DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.

Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1-4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.

RNA-binding motif protein 10 inactivates c-Myc by partnering with ribosomal proteins uL18 and uL5.

RNA-binding motif protein 10 (RBM10) is a frequently mutated tumor suppressor in lung adenocarcinoma (LUAD). Yet, it remains unknown whether cancer-derived mutant RBM10 compromises its tumor suppression function and, if so, the molecular insight of the underlying mechanisms. Here, we show that wild-type RBM10 suppresses lung cancer cell growth and proliferation by inactivating c-Myc that is essential for cancer cell survival. RBM10 directly binds to c-Myc and promotes c-Myc's ubiquitin-dependent degradation, while RBM10 knockdown leads to the induction of c-Myc level and activity. This negative action on c-Myc is further boosted by ribosomal proteins (RPs) uL18 (RPL5) and uL5 (RPL11) via their direct binding to RBM10. Cancer-derived mutant RBM10-I316F fails to bind to uL18 and uL5 and to inactivate c-Myc, thus incapable of suppressing tumorigenesis. Our findings uncover RBM10 as a pivotal c-Myc repressor by cooperating with uL18 and uL5 in lung cancer cells, as its failure to do so upon mutation favors tumorigenesis.

Phosphoinositide species and filamentous actin formation mediate engulfment by senescent tumor cells.

Cancer cells survive chemotherapy and cause lethal relapse by entering a senescent state that facilitates expression of many phagocytosis/macrophage-related genes that engender a novel cannibalism phenotype. We used biosensors and live-cell imaging to reveal the basic steps and mechanisms of engulfment by senescent human and mouse tumor cells. We show filamentous actin in predator cells was localized to the prey cell throughout the process of engulfment. Biosensors to various phosphoinositide (PI) species revealed increased concentration and distinct localization of predator PI(4) P and PI(4,5)P2 at the prey cell during early stages of engulfment, followed by a transient burst of PI(3) P before and following internalization. PIK3C2B, the kinase responsible for generating PI(3)P, was required for complete engulfment. Inhibition or knockdown of Clathrin, known to associate with PIK3C2B and PI(4,5)P2, severely impaired engulfment. In sum, our data reveal the most fundamental cellular processes of senescent cell engulfment, including the precise localizations and dynamics of actin and PI species throughout the entire process.

Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma.

BACKGROUND: In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. METHODS: To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. RESULTS: CD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244-/- bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. CONCLUSION: Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.

Effectiveness of a healthy lifestyle program based on a mobile serious game for childhood cancer survivors: A quasi-randomized trial.

PURPOSE: This study aimed to develop and evaluate the effectiveness of a healthy lifestyle program based on a mobile serious game (HLP-MSG) to enhance the lifestyles of childhood cancer survivors (CCSs). METHODS: This program proceeded in two stages: development and evaluation, using a non-synchronized design with a quasi-randomized trial. The participants were CCSs aged 6-13 years whose treatment was terminated at least 12 months prior. Data were collected at baseline, and post-intervention, with a follow-up after four weeks using the Child Healthy Lifestyle Profile (CHLP). The experimental (n = 26) and control groups (n = 25) were compared. Data were analyzed using descriptive statistics, chi-squared tests, t-tests, and repeated-measures ANOVA. RESULTS: The HLP-MSG promoted a healthy lifestyle by solving 26 quests, including seven sub-elements (nutrition, exercise, hygiene, interpersonal relationships, stress management, meaning of life, and health responsibility). This study revealed significant differences in the interaction between measurement time and group assignment in the CHLP (p = .006) and physical activity (p = .013), one of the seven sub-dimensions. CONCLUSIONS: A healthy lifestyle program based on a mobile serious game is a feasible health education modality to enhance the physical, psychological, social, and spiritual health of CCSs. IMPLICATIONS TO PRACTICE: The findings add to scientific evidence on a mobile serious game for health education among CCSs. The HLP-MSG provides an evolutionary educational modality that can be delivered non-face-to-face to promote CCSs' continuous healthy behavior maintenance. Moreover, the HLP-MSG is adolescent-friendly and can be utilized as a healthcare tool for parents and children to cooperate.

Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza.

The multifunctional influenza virus protein PB1-F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 PB1-F2 protein not only interferes with the mitochondria-dependent pathway of type I interferon (IFN) signaling, but also acquired a novel IFN antagonist function by targeting the DEAD-box helicase DDX3, a key downstream mediator in antiviral interferon signaling, toward proteasome-dependent degradation. Interactome analysis revealed that 1918 PB1-F2, but not PR8 PB1-F2, binds to DDX3 and causes its co-degradation. Consistent with intrinsic protein instability as basis for this gain-of-function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 PB1-F2 protein. Infusing mice with recombinant DDX3 protein completely rescued them from lethal infection with the 1918 PB1-F2-producing virus. Alongside NS1 protein, 1918 PB1-F2 therefore constitutes a potent IFN antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.

Internalized homophobia and HIV testing among Korean gay and bisexual men: a study in a high-income country with pervasive HIV/AIDS stigma.

Limited research has been conducted on factors contributing to HIV testing among sexual minority populations in South Korea (hereafter, Korea), where stigma against homosexuality and HIV/AIDS is pervasive. We used a nationwide cross-sectional survey of 907 Korean cisgender gay and bisexual (GB) men who were HIV-negative or HIV-unknown in 2016. Regarding internalized homophobia (IHP), participants were categorized into tertiles (low, moderate, and high). Past 12-month HIV testing was assessed via a single yes/no question. Using a modified Poisson regression model, we examined the association between IHP and HIV testing among cisgender GB men in Korea. The overall prevalence of obtaining an HIV test was 41.8% among Korean cisgender GB men. We also found a statistically significant association between IHP and past 12-month HIV testing in this population. Specifically, participants with low IHP had a higher prevalence of HIV testing (adjusted PR = 1.37, 95% CI = 1.14-1.65) compared to those with high IHP. Given these findings, more efforts are needed in Korea to enhance GB men's access to HIV testing, such as improving social circumstances to lower IHP of GB men and creating an environment that enables and facilitates GB men to receive HIV testing without stigma against their sexual identity.

Associations between discrimination experiences and symptoms of depression and anxiety among transgender adults: a nationwide cohort study of 269 transgender adults in South Korea.

PURPOSE: Recently, there has been an increase in awareness of social stigma and mental health issues experienced by transgender individuals in South Korea. To provide quantitative evidence, we conducted a nationwide cohort study of transgender adults, first of its kind in Asia. The aim of the study is to assess the prevalence of depressive and anxiety symptoms and examine their associations with discrimination experiences among transgender adults. METHODS: We conducted a two-wave longitudinal survey of 269 Korean transgender adults, where the baseline was collected in October 2020 and the follow-up in October 2021. Experiences of discrimination in the past 12 months at follow-up were categorized accordingly: those who experienced (1) none, (2) only anti-transgender discrimination, (3) only other types of discrimination, and (4) both anti-transgender and other types of discrimination. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression scale at both waves and anxiety symptoms were measured using the Generalized Anxiety Disorder 7 only at follow-up. We used modified Poisson regression to examine the association between experiences of discrimination and mental health outcomes at follow-up and adjusted for sociodemographic characteristics and baseline depressive symptoms. RESULTS: A total of 63.9% had depressive symptoms and 47.2% had anxiety symptoms. Participants who experienced both anti-transgender and other types of discrimination had 1.38-times (95% CI 1.06-1.81) and 1.77-times (95% CI 1.16-2.70) higher prevalence of depressive and anxiety symptoms, respectively, compared to those without any experiences of discrimination. CONCLUSIONS: Interventions to lessen discrimination towards transgender individuals are needed for the promotion of mental health among transgender individuals.

Electronic effects of nano-confinement in functional organic and inorganic materials for optoelectronics.

When various optically and/or electronically active materials, such as conjugated polymers, perovskites, metals, and metal oxides, are confined at the nanoscale, they can exhibit unique nano-confined behavior that significantly differs from the behavior observed at the macroscale. Although controlled nano-confinement of functional materials can allow modulation of their electronic properties without the aid of any synthetic methodologies or additional chemical treatments, limited assembly approaches for nano-confinement and insufficient analytical tools for electronic characterization remain critical challenges in the development of novel optoelectronic materials and the investigation of their modulated properties. This review describes how the nano-confined features of organic and inorganic materials are related to the control and improvement of their optoelectronic properties. In particular, we focus on various assembly approaches for effective nano-confinement as well as methods for nano-electronic characterization. Then, we briefly present challenges and perspectives on the direction of nano-confinement in terms of the preparation of optoelectronic materials with desired functionalities. Furthermore, we believe that this review can provide a basis for developing and designing next-generation optoelectronics through nano-confinement.

Comparison of Pore Structures of Cellulose-Based Activated Carbon Fibers and Their Applications for Electrode Materials.

This study presents the first investigation of cellulose-based activated carbon fibers (RACFs) prepared as electrode materials for the electric double-layer capacitor (EDLC) in lieu of activated carbon, to determine its efficacy as a low-cost, environmentally friendly enhancement alternative to nanocarbon materials. The RACFs were prepared by steam activation and their textural properties were studied by Brunauer-Emmett-Teller and non-localized density functional theory equations with N2/77K adsorption isotherms. The crystallite structure of the RACFs was observed by X-ray diffraction. The RACFs were applied as an electrode material for an EDLC and compared with commercial activated carbon (YP-50F). The electrochemical performance of the EDLC was analyzed using galvanostatic charge/discharge curves, cyclic voltammetry, and electrochemical impedance spectroscopy. The results show that the texture properties of the activated carbon fibers were influenced by the activation time. Crucially, the specific surface area, total pore volume, and mesopore volume ratio of the RACF with a 70-min activation time (RACF-70) were 2150 m2/g, 1.03 cm3/g and 31.1%, respectively. Further, electrochemical performance analysis found that the specific capacitance of RACF-70 increased from 82.6 to 103.6 F/g (at 2 mA/cm2). The overall high specific capacitance and low resistance of the RACFs were probably influenced by the pore structure that developed outstanding impedance properties. The results of this work demonstrate that RACFs have promising application value as performance enhancing EDLC electrode materials.

A Study on Superior Mesoporous Activated Carbons for Ultra Power Density Supercapacitor from Biomass Precursors.

A kenaf-derived activated carbon (KAC) for a high-power density supercapacitor was developed in this study through phosphoric acid activation. The N2/77K isothermal adsorption-desorption curve was used to estimate the textural properties of KAC based on BET and BJH and the pore size distribution based on NLDFT. The electrochemical properties of KAC were analyzed by using the coin-type cell applying 1 M SPBBF4/PC electrolyte, and the specific surface area and total pore volume were 1490-1942 m2/g and 1.18-3.18 cm3/g, respectively. The pore characteristics of KAC varied according to the activation temperature, and most KAC showed a mesoporous structure. As the activation temperature increased, the mesopore volume increased up to 700 °C, then decreased. The mesoporous structure of KAC resulted in a substantial decrease in the Warburg impedance as the ion diffusion resistance decreased. Hence, the specific capacitance of KAC decreased from 82.9 F/g to 59.48 F/g as the charge-discharge rate increased from 1 mA/g to 10 mA/g, with the rate of reduction at approximately 30%. The rate of reduction of KAC's specific capacitance was 50% lower compared with commercial activated carbon; hence, KAC is a more suitable electrode-active material for high power density supercapacitors.

Association between labor union presence and return to work after occupational injury or illness: A nationally representative longitudinal study in South Korea.

BACKGROUND: This study sought to examine the association between labor union presence and return to work after occupational injury or illness (RTW) among workers in South Korea. METHODS: We analyzed the first (2018) and second (2019) wave data from the Panel Study of Workers' Compensation Insurance in South Korea. The cohort consisted of 3,294 workers who had suffered occupational injury or illness and completed their convalescence by 2017. We examined whether RTW was associated with the presence of labor unions in the workplace at the time of the occupational injury or illness occurred. RESULTS: Compared to workers without labor unions, those with labor unions were more likely to report RTW (prevalence ratio: 1.35, 95% confidence interval: 1.20-1.51) after adjusting for potential confounders, including employment status, duration of convalescence, and severity of injury or illness. CONCLUSION: This study found that labor union presence was associated with RTW among workers who suffered occupational injury or illness in South Korea.

Differences in soft-tissue thickness changes after bimaxillary surgery between patients with vertically high angle and normal angle.

INTRODUCTION: We evaluated soft-tissue thickness changes after bimaxillary surgery according to vertical facial patterns in patients with skeletal Class III malocclusion with mandibular prognathism. METHODS: Forty-three Korean patients (16 men and 27 women; mean age, 22.6 ± 4.1 years) with skeletal Class III malocclusion who underwent bimaxillary surgery were divided into 2 groups: normal-angle group (N group) and high-angle group (H group), on the basis of the presurgical angle of the mandibular plane relative to the sella-nasion plane (SN-MP). Changes in hard-tissue landmarks and soft-tissue thickness before and after surgery were analyzed from reconstructed 3-dimensional cone-beam computed tomography images. Postoperative soft-tissue thickness in both groups was compared with that in 40 patients with normal skeletal Class I malocclusion in the reference group. RESULTS: Group N (27°-37°) and group H (>37°) did not differ significantly in terms of sex and age before surgery. Preoperative pogonion (Pog) thickness was significantly less in group H (9.7 ± 1.6 mm) than in group N (10.8 ± 1.9 mm) (P = 0.042). Adjusted multiple linear regression analysis showed a weak positive linear relationship between the SN-MP before surgery and soft-tissue Pog thickness change (R2 of 0.361; P = 0.001) after surgery, but the area below the lower lips was not completely normalized despite surgery. CONCLUSIONS: The thickness of the soft-tissue Pog may increase slightly after surgery in patients with skeletal Class III malocclusion with a higher preoperative mandibular plane angle, but normalization in the area cannot be completely achieved despite surgery.

STIM2 interacts with AMPK and regulates calcium-induced AMPK activation.

AMPK is a crucial regulator of energy homeostasis that acts downstream of its upstream kinase liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase 2 (CaMKK2). LKB1 primarily phosphorylates AMPK after energy stress, whereas calcium-mediated activation of AMPK requires CaMKK2, although the regulatory mechanisms of calcium-mediated AMPK activation remain unclear. Using biochemical, microscopic, and genetic approaches, we demonstrate that the stromal interaction molecule (STIM)2, a calcium sensor, acts as a novel regulator of CaMKK2-AMPK signaling. We reveal that STIM2 interacts with AMPK and CaMKK2 and that the increase in intracellular calcium levels promotes AMPK colocalization and interaction with STIM2. We further show that STIM2 deficiency attenuates calcium-induced but not energy stress-induced AMPK activation, possibly by regulating the CaMKK2-AMPK interaction. Together, our results identify a previously unappreciated mechanism that modulates calcium-mediated AMPK activation.-Chauhan, A. S., Liu, X., Jing, J., Lee, H., Yadav, R. K., Liu, J., Zhou, Y., Gan B. STIM2 interacts with AMPK and regulates calcium-induced AMPK activation.

BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.

The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, Bap1 KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.

Role of Forkhead Box Class O proteins in cancer progression and metastasis.

It is now widely accepted that several gene alterations including transcription factors are critically involved in cancer progression and metastasis. Forkhead Box Class O proteins (FoxOs) including FoxO1/FKHR, FoxO3/FKHRL1, FoxO4/AFX and FoxO6 transcription factors are known to play key roles in proliferation, apoptosis, metastasis, cell metabolism, aging and cancer biology through their phosphorylation, ubiquitination, acetylation and methylation. Though FoxOs are proved to be mainly regulated by upstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 K)/Akt signaling pathway, the role of FoxOs in cancer progression and metastasis still remains unclear so far. Thus, with previous experimental evidences, the present review discussed the role of FoxOs in association with metastasis related molecules including cannabinoid receptor 1 (CNR1), Cdc25A/Cdk2, Src, serum and glucocorticoid inducible kinases (SGKs), CXCR4, E-cadherin, annexin A8 (ANXA8), Zinc finger E-box-binding homeobox 2 (ZEB2), human epidermal growth factor receptor 2 (HER2) and mRNAs such as miR-182, miR-135b, miR-499-5p, miR-1274a, miR-150, miR-34b/c and miR-622, subsequently analyzed the molecular mechanism of some natural compounds targeting FoxOs and finally suggested future research directions in cancer progression and metastasis.

Exploring the Need of HPV Education Programs in Korean American Communities.

Given the significantly higher cervical cancer risks faced by Korea Americans (KA), the aim of this study was to explore cultural influences and barriers affecting human papillomavirus (HPV) vaccination decisions and preferred educational methods to effectively deliver HPV information. Focus groups included 20 KA parents. This study found a lack of knowledge about HPV and the vaccine, along with negative perceptions about the vaccine, affects HPV vaccination decision-making. Ineffective conversations and a lack of HPV vaccine recommendations by health care providers influenced by cultural beliefs were found to be another major barrier. These findings reveal new insights to guide the development of HPV education programs.

Melatonin disturbs SUMOylation-mediated crosstalk between c-Myc and nestin via MT1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells.

Here the underlying antitumor mechanism of melatonin and its potency as a sensitizer of paclitaxel was investigated in X02 cancer stem cells. Melatonin suppressed sphere formation and induced G2/M arrest in X02 cells expressing nestin, CD133, CXCR4, and SOX-2 as biomarkers of stemness. Furthermore, melatonin reduced the expression of CDK2, CDK4, cyclin D1, cyclin E, and c-Myc and upregulated cyclin B1 in X02 cells. Notably, genes of c-Myc related mRNAs were differentially expressed in melatonin-treated X02 cells by microarray analysis. Consistently, melatonin reduced the expression of c-Myc at mRNA and protein levels, which was blocked by MG132. Of note, overexpression of c-Myc increased the expression of nestin, while overexpression of nestin enhanced c-Myc through crosstalk despite different locations, nucleus, and cytoplasm. Interestingly, melatonin attenuated small ubiquitin-related modifier-1 (SUMO-1) more than SUMO-2 or SUMO-3 and disturbed nuclear translocation of nestin for direct binding to c-Myc by SUMOylation of SUMO-1 protein by immunofluorescence and immunoprecipitation. Also, melatonin reduced trimethylated histone H3K4me3 and H3K36me3 more than dimethylation in X02 cells by Western blotting and chromatin immunoprecipitation assay. Notably, melatonin upregulated MT1, not MT2, in X02 cells and melatonin receptor inhibitor luzindole blocked the ability of melatonin to decrease the expression of nestin, p-c-Myc(S62), and c-Myc. Furthermore, melatonin promoted cytotoxicity, sub-G1 accumulation, and apoptotic body formation by Paclitaxcel in X02 cells. Taken together, these findings suggest that melatonin inhibits stemness via suppression of c-Myc, nestin, and histone methylation via MT1 activation and promotes anticancer effect of Paclitaxcel in brain cancer stem cells.

The Anti-Wrinkle Mechanism of Melatonin in UVB Treated HaCaT Keratinocytes and Hairless Mice via Inhibition of ROS and Sonic Hedgehog Mediated Inflammatory Proteins.

Though melatonin is known to improve ultraviolet B (UVB)-induced oxidative damage and inflammatory conditions via the blockade of the nuclear factor (NF)-κB, interleukin (IL)-6, there is no report on the anti-wrinkle effect of melatonin to date. Hence in the present study, the anti-wrinkle mechanism of melatonin was elucidated in UVB treated HaCaT keratinocytes and hairless mice. Herein melatonin protected against a radical initiator tert-Butyl hydroperoxide (t-BOOH) induced reactive oxygen species (ROS) production, matrix metalloprotease 1 (MMP-1), pro-collagen and cytotoxicity in HaCaT keratinocytes. Additionally, melatonin suppressed the expression of sonic hedgehog (SHH) and GLI1 for hedgehog signaling and p-NF-κB, cyclooxygenase (COX-2), phospho-extracellular signal-regulated kinase-1 (p-ERK) for inflammatory responses in UVB treated HaCaT keratinocytes. Furthermore, melatonin protected skin from wrinkle formation, transdermal water loss in hairless mice irradiated by UVB for 8 weeks. Notably, melatonin prevented against epidermal thickness and dermal collagen degradation in UVB irradiated hairless mice by Hematoxylin and Eosin and Masson’s trichrome staining. Taken together, these findings suggest that melatonin reduces wrinkle formation via inhibition of ROS/SHH and inflammatory proteins such as NF-κB/COX-2/ERK/MMP1.