD. CONCLUSION: UV exposure is a promising nonpharmacological intervention for cardiovascular and metabolic disorders. NO and vitamin D may play a crucial role in mediating these effects. However, further investigations are required to elucidate the exact mechanisms and determine the optimal dosage and exposure duration of UV radiation.

SPARC Is Highly Expressed in Young Skin and Promotes Extracellular Matrix Integrity in Fibroblasts via the TGF-ß Signaling Pathway.

The matricellular secreted protein acidic and rich in cysteine (SPARC; also known as osteonectin), is involved in the regulation of extracellular matrix (ECM) synthesis, cell-ECM interactions, and bone mineralization. We found decreased SPARC expression in aged skin. Incubating foreskin fibroblasts with recombinant human SPARC led to increased type I collagen production and decreased matrix metalloproteinase-1 (MMP-1) secretion at the protein and mRNA levels. In a three-dimensional culture of foreskin fibroblasts mimicking the dermis, SPARC significantly increased the synthesis of type I collagen and decreased its degradation. In addition, SPARC also induced receptor-regulated SMAD (R-SMAD) phosphorylation. An inhibitor of transforming growth factor-beta (TGF-ß) receptor type 1 reversed the SPARC-induced increase in type I collagen and decrease in MMP-1, and decreased SPARC-induced R-SMAD phosphorylation. Transcriptome analysis revealed that SPARC modulated expression of genes involved in ECM synthesis and regulation in fibroblasts. RT-qPCR confirmed that a subset of differentially expressed genes is induced by SPARC. These results indicated that SPARC enhanced ECM integrity by activating the TGF-ß signaling pathway in fibroblasts. We inferred that the decline in SPARC expression in aged skin contributes to process of skin aging by negatively affecting ECM integrity in fibroblasts.

Rottlerin-Liposome Inhibits the Endocytosis of Feline Coronavirus Infection.

Rottlerin (R) is a natural extract from Mallotus philippensis with antiviral properties. Feline infectious peritonitis (FIP) is a fatal disease caused by feline coronavirus (FCoV) that is characterized by systemic granulomatous inflammation and high mortality. We investigated the antiviral effect of liposome-loaded R, i.e., rottlerin-liposome (RL), against FCoV. We demonstrated that RL inhibited FCoV replication in a dose-dependent manner, not only in the early endocytosis stage but also in the late stage of replication. RL resolved the low solubility issue of rottlerin and improved its inhibition efficacy at the cellular level. Based on these findings, we suggest that RL is worth further investigation as a potential treatment for FCoV.

Intramuscular administration of recombinant Newcastle disease virus expressing SARS-CoV-2 spike protein protects hACE-2 TG mice against SARS-CoV-2 infection.

Coronavirus disease 2019 (Covid-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) became a pandemic, causing significant burden on public health worldwide. Although the timely development and production of mRNA and adenoviral vector vaccines against SARS-CoV-2 have been successful, issues still exist in vaccine platforms for wide use and production. With the potential for proliferative capability and heat stability, the Newcastle disease virus (NDV)-vectored vaccine is a highly economical and conceivable candidate for treating emerging diseases. In this study, a recombinant NDV-vectored vaccine expressing the spike (S) protein of SARS-CoV-2, rK148/beta-S, was developed and evaluated for its efficacy against SARS-CoV-2 in K18-hACE-2 transgenic mice. Intramuscular vaccination with low dose (106.0 EID50) conferred a survival rate of 76 % after lethal challenge of a SARS-CoV-2 beta (B.1.351) variant. When administered with a high dose (107.0 EID50), vaccinated mice exhibited 100 % survival rate and reduced lung viral load against both beta and delta variants (B.1.617.2). Together with the protective immunity, rK148/beta-S is an accessible and cost-effective SARS-CoV-2 vaccine.

PRDX1 negatively regulates bleomycin-induced pulmonary fibrosis via inhibiting the epithelial-mesenchymal transition and lung fibroblast proliferation in vitro and in vivo.

BACKGROUND: Pulmonary fibrosis is a major category of end-stage changes in lung diseases, characterized by lung epithelial cell damage, proliferation of fibroblasts, and accumulation of extracellular matrix. Peroxiredoxin 1 (PRDX1), a member of the peroxiredoxin protein family, participates in the regulation of the levels of reactive oxygen species in cells and various other physiological activities, as well as the occurrence and development of diseases by functioning as a chaperonin. METHODS: Experimental methods including MTT assay, morphological observation of fibrosis, wound healing assay, fluorescence microscopy, flow cytometry, ELISA, western blot, transcriptome sequencing, and histopathological analysis were used in this study. RESULTS: PRDX1 knockdown increased ROS levels in lung epithelial cells and promoted epithelial-mesenchymal transition (EMT) through the PI3K/Akt and JNK/Smad signalling pathways. PRDX1 knockout significantly increased TGF-ß secretion, ROS production, and cell migration in primary lung fibroblasts. PRDX1 deficiency also increased cell proliferation, cell cycle circulation, and fibrosis progression through the PI3K/Akt and JNK/Smad signalling pathways. BLM treatment induced more severe pulmonary fibrosis in PRDX1-knockout mice, mainly through the PI3K/Akt and JNK/Smad signalling pathways. CONCLUSIONS: Our findings strongly suggest that PRDX1 is a key molecule in BLM-induced lung fibrosis progression and acts through modulating EMT and lung fibroblast proliferation; therefore, it may be a therapeutic target for the treatment of BLM-induced lung fibrosis.

Induction of Targeted Differentiation of Dermal Mesenchymal Stem Cells Into Neural Lineage According to Peroxiredoxin II Expression.

BACKGROUND/AIM: To optimize the therapeutic potential of stem cells in stem cell therapy for neurological diseases, it is crucial to enhance the differentiation, migration, and neural network formation of stem cells, and to eliminate uncertain cell differentiation and proliferation factors. Several studies have shown that reactive oxygen species (ROS) are important factors in the regulation of neurogenesis, and Prx II (Peroxiredoxin II) is a gene that regulates ROS. MATERIALS AND METHODS: As the entry point in this study to conduct a bioinformatics analysis of the sequencing results of Prx II+/+ dermal mesenchymal stem cells (DMSCs) and Prx II-/- DMSCs. lncRNA/miRNA/mRNA networks were then constructed and preliminarily verified in RT-qPCR experiments. RESULTS: In this study, a total of 11 hub genes (Gria1, Nrcam, Sox10, Snap25, Cntn2, Dlg2, Ngf, Ntrk3, Amph, Syt1, and Cd24a), eight miRNAs (miRNA-4661, miRNA-34a, miRNA-185, miRNA-34b-5p, miRNA-34c, miRNA-449a, miRNA-449b, miRNA-449c) and 12 lncRNAs (Dubr, Gas5, Gm20427, Gm26917, Gm42547, Gm8066, Kcnq1ot1, Malat1, Mir17hg, Neat1, Rian, and Tug1) were predicted in lncRNA/miRNA/mRNA network. CONCLUSION: The regulatory mechanism of Prx II in the differentiation of DMSCs into neurons through ROS was explored, and a theoretical basis was determined that can be applied in future research on nervous system diseases and the clinical applications of stem cells.

Association of 5α-Reductase Inhibitor Prescription With Bladder Cancer Progression in Males in South Korea.

Importance: The antiandrogenic effect of the 5α-reductase inhibitor (5-ARI) has been investigated for its role in preventing male-predominant cancers. Although 5-ARI has been widely associated with prostate cancer, its association with urothelial bladder cancer (BC), another cancer experienced predominantly by males, has been less explored. Objective: To assess the association between 5-ARI prescription prior to BC diagnosis and reduced risk of BC progression. Design, Setting, and Participants: This cohort study analyzed patient claims data from the Korean National Health Insurance Service database. The nationwide cohort included all male patients with BC diagnosis in this database from January 1, 2008, to December 31, 2019. Propensity score matching was conducted to balance the covariates between 2 treatment groups: α-blocker only group and 5-ARI plus α-blocker group. Data were analyzed from April 2021 to March 2023. Exposure: Newly dispensed prescriptions of 5-ARIs at least 12 months prior to cohort entry (BC diagnosis), with a minimum of 2 prescriptions filled. Main Outcomes and Measures: The primary outcomes were the risks of bladder instillation and radical cystectomy, and the secondary outcome was all-cause mortality. To compare the risk of outcomes, the hazard ratio (HR) was estimated using a Cox proportional hazards regression model and difference in restricted mean survival time analysis. Results: The study cohort initially included 22 845 males with BC. After propensity score matching, 5300 patients each were assigned to the α-blocker only group (mean [SD] age, 68.3 [8.8] years) and 5-ARI plus α-blocker group (mean [SD] age, 67.8 [8.6] years). Compared with the α-blocker only group, the 5-ARI plus α-blocker group had a lower risk of mortality (adjusted HR [AHR], 0.83; 95% CI, 0.75-0.91), bladder instillation (crude HR, 0.84; 95% CI, 0.77-0.92), and radical cystectomy (AHR, 0.74; 95% CI, 0.62-0.88). The differences in restricted mean survival time were 92.6 (95% CI, 25.7-159.4) days for all-cause mortality, 88.1 (95% CI, 25.2-150.9) days for bladder instillation, and 68.0 (95% CI, 31.6-104.3) days for radical cystectomy. The incidence rates per 1000 person-years were 85.59 (95% CI, 80.53-90.88) for bladder instillation and 19.57 (95% CI, 17.41-21.91) for radical cystectomy in the α-blocker only group and 66.43 (95% CI, 62.22-70.84) for bladder instillation and 13.56 (95% CI, 11.86-15.45) for radical cystectomy in the 5-ARI plus α-blocker group. Conclusions and relevance: Results of this study suggest an association between prediagnostic prescription of 5-ARI and reduced risk of BC progression.

Dual role of enhancer of zeste homolog 2 in the regulation of ultraviolet radiation-induced matrix metalloproteinase-1 and type I procollagen expression in human dermal fibroblasts.

Abnormalities in the extracellular matrix (ECM) caused by ultraviolet (UV) radiation are mediated by epigenetic mechanisms. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is implicated in inflammation, immune regulation, and senescence. However, its role in controlling UV-induced ECM alterations in the skin remains elusive. Here, we investigated the role of EZH2 in UV-induced expression of matrix metalloproteinase (MMP)-1 and type I procollagen. We found that UV induced EZH2 expression in human skin in vivo and in human dermal fibroblasts (HDFs). EZH2 knockdown reduced the expression and promoter activity of MMP-1 and increased those of type I procollagen, whereas EZH2 overexpression had the opposite effects. Mechanistically, EZH2 increased NF-κB activity, and p65 and p50 expression and promoter activity. Intriguingly, chromatin immunoprecipitation assays revealed that the EZH2/p65/p50 complex was recruited and bound to the MMP-1 promoter after UV irradiation, independent of its histone methyltransferase activity. In contrast, EZH2-induced DNA methyltransferase 1 (DNMT1) formed a complex with EZH2 and enhanced the enrichment of H3K27me3 on the COL1A2 promoter following UV irradiation. These findings indicate that EZH2 plays a dual role in regulating MMP-1 and type I procollagen expression and improve our understanding of how this epigenetic mechanism contributes to UV-induced skin responses and photoaging. This study shows that inhibiting EZH2 is a potential anti-aging strategy for preventing UV-induced skin aging by reducing MMP-1 expression and inducing type I procollagen expression.