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Patients with bladder cancer (BCa) frequently acquires resistance to platinum-based chemotherapy, particularly cisplatin. This study centered on the mechanism of cisplatin resistance in BCa and highlighted the pivotal role of lactylation in driving this phenomenon. Utilizing single-cell RNA sequencing, we delineated the single-cell landscape of Bca, pinpointing a distinctive subset of BCa cells that exhibit marked resistance to cisplatin with association with glycolysis metabolism. Notably, we observed that H3 lysine 18 lactylation (H3K18la) plays a crucial role in activating the transcription of target genes by enriching in their promoter regions. Targeted inhibition of H3K18la effectively restored cisplatin sensitivity in these cisplatin-resistant epithelial cells. Furthermore, H3K18la-driven key transcription factors YBX1 and YY1 promote cisplatin resistance in BCa. These findings enhance our understanding of the mechanisms underlying cisplatin resistance, offering valuable insights for identifying novel intervention targets to overcome drug resistance in Bca.
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Cisplatino , Neoplasias da Bexiga Urinária , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Histonas/genética , Histonas/metabolismo , Análise da Expressão Gênica de Célula Única , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismoRESUMO
Bladder cancer is one of the most common malignancies in the world. Cisplatin is one of the most potent and widely used anticancer drugs and has been employed in several malignancies. Cisplatin-based combination chemotherapies have become important adjuvant therapies for bladder cancer patients. Cisplatin-based treatment often results in the development of chemoresistance, leading to therapeutic failure and limiting its application and effectiveness in bladder cancer. To develop improved and more effective cancer therapy, research has been conducted to elucidate the underlying mechanism of cisplatin resistance. Epigenetic modifications have been demonstrated involved in drug resistance to chemotherapy, and epigenetic biomarkers, such as urine tumor DNA methylation assay, have been applied in patients screening or monitoring. Here, we provide a systematic description of epigenetic mechanisms, including DNA methylation, noncoding RNA regulation, m6A modification and posttranslational modifications, related to cisplatin resistance in bladder cancer.
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Antineoplásicos , Neoplasias da Bexiga Urinária , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Epigênese Genética , Metilação , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
OBJECTIVE: Explore the feasibility of a mobile health(mHealth) and virtual reality (VR) based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. METHODS: We recruited cancer patients in the Oncology department of the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from October 2022 to April 2023. The rehabilitation program was provided by a team of medical oncologists, dietitians, psychotherapists, and oncology specialist nurses. Participants received standard anti-cancer therapy and integrated intervention including hospitalized group-based exercise classes, at-home physical activity prescription, behavior change education, oral nutrition supplements, and psychological counseling. An effective intervention course includes two consecutive hospitalization and two periods of home-based rehabilitation (8 weeks). Access the feasibility as well as changes in aspects of physical, nutritional, and psychological status. RESULTS: At the cutoff date of April 2023, the recruitment rate was 75% (123/165). 11.4%patients were lost to follow-up, and 3.25% withdrew halfway. Respectively, the completion rate of nutrition, exercise, and psychology were 85%,55%, and 63%. Nutrition interventions show the highest compliance. The parameters in nutrition, psychology, muscle mass, and quality of life after the rehabilitation showed significant improvements (P < .05). There was no significant statistical difference (P > .05) in handgrip strength and 6-minute walking speed. CONCLUSION: It is feasible to conduct mHealth and VR-based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. A larger multi-center trial is warranted in the future. TRIAL REGISTRATION: ChiCTR2200065748 Registered 14 November 2022.
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Estudos de Viabilidade , Neoplasias , Telemedicina , Realidade Virtual , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Neoplasias/psicologia , Neoplasias/reabilitação , Neoplasias/complicações , Estudos Prospectivos , Adulto , Idoso , Exercício Físico/psicologia , Terapia por Exercício/métodos , Terapia por Exercício/normas , Terapia por Exercício/psicologia , ChinaRESUMO
Cutaneous malignant melanoma is one of the most lethal cutaneous malignancies. Accumulating evidence has demonstrated the potential influence of long non-coding RNAs (lncRNAs) in biological behaviors of melanoma. Herein, we reported a novel lncRNA, lnc-PKNOX1-1 and systematically studied its functions and possible molecular mechanisms in melanoma. Reverse transcription-quantitative PCR assay showed that lnc-PKNOX1-1 was significantly decreased in melanoma cells and tissues. Low lnc-PKNOX1-1 expression was significantly correlated with invasive pathological type and Breslow thickness of melanoma. In vitro and in vivo experiments showed lnc-PKNOX1-1 dramatically inhibited melanoma cell proliferation, migration and invasion. Mechanically, protein microarray analysis suggested that interleukin-8 (IL-8) was negatively regulated by lnc-PKNOX1-1 in melanoma, which was confirmed by western blot and ELISA. Western blot analysis also showed that lnc-PKNOX1-1 could promote p65 phosphorylation at Ser536 in melanoma. Subsequent rescue assays proved IL-8 overexpression could partly reverse the tumor-suppressing function of lnc-PKNOX1-1 overexpression in melanoma cells, indicating that lnc-PKNOX1-1 suppressed the development of melanoma by regulating IL-8. Taken together, our study demonstrated the tumor-suppressing ability of lnc-PKNOX1-1 in melanoma, suggesting its potential as a novel diagnostic biomarker and therapeutic target for melanoma.
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Melanoma , RNA Longo não Codificante , Neoplasias Cutâneas , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Homeodomínio , Interleucina-8/genética , Melanoma/genética , Melanoma Maligno Cutâneo , NF-kappa B , RNA Longo não Codificante/metabolismo , Neoplasias Cutâneas/genéticaRESUMO
Smart artificial ion channels with tunable properties have wide applications in many fields to achieve ion transport manipulation. Most reported artificial ions are constructed with vertical structures, limiting the further integration of ionic diodes into complex iontronic systems. Inspired by the asymmetric concentration polarization induced by the asymmetric geometry of nanochannels, a novel method is developed to construct horizontally arranged and pH-regulated ionic diodes in nanofluidic chips by self-assembling pH-responsive polymers. The effects of the fabrication and operation parameters on the performance of the ionic diode are systematically investigated. The current rectification ratio of the ionic diode can be modulated flexibly by regulating the pH conditions of the working fluid. An ionic diode bridge circuit for rectifying alternating current signals is built in a single nanofluidic chip and demonstrated, highlighting the feasibility of the ionic diode for complex iontronic system integration. The method presented in this paper provides a promising platform for the development of smart nanofluidic iontronic devices with widespread applicability in biological analysis, sensing, and logic computing.
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Eletricidade , Polímeros , Polímeros/química , Íons/química , Transporte de Íons , Concentração de Íons de HidrogênioRESUMO
Recently, artificial channel-based ionic diodes and transistors are extensively studied to mimic biological systems. Most of them are constructed vertically and are challenging to be further integrated. Several examples of ionic circuits with horizontal ionic diodes are reported. However, they generally require nanoscale channel sizes to meet the demand for ion-selectivity, resulting in low current output and restricting potential applications. In this paper, a novel ionic diode is developed based on multiple-layer polyelectrolyte nanochannel network membranes. Both bipolar and unipolar ionic diodes can be achieved by simply switching the modification solution. Ionic diodes with a high rectification ratio of ≈226 are achieved in single channels with the largest channel size of 2.5 µm. This design can significantly reduce the channel size requirement and improve the output current level of ionic devices. The high-performance ionic diode with a horizontal structure enables the integration of advanced iontronic circuits. Ionic transistors, logic gates, and rectifiers are fabricated on a single chip and demonstrated for current rectification. Furthermore, the excellent current rectification ratio and the high output current of the on-chip ionic devices highlight the promise of the ionic diode as a component of complex iontronic systems for practical applications.
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Metformin is commonly used, but approximately 20% of patients experience gastrointestinal intolerance, leading to medication discontinuation for unclear reasons and a lack of effective management strategies. In this study, the 18 fecal and blood samples were analyzed using 16S rRNA and mRNA transcriptome, respectively. These samples included 3 fecal and 4 blood from metformin-tolerant T2D patients before and after metformin treatment (T and Ta), 3 fecal and 5 blood from metformin-intolerant T2D patients before and after treatment (TS and TSa), and 6 fecal samples from healthy controls. The results showed that certain anti-inflammatory gut bacteria and gene, such as Barnesiella (p = 0.046), Parabacteroides goldsteinii (p = 0.016), and the gene JUND (p = 0.0002), exhibited higher levels in metformin-intolerant patients, and which decreased after metformin treatment (p < 0.05). This potentially invalidates patients' anti-inflammatory effect and intestinal mucus barrier protection, which may lead to alterations in intestinal permeability, decreased gut barrier function, and gastrointestinal symptoms, including diarrhea, bloating, and nausea. After metformin treatment, primary bile acids (PBAs) production species: Weissella confusa, Weissella paramesenteroides, Lactobacillus brevis, and Lactobacillus plantarum increased (p < 0.05). The species converting PBAs to secondary bile acids (SBAs): Parabacteroides distasonis decreased (p < 0.05). This might result in accumulation of PBAs, which also may lead to anti-inflammatory gene JUND and SQSTM1 downregulated. In conclusion, this study suggests that metformin intolerance may be attributed to a decrease in anti-inflammatory-related flora and genes, and also alterations in PBAs accumulation-related flora. These findings open up possibilities for future research targeting gut flora and host genes to prevent metformin intolerance.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Metformina , Humanos , Metformina/uso terapêutico , Microbioma Gastrointestinal/genética , Diabetes Mellitus Tipo 2/complicações , RNA Ribossômico 16S , Ácidos e Sais Biliares , Anti-Inflamatórios/uso terapêuticoRESUMO
This study investigates the surface charging and electrophoretic motion of polyethylene glycol-rich (PEG-rich) micro-droplets in dextran-rich solutions or dextran-rich micro-droplets in PEG-rich solutions. The electrophoretic velocities of the droplets were measured in a centimeter-sized chamber under an optical microscope. It was found that the direction of electrophoretic motion of both the PEG-rich droplets and dextran-rich droplets is opposite to the applied electric field, meaning that both the PEG-rich droplets and dextran-rich droplets are negatively charged. The electrophoretic velocity is independent of droplet size but proportional to the electric field strength. Increasing the NaCl concentration reduces the electrophoretic velocity of PEG-rich droplets and increases it for dextran-rich droplets, suggesting different surface charge changes due to ion affinity. The charge densities and velocities are affected by the PEG and dextran mass fractions. Physical models for droplet surface charging under different conditions were proposed to explain the experimental results.
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In this study, we aimed to examine the actor and partner effects of overcommitment on depression in dual-earner couples and the potential mediating role of emotional exhaustion at the actor and partner levels. With a cross-sectional design, 172 dual-earner couples in Chongqing, China, completed the measures of overcommitment, emotional exhaustion, and depression. The results showed that (a) overcommitment has a significant actor effect on depression for the husband and wife, and there were gender differences in the partner effects; that is, a wife's overcommitment has a significant partner effect on the husband's depression, while a husband's partner effect was not significant; (b) emotional exhaustion mediated the effects of overcommitment on depression for both husbands and wives at the actor level, while at the partner level, only a wife's exhaustion mediated the partner effect of a wife's overcommitment on a husband's depression. Focusing on couples' interdependence, these results enriched the understanding of the relationship between overcommitment and depression within dual-earner couples.
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Depressão , Casamento , Humanos , Casamento/psicologia , Depressão/epidemiologia , Depressão/psicologia , Estudos Transversais , Cônjuges/psicologia , Inquéritos e QuestionáriosRESUMO
Keloids are a type of fibrotic disease characterized by excessive collagen production and extracellular matrix (ECM) deposition. The symptoms of pain and itching and frequent recurrence after treatment significantly impact the quality of life and mental health of patients. A deeper understanding of the pathogenesis of keloids is crucial for the development of an effective therapeutic approach. Fibroblasts play a central role in the pathogenesis of keloids by producing large amounts of collagen fibers. Recent evidence indicates that keloids exhibit high immune cell infiltration, and these cells secrete cytokines or growth factors to support keloid fibroblast proliferation. This article provides an update on the knowledge regarding the keloid microenvironment based on recent single-cell sequencing literature. Many inflammatory cells gathered in keloid lesions, such as macrophages, mast cells, and T lymphocytes, indicate that keloids may be an inflammatory skin disease. In this review, we focus on the communication from immune cells to the fibroblasts and the potential of immunotherapy for keloids. We hope that this review will trigger interest in investigating keloids as an inflammatory disease, which may open up new avenues for drug development by targeting immune mediators.
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Queloide , Humanos , Queloide/metabolismo , Qualidade de Vida , Colágeno/metabolismo , Fibroblastos/metabolismo , Células Cultivadas , Imunoterapia , ComunicaçãoRESUMO
Building an optical filtration function into a microfluidic chip is a promising way of simplifying the optical detection system of a microfluidic device. In this paper, a PDMS microfluidic chip filter that is capable of transmitting chlorophyll fluorescence and blocking interfering light in the visible wavelength range was developed for living algae detection with a smartphone. The chip was fabricated by sealing a layer of crystal violet solution in a PDMS layer on the top of the Sudan II-doped PDMS slab, which has a straight microchannel. Optimum dye concentrations and thicknesses for the crystal violet solution layer and Sudan II-doped PDMS slab were investigated and determined by spectrum measurements. It was found that the cut-on range of this integrated microfluidic chip is extended to about 625 nm and the transmittance in the chlorophyll fluorescence range (650 nm to 710 nm) is as high as 95%, when 25 mg L-1 Sudan II-doped PDMS slab (with a 3 mm thickness) and 2 mg L-1 crystal violet solution (with a 0.3 mm thickness) were used. Living algae detection using this chlorophyll-fluorescence-filtering PDMS microfluidic chip and a smartphone-based imaging platform was achieved, and the results compared favorably with those using a commercial filter.
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Técnicas Analíticas Microfluídicas , Microfluídica , Clorofila , Dimetilpolisiloxanos/química , Violeta Genciana , Técnicas Analíticas Microfluídicas/métodos , Microfluídica/métodos , SmartphoneRESUMO
A conductivity-difference-based method for increasing dielectrophoretic (DEP) force for particle separation in a microfluidic chip is presented in this paper. By applying a direct-current (DC) voltage across two immiscible electrolyte solutions with a conductivity difference, an enhanced electric field gradient is generated at the liquid-liquid interface. Theoretical analysis based on equivalent circuit theory found that the gradient of the electric field squared increases with the decrease in the conductivity ratio of the two liquids (main channel to the side channel). As a result, the particle separation distance (an indicator of DEP force) increases with the decrease in the conductivity ratio, which is both numerically predicted and experimentally verified. Numerical simulations also show that the separation distance increases with the increase in the magnitude of the electric field and the decrease in the width of the orifice. The method presented in this paper is simple and advantageous for increasing DEP force without applying higher DC voltages or fabricating smaller orifices.
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BACKGROUND: Stool DNA (sDNA) tests and fecal immunochemical test (FIT) are used for the detection of colorectal cancer (CRC). Here we performed a novel evaluation using sDNA and FIT to assess their performance in CRC screening and monitoring in Hubei, China. METHODS: Stool samples were collected from a high-risk population in Hubei, China (n = 359). sDNA tests and FIT were performed to test for KRAS mutations, NDRG4 and BMP3 methylation, and check hemoglobin levels. The methylation in BMP3 and NDRG4 genes was detected by TaqMan PCR method from human fecal samples. KRAS gene mutation in human fecal DNA was tested using TaqMan probe and amplification-refractory mutation system method. The colloid gold method was used for detection of hemoglobin in fecal samples. Finally, a novel evaluation by software was used to calculate the comprehensive value of the combined results for CRC detection and monitoring. RESULTS: The sensitivity and specificity of the novel evaluation for early CRC (stage I and II), advanced adenoma (AA), and non-colon cancer neoplasm (NA) detection were 95.45% and 81.6%, 29.63% and 75.9%, and 23.08% and 75.17%, respectively. The receiver operating characteristic (ROC) curves of the combined value for the above diseases were 0.945 ± 0.015, 0.543 ± 0.055, and 0.547 ± 0.038, respectively. The levels of the novel evaluation were not significantly associated with the pathology and stage (P > 0.05). In 20 out of 22 CRC patients, the novel evaluation of sDNA and FIT had decreased below threshold (< 165) at after surgery. DISCUSSION: The novel evaluation with sDNA test and FIT has increased sensitivity for screening of CRC and AA. The novel evaluation may have potential importance as an indicator of early CRC. Additionally, the dynamic changes of the comprehensive value after surgery were correlated with CRC treatment.
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Adenoma , Neoplasias Colorretais , Adenoma/diagnóstico , Adenoma/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , DNA/análise , DNA/genética , Estudos de Viabilidade , Hemoglobinas/análise , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
An increasing number of studies reveal the importance of long noncoding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. Our study focused on a skin-specific lncRNA, LOC105372576, whose expression was increased during physiological wound healing. In human nonhealing wounds, however, its level was significantly lower compared with normal wounds under reepithelialization. We characterized LOC105372576 as a nuclear-localized, RNAPII-transcribed, and polyadenylated lncRNA. In keratinocytes, its expression was induced by TGF-ß signaling. Knockdown of LOC105372576 and activation of its endogenous transcription, respectively, reduced and increased the motility of keratinocytes and reepithelialization of human ex vivo skin wounds. Therefore, LOC105372576 was termed "wound and keratinocyte migration-associated lncRNA 1" (WAKMAR1). Further study revealed that WAKMAR1 regulated a network of protein-coding genes important for cell migration, most of which were under the control of transcription factor E2F1. Mechanistically, WAKMAR1 enhanced E2F1 expression by interfering with E2F1 promoter methylation through the sequestration of DNA methyltransferases. Collectively, we have identified a lncRNA important for keratinocyte migration, whose deficiency may be involved in the pathogenesis of chronic wounds.
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Movimento Celular , Queratinócitos/metabolismo , RNA Longo não Codificante/biossíntese , Transdução de Sinais , Pele/metabolismo , Cicatrização , Ferimentos e Lesões/metabolismo , Doença Crônica , Fator de Transcrição E2F1/metabolismo , Regulação da Expressão Gênica , Humanos , Queratinócitos/patologia , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Ferimentos e Lesões/patologiaRESUMO
Due to the increase of the world's population aging, how to restore youthfulness to the skin has attracted much attention. It is well known that collagen synthesis and changes in skin barrier play an important role in the process of skin aging. However, whether Q-switched 1064-nm Nd:YAG laser (1064-QSNYL) determines the involvement of miRNAs in skin collagen synthesis and skin barrier changes remains to be elucidated. Upstream miRNAs of p38 molecular pathway have been predicted by bioinformatic database and the relationship between miRNAs and p38 verified by dual-luciferase reporter gene and Western blotting. RT-qPCR analysis detected the expression of miR-24-3p and mRNA for collagen and skin barrier-related molecules, such as keratin 10 (K10), filaggrin, and Aquaporin 4 (APQ4), in mice back skin and in the keratinocyte cell line HaCaT. Western blotting and immunofluorescence (IF) have been used to detect collagen expression and to localize, as well as quantify K10, filaggrin, and APQ4, respectively. In this study, we show that p38 is the main target gene of miRNA-24-3p, and laser irradiation at 1.5 J/cm2 inhibits miR-24-3p expression. Irradiation treatment upregulates the moisture, elasticity, hydroxyproline, and superoxide dismutase content of mice skin, as well as inhibits trans-epidermal water loss. Irradiation also increases collagen, K10, filaggrin, and APQ4 in both mice skin and HaCaT cells. Interestingly, we found that miR-24-3p overexpression inhibits the effect of irradiation on collagen synthesis and skin barrier. We show for the first time that 1064-QSNYL promotes collagen synthesis and protective effects on skin barrier by downregulating miR-24-3p.
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Lasers de Estado Sólido , MicroRNAs , Envelhecimento da Pele , Animais , Colágeno , Camundongos , MicroRNAs/genética , Pele , Envelhecimento da Pele/genéticaRESUMO
Myocardial infarction (MI) will inevitably result in cardiac fibrosis. In this study, we investigated the effect of microRNA-145 (miR-145) and transcription factor sex-determining region Y box 9 (SOX9) in the production of cardiac fibrosis induced by MI. MI rat models were established by left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD, the cardiac fibrosis level was assessed by Masson's trichrome staining. Cardiac fibroblasts (CFs) exposed to hypoxia were used to simulate MI-induced fibrosis. Flow cytometry, cell counting kit-8, and transwell assays were used to examine changes in CF apoptosis, proliferation, and migration, respectively. miR-145 expression was measured by quantitative real-time polymerase chain reaction. Immunofluorescence and Western blot analysis were performed to determine the relative expression of proteins. In comparison to the sham-operated group, the expression of miR-145 was significantly downregulated in the infarction peripheral area, whereas, SOX9 was upregulated. In the infarcted heart, the overexpression of miR-145 significantly ameliorated cardiac fibrosis and cardiac function, and there was a negative correlation between miR-145 and SOX9 expressions in hypoxic CFs in vitro. In addition, SOX9 was verified to be a functional target of miR-145. Overexpression of miR-145 or inhibition of SOX9 decreased CF proliferation, migration, and fibrosis, but augmented their apoptotic rate. Moreover, the upregulation of miR-145 or suppression of SOX9 inhibited AKT and ß-catenin signaling in hypoxic CFs. Taken together, this study highlights a potential treatment for cardiac fibrosis through the targeted regulation of SOX9 by miR-145, and our findings indicate that miR-145 exerts anti-fibrotic effects in MI via the negative regulation of SOX9 and its downstream AKT/GSK-3ß/ß-catenin pathways.
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Fibroblastos/metabolismo , Fibrose/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOX9/metabolismo , beta Catenina/metabolismo , Animais , Fibrose/genética , Citometria de Fluxo , Glicogênio Sintase Quinase 3 beta/genética , Masculino , MicroRNAs/genética , Infarto do Miocárdio/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOX9/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , beta Catenina/genéticaRESUMO
BACKGROUND: Cell division cycle 25A (CDC25A) is a well-recognized regulator of cell cycle progression and is involved in cancer development. This work focused on the function of CDC25A in cervical cancer cell growth and the molecules involved. METHODS: A GEO dataset GSE63514 comprising data of cervical squamous cell carcinoma (CSCC) tissues was used to screen the aberrantly expressed genes in cervical cancer. The CDC25A expression in cancer and normal tissues was predicted in the GEPIA database and that in CSCC and normal cells was determined by RT-qPCR and western blot assays. Downregulation of CDC25A was introduced in CSCC cells to explore its function in cell growth and the cell cycle progression. The potential regulators of CDC25A activity and the possible involved signaling were explored. RESULTS: CDC25A was predicted to be overexpressed in CSCC, and high expression of CDC25A was observed in CSCC cells. Downregulation of CDC25A in ME180 and C33A cells reduced cell proliferation and blocked cell cycle progression, and it increased cell apoptosis. ALX3 was a positive regulator of CDC25A through transcription promotion. It recruited a histone demethylase, lysine demethylase 2B (KDM2B), to the CDC25A promoter, which enhanced CDC25A expression through demethylation of H3k4me3. Overexpression of ALX3 in cells blocked the inhibitory effects of CDC25A silencing. CDC25A was found as a positive regulator of the PI3K/Akt signaling pathway. CONCLUSION: This study suggested that the ALX3 increased CDC25A expression through KDM2B-mediated demethylation of H3K4me3, which induced proliferation and cell cycle progression of cervical cancer cells.
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Histona Desmetilases/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias do Colo do Útero/metabolismo , Animais , Proliferação de Células/fisiologia , Feminino , Humanos , Camundongos , Camundongos Nus , Transfecção , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.
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Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Queratinócitos/citologia , Queratinócitos/metabolismo , Lectinas Tipo C/metabolismo , Pele/lesões , Pele/metabolismo , Animais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Diferenciação Celular/genética , Proliferação de Células , Epiderme/efeitos dos fármacos , Epiderme/lesões , Epiderme/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-17/farmacologia , Queratinócitos/efeitos dos fármacos , Lectinas Tipo C/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , N-Acetilglucosaminiltransferases/metabolismo , Proteínas Associadas a Pancreatite , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Transdução de Sinais , Pele/efeitos dos fármacos , Cicatrização/genéticaRESUMO
The appropriate inflammatory response is essential for normal wound repair, and skin commensal Staphylococcus epidermidis has been shown to regulate TLR3-mediated inflammatory response to maintain skin homeostasis after injury. However, the underlying mechanism by which S. epidermidis regulates wound-induced inflammation remains largely unexplored. In this study we identified a previously unknown lipopeptide 78 (LP78) from S. epidermidis and showed that LP78 inhibited TLR3-mediated skin inflammation to promote wound healing. Skin injury activated TLR3/NF-κB to promote the interaction of p65 and PPARγ in nuclei and then initiated the inflammatory response in keratinocytes. LP78 activated TLR2-SRC to induce ß-catenin phosphorylation at Tyr654 The phospho-ß-catenin translocated into nuclei to bind to PPARγ, thus disrupting the interaction between p65 and PPARγ. The disassociation between p65 and PPARγ reduced the expression of TLR3-induced inflammatory cytokines in skin wounds of normal and diabetic mice, which correlated with accelerated wound healing. Our data demonstrate that S. epidermidis-derived LP78 inhibits skin inflammation to promote wound healing and suggest that LP78 might be a potential compound for the treatment of delayed or unhealed wounds.
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Inflamação/tratamento farmacológico , Lipopeptídeos/farmacologia , Pele/efeitos dos fármacos , Staphylococcus epidermidis/química , beta Catenina/metabolismo , Animais , Células Cultivadas , Humanos , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Pele/metabolismo , Cicatrização/efeitos dos fármacosRESUMO
Complete autotrophic nitrogen removal over nitrite (CANON) is used in wastewater treatment. However, the performance of the CANON system significantly decreases at low temperatures; thus, a new strategy to improve the resistance of the CANON system is required. To investigate the impact of sludge ratio control (high-granule, equivalent, and high-floc systems) on the resistance of CANON to low temperatures, and their recovery after restoring to normal temperature, the nitrogen removal performance of hybrid systems with different ratios was evaluated. The equivalent system had the lowest nitrite accumulation rate and highest nitrogen removal rate. Anaerobic ammonia oxidation was the rate-limiting step of each system, and hzs was the rate-limiting gene. The higher anaerobic ammonium oxidizing bacteria (AAOB) abundance and hzs expression levels resulted in an equivalent system with better resistance and recovery to short-term low temperatures at the gene level.