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1.
PLoS One ; 19(5): e0303758, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38768136

RESUMEN

Nitric oxide (NO) promotes angiogenesis via various mechanisms; however, the effective transmission of NO in ischemic diseases is unclear. Herein, we tested whether NO-releasing nanofibers modulate therapeutic angiogenesis in an animal hindlimb ischemia model. Male wild-type C57BL/6 mice with surgically-induced hindlimb ischemia were treated with NO-releasing 3-methylaminopropyltrimethoxysilane (MAP3)-derived or control (i.e., non-NO-releasing) nanofibers, by applying them to the wound for 20 min, three times every two days. The amount of NO from the nanofiber into tissues was assessed by NO fluorometric assay. The activity of cGMP-dependent protein kinase (PKG) was determined by western blot analysis. Perfusion ratios were measured 2, 4, and 14 days after inducing ischemia using laser doppler imaging. On day 4, Immunohistochemistry (IHC) with F4/80 and gelatin zymography were performed. IHC with CD31 was performed on day 14. To determine the angiogenic potential of NO-releasing nanofibers, aorta-ring explants were treated with MAP3 or control fiber for 20 min, and the sprout lengths were examined after 6 days. As per either LDPI (Laser doppler perfusion image) ratio or CD31 capillary density measurement, angiogenesis in the ischemic hindlimb was improved in the MAP3 nanofiber group; further, the total nitrate/nitrite concentration in the adduct muscle increased. The number of macrophage infiltrations and matrix metalloproteinase-9 (MMP-9) activity decreased. Vasodilator-stimulated phosphoprotein (VASP), one of the major substrates for PKG, increased phosphorylation in the MAP3 group. MAP3 nanofiber or NO donor SNAP (s-nitroso-n-acetyl penicillamine)-treated aortic explants showed enhanced sprouting in an ex vivo aortic ring assay, which was partially abrogated by KT5823, a potent inhibitor of PKG. These findings suggest that the novel NO-releasing nanofiber, MAP3 activates PKG and promotes therapeutic angiogenesis in response to hindlimb ischemia.


Asunto(s)
Proteínas Quinasas Dependientes de GMP Cíclico , Miembro Posterior , Isquemia , Ratones Endogámicos C57BL , Nanofibras , Neovascularización Fisiológica , Óxido Nítrico , Animales , Nanofibras/química , Masculino , Óxido Nítrico/metabolismo , Isquemia/tratamiento farmacológico , Isquemia/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Ratones , Miembro Posterior/irrigación sanguínea , Neovascularización Fisiológica/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Microfilamentos/metabolismo , Moléculas de Adhesión Celular
2.
Sci Rep ; 14(1): 10105, 2024 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-38698020

RESUMEN

Colorectal cancer (CRC) is one of the top five most common and life-threatening malignancies worldwide. Most CRC develops from advanced colorectal adenoma (ACA), a precancerous stage, through the adenoma-carcinoma sequence. However, its underlying mechanisms, including how the tumor microenvironment changes, remain elusive. Therefore, we conducted an integrative analysis comparing RNA-seq data collected from 40 ACA patients who visited Dongguk University Ilsan Hospital with normal adjacent colons and tumor samples from 18 CRC patients collected from a public database. Differential expression analysis identified 21 and 79 sequentially up- or down-regulated genes across the continuum, respectively. The functional centrality of the continuum genes was assessed through network analysis, identifying 11 up- and 13 down-regulated hub-genes. Subsequently, we validated the prognostic effects of hub-genes using the Kaplan-Meier survival analysis. To estimate the immunological transition of the adenoma-carcinoma sequence, single-cell deconvolution and immune repertoire analyses were conducted. Significant composition changes for innate immunity cells and decreased plasma B-cells with immunoglobulin diversity were observed, along with distinctive immunoglobulin recombination patterns. Taken together, we believe our findings suggest underlying transcriptional and immunological changes during the adenoma-carcinoma sequence, contributing to the further development of pre-diagnostic markers for CRC.


Asunto(s)
Adenoma , Neoplasias Colorrectales , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Adenoma/genética , Adenoma/inmunología , Adenoma/patología , República de Corea , Biología Computacional/métodos , Masculino , Femenino , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Pronóstico , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Estimación de Kaplan-Meier , Perfilación de la Expresión Génica
3.
Food Res Int ; 180: 114044, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38395545

RESUMEN

Red seabream (Pagrus major) has been one of the most popular fish in East Asia since early times. However, the discharge of nuclear wastewater into the sea following the Fukushima nuclear disaster in Japan has led to violations of the country of origin labeling. Therefore, the aim of the present study was to determine the origin of fish based on fatty acid, amino acid, and mineral analyses, and to develop biomarkers that can discriminate between Japanese and Korean red seabream. To identify the differences between the two groups, 29 fatty acid families, 17 amino acids, and 4 minerals were analyzed in 60 fish samples (standard sample collected in autumn), and fatty acid profiles were analyzed using heatmap with hierarchical clustering analysis and orthogonal projections to latent structures discriminant analysis. The top 10 fatty acids that were different between the two groups were selected from all seasonal fish samples by combining variable importance in projection scores and p-values. According to the receiver operating characteristic curve analysis results, we proposed percentage linoleic acid (C18:2n-6, cis) as a candidate biomarker with excellent sensitivity and specificity. This study introduces a strategy to identify the origins of red seabream using linoleic acid obtained from fatty acid analysis.


Asunto(s)
Perciformes , Dorada , Humanos , Animales , Ácidos Grasos/análisis , Japón , Aminoácidos/metabolismo , Ácido Linoleico , Minerales/análisis , República de Corea
4.
Int J Mol Sci ; 25(2)2024 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-38255990

RESUMEN

Plants monitor day length and memorize changes in temperature signals throughout the day, creating circadian rhythms that support the timely control of physiological and metabolic processes. The DEHYDRATION-RESPONSE ELEMENT-BINDING PROTEIN 1/C-REPEAT BINDING FACTOR (DREB1/CBF) transcription factors are known as master regulators for the acquisition of cold stress tolerance, whereas PHYTOCHROME INTERACTING FACTOR 4 (PIF4) is involved in plant adaptation to heat stress through thermomorphogenesis. Recent studies have shown that circadian clock genes control plant responses to temperature. Temperature-responsive transcriptomes show a diurnal cycle and peak expression levels at specific times of throughout the day. Circadian clock genes play essential roles in allowing plants to maintain homeostasis by accommodating temperature changes within the normal temperature range or by altering protein properties and morphogenesis at the cellular level for plant survival and growth under temperature stress conditions. Recent studies revealed that the central oscillator genes CIRCADIAN CLOCK ASSOCIATED 1/LATE ELONGATED HYPOCOTYL (CCA1/LHY) and PSEUDO-RESPONSE REGULATOR5/7/9 (PRR5/7/9), as well as the EVENING COMPLEX (EC) genes REVEILLE4/REVEILLE8 (REV4/REV8), were involved in the DREB1 pathway of the cold signaling transcription factor and regulated the thermomorphogenesis gene PIF4. Further studies showed that another central oscillator, TIMING OF CAB EXPRESSION 1 (TOC1), and the regulatory protein ZEITLUPE (ZTL) are also involved. These studies led to attempts to utilize circadian clock genes for the acquisition of temperature-stress resistance in crops. In this review, we highlight circadian rhythm regulation and the clock genes involved in plant responses to temperature changes, as well as strategies for plant survival in a rapidly changing global climate.


Asunto(s)
Relojes Circadianos , Temperatura , Relojes Circadianos/genética , Frío , Ritmo Circadiano/genética , Clima
5.
Gut Liver ; 18(1): 70-76, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-37309193

RESUMEN

Background/Aims: H2 receptor antagonists (H2RA) have been used to treat gastritis by inhibiting gastric acid. Proton pump inhibitors (PPIs) are more potent acid suppressants than H2RA. However, the efficacy and safety of low-dose PPI for treating gastritis remain unclear. The aim was to investigate the efficacy and safety of low-dose PPI for treating gastritis. Methods: A double-blind, noninferiority, multicenter, phase 3 clinical trial randomly assigned 476 patients with endoscopic erosive gastritis to a group using esomeprazole 10 mg (DW1903) daily and a group using famotidine 20 mg (DW1903R1) daily for 2 weeks. The full-analysis set included 319 patients (DW1903, n=159; DW1903R1, n=160) and the per-protocol set included 298 patients (DW1903, n=147; DW1903R1, n=151). The primary endpoint (erosion improvement rate) and secondary endpoint (erosion and edema cure rates, improvement rates of hemorrhage, erythema, and symptoms) were assessed after the treatment. Adverse events were compared. Results: According to the full-analysis set, the erosion improvement rates in the DW1903 and DW1903R1 groups were 59.8% and 58.8%, respectively. According to the per-protocol analysis, the erosion improvement rates in the DW1903 and DW1903R1 groups were 61.9% and 59.6%, respectively. Secondary endpoints were not significantly different between two groups except that the hemorrhagic improvement rate was higher in DW1903 with statistical tendency. The number of adverse events were not statistically different. Conclusions: DW1903 of a low-dose PPI was not inferior to DW1903R1 of H2RA. Thus, lowdose PPI can be a novel option for treating gastritis (ClinicalTrials.gov Identifier: NCT05163756).


Asunto(s)
Famotidina , Gastritis , Humanos , Famotidina/uso terapéutico , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Gastritis/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , Método Doble Ciego
6.
Front Microbiol ; 14: 1273095, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37860134

RESUMEN

In the human pathogen Vibrio vulnificus, the quorum-sensing (QS) signal molecule cyclo-(L-phenylalanine-L-proline) (cFP) plays a critical role in triggering a signaling pathway involving the components LeuO-vHUαß-RpoS-KatG via the membrane signal receptor ToxR. In this study, we investigated the impact of iron on the expression of these signaling components. We found that the transcription of the membrane sensor protein ToxR was not significantly affected by Fur-iron. However, Fur-iron repressed the transcription of genes encoding all the downstream cytoplasmic components in this pathway by binding to the upstream regions of these genes. Consequently, the expression of genes regulated by the alternative sigma factor RpoS, as well as the resistance to hydrogen peroxide conferred by KatG, were repressed. Additionally, we observed that in Vibrio cholerae, genes dependent on ToxR showed higher expression levels in a fur-deletion mutant compared to the wild type. These findings indicate that iron, in association with Fur, represses virtually all the cytoplasmic components responsible for the ToxR-dependent cFP-signaling pathways in these two pathogenic Vibrio species. This study, along with our previous reports demonstrating the repression of components involved in AI-2 dependent QS signaling by Fur-iron, highlights the crucial role of iron in quorum-sensing regulation, which is closely associated with the pathogenicity of this human pathogen.

7.
J Biomater Sci Polym Ed ; 34(14): 1981-1999, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37071065

RESUMEN

Tumor-associated macrophages and monocytes are the major stromal cell types found in the tumor immune microenvironment (TIME), which modulates tumor progression, invasion, and chemoresistance. To address the need for an in vitro three-dimensional tumor model for understanding the complex cellular interactions within the TIME, we propose a TIME-mimetic co-culture matrix composed of photo-crosslinked poly(ethylene glycol) hydrogels mimicking the characteristics of the tumor and stroma. Desmoplasia-mimetic microgels encapsulating lung adenocarcinoma cells (A549) were embedded with monocyte- or macrophage-type U937 cells in normal stroma-mimetic hydrogel, increasing the proximity between the two cell types. By modulating the proteolytic degradability of the hydrogels, we could separate different cell types with high purities for use in orthogonal assays. In addition, we demonstrated that U937 cells had distinct influences on A549 cell death depending on their activation states (i.e. monocyte, M0, or M1 phenotype). M1 macrophages suppressed tumor growth and increased the susceptibility of A549 cells to cisplatin. In contrast, monocytes upregulated cancer stem cell markers (OCT4, SOX2, and SHH) of A549 cells, showing M2-like features, such as downregulated expression of proinflammatory markers (IL6 and TNFα). These findings suggest that this co-culture system is potentially used for investigation of heterotypic cellular interactions in the TIME.


The developed co-culture model successfully reproduces complex tumor immune microenvironment.The model is composed of tumor- and stroma-mimetic matrices containing tumor and immune cells.Sequential matrix degradation enabled the independent cell collection.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Técnicas de Cocultivo , Macrófagos , Materiales Biocompatibles , Hidrogeles , Microambiente Tumoral
8.
PLoS One ; 17(12): e0277956, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36525420

RESUMEN

Standard treatment for patients with high-risk neuroblastoma remains multimodal therapy including chemoradiation, surgical resection, and autologous stem cell rescue. Immunotherapy has demonstrated success in treating many types of cancers; however, its use in pediatric solid tumors has been limited by low tumor mutation burdens. Gastrin-releasing peptide receptor (GRP-R) is overexpressed in numerous malignancies, including poorly-differentiated neuroblastoma. Monoclonal antibodies (mAbs) to GRP-R have yet to be developed but could serve as a potential novel immunotherapy. This preclinical study aims to evaluate the efficacy of a novel GRP-R mAb immunotherapy against neuroblastoma. We established four candidate anti-GRP-R mAbs by screening a single-chain variable fragment (scFv) library. GRP-R mAb-1 demonstrated the highest efficacy with the lowest EC50 at 4.607 ng/ml against GRP-R expressing neuroblastoma cells, blocked the GRP-ligand activation of GRP-R and its downstream PI3K/AKT signaling. This resulted in functional inhibition of cell proliferation and anchorage-independent growth, indicating that mAb-1 has an antagonist inhibitory role on GRP-R. To examine the antibody-dependent cellular cytotoxicity (ADCC) of GRP-R mAb-1 on neuroblastoma, we co-cultured neuroblastoma cells with natural killer (NK) cells versus GRP-R mAb-1 treatment alone. GRP-R mAb-1 mediated ADCC effects on neuroblastoma cells and induced release of IFNγ by NK cells under co-culture conditions in vitro. The cytotoxic effects of mAb-1 were confirmed with the secretion of cytotoxic granzyme B from NK cells and the reduction of mitotic tumor cells in vivo using a murine tumor xenograft model. In summary, GRP-R mAb-1 demonstrated efficacious anti-tumor effects on neuroblastoma cells in preclinical models. Importantly, GRP-R mAb-1 may be an efficacious, novel immunotherapy in the treatment of high-risk neuroblastoma patients.


Asunto(s)
Neuroblastoma , Receptores de Bombesina , Niño , Humanos , Ratones , Animales , Receptores de Bombesina/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Neuroblastoma/metabolismo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico
9.
Sci Rep ; 12(1): 19312, 2022 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-36369267

RESUMEN

The common final pathway to blindness in many forms of retinal degeneration is the death of the light-sensitive primary retinal neurons. However, the normally light-insensitive second- and third-order neurons persist optogenetic gene therapy aims to restore sight by rendering such neurons light-sensitive. Here, we investigate whether bReaChES, a newly described high sensitivity Type I opsin with peak sensitivity to long-wavelength visible light, can restore vision in a murine model of severe early-onset retinal degeneration. Intravitreal injection of an adeno-associated viral vector carrying the sequence for bReaChES downstream of the calcium calmodulin kinase IIα promoter resulted in sustained retinal expression of bReaChES. Retinal ganglion cells (RGCs) expressing bReaChES generated action potentials at light levels consistent with bright indoor lighting (from 13.6 log photons cm-2 s-1). They could also detect flicker at up to 50 Hz, which approaches the upper temporal limit of human photopic vision. Topological response maps of bReaChES-expressing RGCs suggest that optogenetically activated RGCs may demonstrate similar topographical responses to RGCs stimulated by photoreceptor activation. Furthermore, treated dystrophic mice displayed restored cortical neuronal activity in response to light and rescued behavioral responses to a looming stimulus that simulated an aerial predator. Finally, human surgical retinal explants exposed to the bReaChES treatment vector demonstrated transduction. Together, these findings suggest that intravitreal gene therapy to deliver bReaChES to the retina may restore vision in human retinal degeneration in vivo at ecologically relevant light levels with spectral and temporal response characteristics approaching those of normal human photopic vision.


Asunto(s)
Degeneración Retiniana , Ratones , Humanos , Animales , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Degeneración Retiniana/genética , Degeneración Retiniana/terapia , Degeneración Retiniana/metabolismo , Optogenética/métodos , Opsinas de Bastones/metabolismo , Células Ganglionares de la Retina/metabolismo
10.
Theranostics ; 12(15): 6705-6722, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36185611

RESUMEN

Rationale: Müller cells play an essential role in maintaining the health of retinal photoreceptors. Dysfunction of stressed Müller cells often results in photoreceptor degeneration. However, how these cells communicate under stress and the signalling pathways involved remain unclear. In this study, we inhibited the MAPK (ERK1/2) signalling, mainly activated in Müller cells, evaluated the protective effects on the photoreceptors and further explored the signalling communication between stressed Müller cells and degenerating photoreceptors. Methods: We evaluated the changes of MAPK (ERK1/2) signalling and its downstream targets in human retinal explants treated with PD98059, a specific phosphorylated ERK1/2 inhibitor, by western blot and immunostaining. We further assessed photoreceptor degeneration by TUNEL staining and outer nuclear layer thickness. We also injected PD98059 into the eyes of mice exposed to photo-oxidative stress. We evaluated the protective effects on photoreceptor degeneration by optical coherence tomography (OCT) and electroretinography (ERG). The crosstalk between Müller cells and photoreceptors was further dissected based on the changes of transcription factors by RNA sequencing and protein profiles of multiple signalling pathways. Results: We found that MAPK (ERK1/2) signalling was mainly activated in Müller cells under stress, both ex vivo and in vivo. PD98059 inhibited the phosphorylation of ERK1/2, reduced expression of the gliotic marker glial fibrillary acidic protein (GFAP) in Müller cells and increased levels of the neuroprotective factor, interphotoreceptor retinoid-binding protein (IRBP) in photoreceptors. Inhibition of pERK1/2 also reduced retinal photo-oxidative damage in mice retinas assessed by OCT and ERG. We also identified that the JAK/STAT3 signalling pathway might mediate signalling transduction from Müller cells to photoreceptors. Conclusion: MAPK (ERK1/2) deactivation through chemical inhibition, mainly in stressed Müller cells, can alleviate gliosis in Müller cells and restore the expression of IRBP in photoreceptors, which appears to prevent retinal degeneration. Our findings suggested a new way to prevent photoreceptor degeneration by manipulating the stress response in Müller cells.


Asunto(s)
Degeneración Retiniana , Animales , Células Ependimogliales , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Degeneración Retiniana/genética , Factores de Transcripción/metabolismo
11.
Cancer Discov ; 12(12): 2838-2855, 2022 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-36108240

RESUMEN

Prostate cancer is one of the most heritable human cancers. Genome-wide association studies have identified at least 185 prostate cancer germline risk alleles, most noncoding. We used integrative three-dimensional (3D) spatial genomics to identify the chromatin interaction targets of 45 prostate cancer risk alleles, 31 of which were associated with the transcriptional regulation of target genes in 565 localized prostate tumors. To supplement these 31, we verified transcriptional targets for 56 additional risk alleles using linear proximity and linkage disequilibrium analysis in localized prostate tumors. Some individual risk alleles influenced multiple target genes; others specifically influenced only distal genes while leaving proximal ones unaffected. Several risk alleles exhibited widespread germline-somatic interactions in transcriptional regulation, having different effects in tumors with loss of PTEN or RB1 relative to those without. These data clarify functional prostate cancer risk alleles in large linkage blocks and outline a strategy to model multidimensional transcriptional regulation. SIGNIFICANCE: Many prostate cancer germline risk alleles are enriched in the noncoding regions of the genome and are hypothesized to regulate transcription. We present a 3D genomics framework to unravel risk SNP function and describe the widespread germline-somatic interplay in transcription control. This article is highlighted in the In This Issue feature, p. 2711.


Asunto(s)
Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata , Masculino , Humanos , Alelos , Transcriptoma , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Genómica/métodos , Mutación , Células Germinativas/patología , Polimorfismo de Nucleótido Simple
12.
PLoS One ; 17(9): e0274879, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36174000

RESUMEN

Uterine fibroid is one of the most prevalent benign tumors in women, with high socioeconomic costs. Although genome-wide association studies (GWAS) have identified several loci associated with uterine fibroid risks, they could not successfully interpret the biological effects of genomic variants at the gene expression levels. To prioritize uterine fibroid susceptibility genes that are biologically interpretable, we conducted a transcriptome-wide association study (TWAS) by integrating GWAS data of uterine fibroid and expression quantitative loci data. We identified nine significant TWAS genes including two novel genes, RP11-282O18.3 and KBTBD7, which may be causal genes for uterine fibroid. We conducted functional enrichment network analyses using the TWAS results to investigate the biological pathways in which the overall TWAS genes were involved. The results demonstrated the immune system process to be a key pathway in uterine fibroid pathogenesis. Finally, we carried out chemical-gene interaction analyses using the TWAS results and the comparative toxicogenomics database to determine the potential risk chemicals for uterine fibroid. We identified five toxic chemicals that were significantly associated with uterine fibroid TWAS genes, suggesting that they may be implicated in the pathogenesis of uterine fibroid. In this study, we performed an integrative analysis covering the broad application of bioinformatics approaches. Our study may provide a deeper understanding of uterine fibroid etiologies and informative notifications about potential risk chemicals for uterine fibroid.


Asunto(s)
Leiomioma , Transcriptoma , Femenino , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Leiomioma/genética , Toxicogenética
13.
Redox Biol ; 54: 102379, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35779441

RESUMEN

The Pentose Phosphate Pathway (PPP), a metabolic offshoot of the glycolytic pathway, provides protective metabolites and molecules essential for cell redox balance and survival. Transketolase (TKT) is the critical enzyme that controls the extent of "traffic flow" through the PPP. Here, we explored the role of TKT in maintaining the health of the human retina. We found that Müller cells were the primary retinal cell type expressing TKT in the human retina. We further explored the role of TKT in human Müller cells by knocking down its expression in primary cultured Müller cells (huPMCs), isolated from the human retina (11 human donors in total), under light-induced oxidative stress. TKT knockdown and light stress reduced TKT enzymatic activities and the overall metabolic activities of huPMCs with no detectable cell death. TKT knockdown restrained the PPP traffic flow, reduced the expression of NAD(P)H Quinone Dehydrogenase 1 (NQO1), impaired the antioxidative response of NRF2 to light stress and aggravated the endoplasmic reticulum (ER) stress. TKT knockdown also inhibited overall glucose intake, reduced expression of Dihydrolipoamide dehydrogenase (DLD) and impaired the energy supply of the huPMCs. In summary, Müller cell-mediated TKT activity plays a critical protective role in the stressed retina. Knockdown of TKT disrupted the PPP and impaired overall glucose utilisation by huPMCs and rendered huPMCs more vulnerable to light stress by impairing energy supply and antioxidative NRF2 responses.


Asunto(s)
Factor 2 Relacionado con NF-E2 , Transcetolasa , Células Ependimogliales/metabolismo , Glucosa/metabolismo , Humanos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Vía de Pentosa Fosfato , Pentosas , Fosfatos , Transcetolasa/genética , Transcetolasa/metabolismo
14.
Commun Biol ; 5(1): 615, 2022 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-35729261

RESUMEN

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases, which significantly impact the quality of life. Transcriptome-wide association study (TWAS) was conducted to estimate both transcriptomic and genomic features of AD and detected significant associations between 31 expression quantitative loci and 25 genes. Our results replicated well-known genetic markers for AD, as well as 4 novel associated genes. Next, transcriptome meta-analysis was conducted with 5 studies retrieved from public databases and identified 5 additional novel susceptibility genes for AD. Applying the connectivity map to the results from TWAS and meta-analysis, robustly enriched perturbations were identified and their chemical or functional properties were analyzed. Here, we report the first research on integrative approaches for an AD, combining TWAS and transcriptome meta-analysis. Together, our findings could provide a comprehensive understanding of the pathophysiologic mechanisms of AD and suggest potential drug candidates as alternative treatment options.


Asunto(s)
Dermatitis Atópica , Transcriptoma , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/genética , Dermatitis Atópica/metabolismo , Reposicionamiento de Medicamentos , Estudio de Asociación del Genoma Completo/métodos , Humanos , Calidad de Vida
15.
JCI Insight ; 7(9)2022 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-35349486

RESUMEN

The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC). We hypothesized novel combinatorial strategies are likely to enhance the efficacy of BETi. By using PCa patient-derived explants and xenograft models, we show that BETi treatment enhanced the efficacy of radiation therapy (RT) and overcame radioresistance. Mechanistically, BETi potentiated the activity of RT by blocking DNA repair. We also report a synergistic relationship between BETi and topoisomerase I (TOP1) inhibitors (TOP1i). We show that the BETi OTX015 synergized with the new class of synthetic noncamptothecin TOP1i, LMP400 (indotecan), to block tumor growth in aggressive CRPC xenograft models. Mechanistically, BETi potentiated the antitumor activity of TOP1i by disrupting replication fork stability. Longitudinal analysis of patient tumors indicated that TOP1 transcript abundance increased as patients progressed from hormone-sensitive prostate cancer to CRPC. TOP1 was highly expressed in metastatic CRPC, and its expression correlated with the expression of BET family genes. These studies open new avenues for the rational combinatorial treatment of aggressive PCa.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Histonas/metabolismo , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Factores de Transcripción/genética
16.
Life (Basel) ; 12(2)2022 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-35207485

RESUMEN

Dyslipidemia, the commonest cause of cardiovascular disease, leads to lipid deposits on the arterial wall, thereby aggravating atherosclerosis. DSHT (Daeshiho-tang) has long been used as an anti-dyslipidemia agent in oriental medicine. However, the anti-atherosclerotic effects of DSHT have not been fully investigated. Therefore, this study was designed to evaluate whether DSHT could exert beneficial anti-atherosclerotic effects. We fed apolipoprotein E-deficient (ApoE-/-) mice on a high-fat diet and treated them with atorvastatin (AT) or DSHT, or the combination of DSHT and AT for 12 weeks. To determine the role of DSHT, atherosclerotic lesions in the aorta, aortic root, and aortic arch; lipids and apolipoprotein levels in serum; and macrophage polarization markers in aorta tissues were examined. We show here that the DSHT decreased the atherosclerotic plaque ratio in the aortic arch, aorta, and aortic root. DSHT also regulated lipid levels by decreasing the ApoB level and increasing the ApoA1 level. Moreover, DSHT effectively regulated cholesterol metabolism by increasing the levels of PPARγ, ABCA1 and ABCG1, and the LDL receptor genes. We further found that DSHT promoted polarization to the M2 phenotype by increasing the levels of M2 macrophage (ARG1, CD163, and PPARγ) markers. Our data suggested that DSHT enhances the anti-atherosclerotic effect by regulating cholesterol metabolism through the activation of the PPARγ signaling pathway and by promoting anti-inflammatory M2 macrophage polarization.

17.
Int J Mol Sci ; 23(2)2022 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-35055028

RESUMEN

Erythroid differentiation regulator 1 (Erdr1) has previously been reported to control thymocyte selection via TCR signal regulation, but the effect of Erdr1 as a TCR signaling modulator was not studied in peripheral T cells. In this report, it was determined whether Erdr1 affected TCR signaling strength in CD4 T cells. Results revealed that Erdr1 significantly enhanced the anti-TCR antibody-mediated activation and proliferation of T cells while failing to activate T cells in the absence of TCR stimulation. In addition, Erdr1 amplified Ca2+ influx and the phosphorylation of PLCγ1 in CD4 T cells with the TCR stimuli. Furthermore, NFAT1 translocation into nuclei in CD4 T cells was also significantly promoted by Erdr1 in the presence of TCR stimulation. Taken together, our results indicate that Erdr1 positively modulates TCR signaling strength via enhancing the PLCγ1/Ca2+/NFAT1 signal transduction pathway.


Asunto(s)
Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Transducción de Señal , Linfocitos T/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Animales , Biomarcadores , Calcio/metabolismo , Señalización del Calcio , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Inmunofenotipificación , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Fosfolipasa C gamma/metabolismo , Fosforilación , Receptores de Antígenos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T/inmunología
19.
Health Res Policy Syst ; 20(1): 4, 2022 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-34991612

RESUMEN

BACKGROUND: The pharmaceutical industry is heavily regulated. Partly for this reason, new drugs generally take over 10 years from the product development stage to market entry. Although regulations affect the pharmaceutical industry over a long period, previous studies investigating the impact of new regulatory policies have usually focused on the short period before and after implementing that policy. Therefore, the purpose of this study is to examine whether and how significantly regulatory policies affect long-term innovation in the pharmaceutical industry in Korea. METHODS: This study focused on three significant regulatory policies: the introduction of the product patent system, changes in the Good Manufacturing Practice (GMP) system, and the Drug Expenditure Rationalization Plan (DERP). The study used interrupted time series (ITS) analysis to investigate the long-term impacts of the policies before and after implementation. RESULTS: Our results show that introducing the product patent system in 1987 significantly increased the number of Korean patent applications. The effect of the revised GMP policies was also statistically significant, both before and after implementation and between pre-emptive companies and non-pre-emptive ones. However, due to the companies' negotiations with the regulatory authorities or the regulatory system that links drug approval and price evaluation, the DERP did not significantly delay new drug registration in Korea. CONCLUSION: This study showed that the policies of the product patent system, GMP policies, and DERP regulations have significantly encouraged pharmaceutical companies to strive to meet regulatory requirements and promote innovation in Korea. The study suggests that it is necessary for companies to pre-emptively respond to systemic changes in development and production strategies to deal with regulatory changes and achieve sustainable growth. Also, our study results indicate that since government policies motivate the innovative system of the pharmaceutical industry, governmental authorities, when formulating pharmaceutical policies, need to consider the impact on the long-term innovation of the industry.


Asunto(s)
Aprobación de Drogas , Industria Farmacéutica , Comercio , Estudios Longitudinales , República de Corea
20.
Am J Cardiovasc Drugs ; 22(2): 117-125, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34151411

RESUMEN

The anti-cancer agent doxorubicin (DOX) has high cardiotoxicity that is linked to DOX-mediated increase in oxidative stress, mitochondrial iron overload, DNA damage, autophagy, necrosis, and apoptosis, all of which are also associated with secondary tumorigenicity. This limits the clinical application of DOX therapies. Previous studies have attributed DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the production of reactive oxygen species (ROS), which seem to be independent of its anti-tumor DNA damaging effects. Chemo-sensitization of soluble guanylate cyclase (sGC) in the cyclic guanosine monophosphate (cGMP) pathway induces tumor cell death despite the cardiotoxicity associated with DOX treatment. However, sGC-cGMP signaling must be activated during heart failure to facilitate myocardial cell survival. The sGC pathway is dependent on nitric oxide and signal transduction via the nitric oxide-sGC-cGMP pathway and is attenuated in various cardiovascular diseases. Additionally, cGMP signaling is regulated by the action of certain phosphodiesterases (PDEs) that protect the heart by inhibiting PDE, an enzyme that hydrolyses cGMP to GMP activity. In this review, we discuss the studies describing the interactions between cGMP regulation and DOX-mediated cardiotoxicity and their application in improving DOX therapeutic outcomes. The results provide novel avenues for the reduction of DOX-induced secondary tumorigenicity and improve cellular autonomy during DOX-mediated cardiotoxicity.


Asunto(s)
GMP Cíclico , Insuficiencia Cardíaca , GMP Cíclico/metabolismo , GMP Cíclico/farmacología , Doxorrubicina/efectos adversos , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Transducción de Señal , Guanilil Ciclasa Soluble/metabolismo , Guanilil Ciclasa Soluble/farmacología
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