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1.
J Hepatol ; 78(4): 754-769, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36681161

RESUMO

BACKGROUND & AIMS: Cholangiocytes transit from quiescence to hyperproliferation during cystogenesis in polycystic liver disease (PLD), the severity of which displays prominent sex differences. Epigenetic regulation plays important roles in cell state transition. We aimed to investigate the sex-specific epigenetic basis of hepatic cystogenesis and to develop therapeutic strategies targeting epigenetic modifications for PLD treatment. METHODS: Normal and cystic primary cholangiocytes were isolated from wild-type and PLD mice of both sexes. Chromatin states were characterized by analyzing chromatin accessibility (ATAC sequencing) and multiple histone modifications (chromatin immunoprecipitation sequencing). Differential gene expression was determined by transcriptomic analysis (RNA sequencing). Pharmacologic inhibition of epigenetic modifying enzymes was undertaken in PLD model mice. RESULTS: Through genome-wide profiling of chromatin dynamics, we revealed a profound increase of global chromatin accessibility during cystogenesis in both male and female PLD cholangiocytes. We identified a switch from H3K9me3 to H3K9ac on cis-regulatory DNA elements of cyst-associated genes and showed that inhibition of H3K9ac acetyltransferase or H3K9me3 demethylase slowed cyst growth in male, but not female, PLD mice. In contrast, we found that H3K27ac was specifically increased in female PLD mice and that genes associated with H3K27ac-gained regions were enriched for cyst-related pathways. In an integrated epigenomic and transcriptomic analysis, we identified an estrogen receptor alpha-centered transcription factor network associated with the H3K27ac-regulated cystogenic gene expression program in female PLD mice. CONCLUSIONS: Our findings highlight the multi-layered sex-specific epigenetic dynamics underlying cholangiocyte state transition and reveal a potential epigenetic therapeutic strategy for male PLD patients. IMPACT AND IMPLICATIONS: In the present study, we elucidate a sex-specific epigenetic mechanism underlying the cholangiocyte state transition during hepatic cystogenesis and identify epigenetic drugs that effectively slow cyst growth in male PLD mice. These findings underscore the importance of sex difference in the pathogenesis of PLD and may guide researchers and physicians to develop sex-specific personalized approaches for PLD treatment.


Assuntos
Cistos , Hepatopatias , Feminino , Masculino , Camundongos , Animais , Epigênese Genética , Multiômica , Hepatopatias/genética , Hepatopatias/metabolismo , Cistos/metabolismo , Cromatina/genética
2.
Dermatology ; 239(5): 802-810, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37311426

RESUMO

BACKGROUND: Newer biologics, such as interleukin (IL)-17 inhibitors, make it possible to achieve complete skin clearance (CSC) in patients with moderate-to-severe psoriasis. However, the clinical meaningfulness and predictive factors of CSC in daily practice have not yet been fully investigated. OBJECTIVE: The study was conducted to, first, assess the impact of CSC on quality of life (QoL) improvements compared with treatment responses without clearance and, second, identify clinical parameters as predictors of CSC response in psoriasis patients treated with ixekizumab. METHODS: Patients attending 26 dermatology centers across China were recruited into this real-world setting between August 2020 and May 2022. Prospective cohort study in which response to ixekizumab was assessed using the Psoriasis Area and Severity Index (PASI) and Dermatology Quality of Life Index (DLQI). The absolute DLQI score and DLQI (0) response at week 12 were compared between groups achieving various levels of skin clearance. A stepwise logistic regression analysis was applied to identify which baseline clinical characteristics were predictive factors for CSC. RESULTS: After 12 weeks of treatment, 226 of 511 (44.2%) patients achieved CSC, defined as 100% improvement in PASI score (PASI-100). A significantly higher proportion of patients with CSC versus almost clear skin (PASI 90-99) achieved DLQI score of 0, corresponding to the experience of no impairment on QoL (54.4% vs. 37.7%, p = 0.001). Females patients were more likely than males to achieve CSC response (odds ratio [OR] = 1.83; 95% confidence interval [CI]: 1.24-2.70), while previous biologic treatment (OR = 0.43; 95% CI: 0.24-0.81) and joint affected (OR = 0.61; 95% CI: 0.42-0.89) were significantly associated with less CSC response. CONCLUSIONS: This study highlights the fact that clinical parameters are important in determining CSC response in psoriasis. In daily practice, achieving CSC represents a clinically meaningful treatment goal, especially from the patient perspective.


Assuntos
Psoríase , Qualidade de Vida , Masculino , Feminino , Humanos , Estudos Prospectivos , Resultado do Tratamento , Pele , Psoríase/tratamento farmacológico , Psoríase/complicações , Inibidores de Interleucina , Índice de Gravidade de Doença
3.
J Am Soc Nephrol ; 33(9): 1708-1725, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35918147

RESUMO

BACKGROUND: Emerging evidence indicates that epigenetic modulation of gene expression plays a key role in the progression of autosomal dominant polycystic kidney disease (ADPKD). However, the molecular basis for how the altered epigenome modulates transcriptional responses, and thereby disease progression in ADPKD, remains largely unknown. METHODS: Kidneys from control and ADPKD mice were examined for the expression of CDYL and histone acylations. CDYL expression and its correlation with disease severity were analyzed in a cohort of patients with ADPKD. Cdyl transgenic mice were crossed with Pkd1 knockout mice to explore CDYL's role in ADPKD progression. Integrated cistromic and transcriptomic analyses were performed to identify direct CDYL target genes. High-sensitivity mass spectrometry analyses were undertaken to characterize CDYL-regulated histone lysine crotonylations (Kcr). Biochemical analysis and zebrafish models were used for investigating CDYL phase separation. RESULTS: CDYL was downregulated in ADPKD kidneys, accompanied by an increase of histone Kcr. Genetic overexpression of Cdyl reduced histone Kcr and slowed cyst growth. We identified CDYL-regulated cyst-associated genes, whose downregulation depended on CDYL-mediated suppression of histone Kcr. CDYL assembled nuclear condensates through liquid-liquid phase separation in cultured kidney epithelial cells and in normal kidney tissues. The phase-separating capacity of CDYL was required for efficient suppression of locus-specific histone Kcr, of expression of its target genes, and of cyst growth. CONCLUSIONS: These results elucidate a mechanism by which CDYL nuclear condensation links histone Kcr to transcriptional responses and cystogenesis in ADPKD.


Assuntos
Cistos , Rim Policístico Autossômico Dominante , Camundongos , Animais , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/metabolismo , Histonas/metabolismo , Peixe-Zebra/metabolismo , Rim/metabolismo , Camundongos Transgênicos , Camundongos Knockout , Cistos/genética , Canais de Cátion TRPP/genética
4.
Nucleic Acids Res ; 48(12): 6563-6582, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32459350

RESUMO

Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we discover an HRP2-DPF3a-BAF epigenetic pathway that coordinates methylated histone H3 lysine 36 (H3K36me) and ATP-dependent chromatin remodeling to regulate chromatin dynamics and gene transcription during myogenic differentiation. Using siRNA screening targeting epigenetic modifiers, we identify hepatoma-derived growth factor-related protein 2 (HRP2) as a key regulator of myogenesis. Knockout of HRP2 in mice leads to impaired muscle regeneration. Mechanistically, through its HIV integrase binding domain (IBD), HRP2 associates with the BRG1/BRM-associated factor (BAF) chromatin remodeling complex by interacting directly with the BAF45c (DPF3a) subunit. Through its Pro-Trp-Trp-Pro (PWWP) domain, HRP2 preferentially binds to H3K36me2. Consistent with the biochemical studies, ChIP-seq analyses show that HRP2 colocalizes with DPF3a across the genome and that the recruitment of HRP2/DPF3a to chromatin is dependent on H3K36me2. Integrative transcriptomic and cistromic analyses, coupled with ATAC-seq, reveal that HRP2 and DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of BRG1, the ATPase subunit of the BAF complex. Taken together, these results illuminate a key role for the HRP2-DPF3a-BAF complex in the epigenetic coordination of gene transcription during myogenic differentiation.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas de Ligação a DNA/metabolismo , Código das Histonas , Mioblastos/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Masculino , Camundongos , Desenvolvimento Muscular , Mioblastos/citologia , Ligação Proteica , Fatores de Transcrição/genética
5.
J Am Soc Nephrol ; 32(10): 2529-2541, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34162733

RESUMO

BACKGROUND: Genome-wide mapping of transcription factor (TF) binding sites is essential to identify a TF's direct target genes in kidney development and diseases. However, due to the cellular complexity of the kidney and limited numbers of a given cell type, it has been challenging to determine the binding sites of a TF in vivo. cAMP response element-binding protein (CREB) is phosphorylated and hyperactive in autosomal dominant polycystic kidney disease (ADPKD). We focus on CREB as an example to profile genomic loci bound by a TF and to identify its target genes using low numbers of specific kidney cells. METHODS: Cleavage under targets and release using nuclease (CUT&RUN) assays were performed with Dolichos biflorus agglutinin (DBA)-positive tubular epithelial cells from normal and ADPKD mouse kidneys. Pharmacologic inhibition of CREB with 666-15 and genetic inhibition with A-CREB were undertaken using ADPKD mouse models. RESULTS: CUT&RUN to profile genome-wide distribution of phosphorylated CREB (p-CREB) indicated correlation of p-CREB binding with active histone modifications (H3K4me3 and H3K27ac) in cystic epithelial cells. Integrative analysis with CUT&RUN and RNA-sequencing revealed CREB direct targets, including genes involved in ribosome biogenesis and protein synthesis. Pharmacologic and genetic inhibition of CREB suppressed cyst growth in ADPKD mouse models. CONCLUSIONS: CREB promotes cystogenesis by activating ribosome biogenesis genes. CUT&RUN, coupled with transcriptomic analysis, enables interrogation of TF binding and identification of direct TF targets from a low number of specific kidney cells.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/metabolismo , Anilidas/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Progressão da Doença , Células Epiteliais/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Histonas/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Camundongos , Naftalenos/farmacologia , Fosforilação , Rim Policístico Autossômico Dominante/patologia , Análise de Sequência de RNA
6.
Biochem Biophys Res Commun ; 520(3): 544-550, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31615655

RESUMO

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Anilidas/administração & dosagem , Anilidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Reparo do DNA/genética , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Nucleares/genética , Oncogenes , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Transcrição Gênica/efeitos dos fármacos , Proteína ran de Ligação ao GTP/genética
7.
Biochim Biophys Acta ; 1841(12): 1709-15, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25240836

RESUMO

Psoriasis is a chronic inflammatory skin disease, which has been linked to dyslipidemia with potential functional impairment of lipoproteins. This cross-sectional study was designed to characterize the biological activities of plasma lipoproteins in 25 patients with psoriasis and 25 age- and sex-matched healthy controls. In the present study, we found that plasma levels of high-density lipoprotein (HDL) cholesterol were decreased in the psoriasis group compared to healthy controls. The malondialdehyde (MDA) content in plasma, in HDL3 and in low-density lipoprotein (LDL) were increased. However, the activity of plasma paraoxonase-1 (PON-1) decreased in psoriasis and negatively correlated with the psoriasis area and severity index (PASI). Moreover, plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were increased in psoriasis and positively correlated with the PASI. High-sensitivity C-reactive protein (hs-CRP) was increased in psoriasis, but did not reach significance when correlated with PASI. In vitro tests displayed that the functionalities of HDL3 isolated from psoriatic patients significantly decreased, which were assessed in four independent ways, namely (1) protection against LDL oxidation, (2) inhibition of tumor necrosis factor-α (TNF-α) induced monocyte adherence to endothelial cells, (3) prevention of oxidized low density lipoprotein (ox-LDL) induced monocyte migration, and (4) protection of endothelial cells from TNF-α induced apoptosis. Further, pro-oxidative and pro-inflammatory properties of LDL isolated from psoriatic patients were increased. In conclusion, the biological activities of psoriatic lipoproteins are impaired in both HDL and LDL which may provide a link between psoriasis and cardiovas- cular disease.


Assuntos
Inflamação/patologia , Lipoproteínas HDL/metabolismo , Psoríase/patologia , Adulto , Biomarcadores/sangue , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Oxirredução , Psoríase/sangue
8.
J Eukaryot Microbiol ; 62(4): 470-80, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25523905

RESUMO

We investigated the toxicity of Karenia mikimotoi toward three model grazers, the cladoceran Moina mongolica, the copepod Pseudodiaptomus annandalei, and the crustacean Artemia salina, and explored its chemical response upon zooplankton grazing. An induction experiment, where K. mikimotoi was exposed to grazers or waterborne cues from the mixed cultures revealed that K. mikimotoi might be toxic or nutritionally inadequate toward the three grazers. In general, direct exposure to the three grazers induced the production of hemolytic toxins and the synthesis of eicosapentaenoic acid (EPA). Both EPA and the hemolytic toxins from K. mikimotoi decreased the survival rate of the three grazers. In addition, the survival rates of M. mongolica, P. annandalei, and A. salina in the presence of induced K. mikimotoi that had previously been exposed to a certain grazer were lower than their counterparts caused by fresh K. mikimotoi, suggesting that exposure to some grazers might increase the toxicity of K. mikimotoi. The chemical response and associated increased resistance to further grazing suggested that K. mikimotoi could produce deterrents to protect against grazing by zooplankton and that the substances responsible might be hemolytic toxins and EPA.


Assuntos
Dinoflagellida/química , Dinoflagellida/fisiologia , Zooplâncton/fisiologia , Animais , Artemia/crescimento & desenvolvimento , Artemia/fisiologia , Cladocera/crescimento & desenvolvimento , Cladocera/fisiologia , Ácido Eicosapentaenoico/biossíntese , Comportamento Alimentar , Herbivoria , Toxinas Marinhas/toxicidade , Zooplâncton/crescimento & desenvolvimento
9.
Cytotechnology ; 76(4): 425-439, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38933868

RESUMO

A previous study indicated that patients with androgenic alopecia (AGA) have significantly reduced levels of LncRNA RP11-818O24.3. This study investigates whether LncRNA RP11-818O24.3 promotes hair-follicle recovery and its possible mechanism. Hair alteration and cutaneous histopathological changes induced by testosterone propionate were observed by H&E and bromodeoxyuridinc (BrdU) stain to evaluate the therapeutic effect of LncRNA RP11-818O24.3 in C57BL/6 J mice. The cellular viability was analyzed in LncRNA RP11-818O24.3-transfected human hair-follicle stem cells (HFSCs) in vitro. The signaling pathways and pro-proliferative factors were investigated by transcriptomic gene sequencing and qRT-PCR. LncRNA RP11-818O24.3 transfection successfully recovered hair growth and hair-follicle cells in AGA mice. In a series of HFSC studies in vitro, LncRNA RP11-818O24.3 transfection greatly promoted cellular proliferation and decreased cellular apoptosis. Transcriptome gene sequencing suggested that the phosphatidylinositol 3-kinase (PI3K)-Akt pathway was upregulated by LncRNA RP11-818O24.3. The qRT-PCR results showed that fibroblast growth factor (FGF)-2 was 14-times upregulated after LncRNA RP11-818O24.3 transfection. Hair-follicle recovery activity of LncRNA RP11-818O24.3 may involve the upregulation of FGF2 and PI3K-Akt to promote follicle stem cell survival. These data not only provide a theoretical basis for AGA development but also reveal a novel therapeutic method for AGA patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-024-00624-3.

10.
Biomolecules ; 14(7)2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39062561

RESUMO

Cancer poses a significant public health challenge worldwide, and timely screening has the potential to mitigate cancer progression and reduce mortality rates. Currently, early identification of most tumors relies on imaging techniques and tissue biopsies. However, the use of low-cost, highly sensitive, non-invasive detection methods for early cancer screening has become more attractive. Extracellular Vesicles (EVs) released by all living cells contain distinctive biological components, such as nucleic acids, proteins, and lipids. These vesicles play crucial roles in the tumor microenvironment and intercellular communication during tumor progression, rendering liquid biopsy a particularly suitable method for diagnosis. Nevertheless, challenges related to purification methods and validation of efficacy currently hinder its widespread clinical implementation. These limitations underscore the importance of refining isolation techniques and conducting comprehensive investigations on EVs. This study seeks to evaluate the potential of liquid biopsy utilizing blood-derived EVs as a practical, cost-effective, and secure approach for early cancer detection.


Assuntos
Detecção Precoce de Câncer , Vesículas Extracelulares , Neoplasias , Humanos , Vesículas Extracelulares/metabolismo , Biópsia Líquida/métodos , Detecção Precoce de Câncer/métodos , Neoplasias/diagnóstico , Neoplasias/patologia , Biomarcadores Tumorais , Microambiente Tumoral
11.
Cell Biochem Biophys ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722470

RESUMO

Percutaneous coronary intervention (PCI) is the main treatment for patients with severe coronary vascular stenosis. However, In-stent neo-atherosclerosis (ISNA) is an important clinical complication in patients after PCI, which is mainly caused by a persistent inflammatory response and endothelial insufficiency. In the cardiovascular field, magnesium-based scaffolds stand out due to their properties. Magnesium plays a key role in regulating cardiovascular physiology. Magnesium deficiency can promote endothelial cell dysfunction, which contributes to the formation of atherosclerosis. Since astragaloside IV (AS­IV) has been proven to have potent cardioprotective effects, we asked whether high levels of magnesium cooperate with AS­IV might have effects on endothelial function and ISNA. We performed in vitro experiments on endothelial cells. Being treated with different concentrations of magnesium or/and AS-IV, the cell growth and migration were detected by CCK-8 and wound healing assay, respectively. The pro-inflammatory factors tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), and NF-kB were determined by qRT-PCR, ELISA kits or western blot. Results showed that high magnesium and AS-IV improved endothelial function, including promoting cell migration and decreasing the content of TNF-α, IL-6, VCAM-1, and NF-kB. With the supplement of AS-IV, additive magnesium maintains cell proliferation, migration, and function of endothelial cells. In conclusion, these findings suggest that high magnesium and AS­IV could improve vascular endothelial dysfunction. Early detection and treatment for neo-atherosclerosis may be of great clinical significance for improving stent implantation efficacy and long-term prognosis.

12.
Drug Saf ; 47(7): 711-719, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38689136

RESUMO

INTRODUCTION: Ixekizumab, a monoclonal antibody against interleukin-17A, is efficacious and well tolerated for the treatment of moderate-to-severe plaque psoriasis. However, there are limited data on the real-world safety of ixekizumab in Chinese patient populations. We performed an observational study of ixekizumab for the treatment of moderate-to-severe plaque psoriasis in routine clinical practice in China. Here we present a further safety analysis of this study. METHODS: In this prospective, observational, single-arm, multicenter, post-marketing safety study, adults (≥18 years) with moderate-to-severe plaque psoriasis receiving ixekizumab were enroled at dermatology departments in hospitals across China and prospectively followed for 12 weeks or until their last dose of ixekizumab. In this analysis, we evaluated adverse events (AEs) of special interest (AESIs) identified using MedDRA® search strategies. We also analyzed AEs and AESIs occurring in greater than ten patients in subgroups by age (< 65/≥ 65 years), sex, body weight (< 60/60 kg to < 80/≥ 80 kg), renal impairment, hepatic impairment, history of tuberculosis, history of HBV infection, recent or active infection, history of allergic reaction/hypersensitivity, and number (0-1/2-4/5-7) of ixekizumab 80 mg injections after baseline until day 105. RESULTS: This analysis included 663/666 patients enrolled in the primary study. At least one AESI was reported in 224 (33.8%) patients and considered related to ixekizumab in 181 (27.3%); the most common were injection site reactions (n = 131, 19.8%), infections (n = 80, 12.1%), and allergic reactions/hypersensitivity events (n = 59, 8.9%). The proportion of patients with ≥ 1 AE was higher for females versus males (99/186, 53.2% versus 184/477, 38.6%, p = 0.0006). The proportion of patients with ≥ 1 AE increased with the number of ixekizumab injections after baseline [61/188 (32.4%) for zero to one injection, 151/338 (44.7%) for two to four injections, and 61/106 (57.5%) for five to seven injections; p = 0.0001]. CONCLUSIONS: In this real-world study, ixekizumab was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis, with no difference in safety across most patient subgroups.


Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Humanos , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto , Idoso , Povo Asiático , China , Índice de Gravidade de Doença , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Vigilância de Produtos Comercializados , População do Leste Asiático
13.
Adv Sci (Weinh) ; : e2404731, 2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-39072943

RESUMO

Real-time tracking of drug release from nanomedicine in vivo is crucial for optimizing its therapeutic efficacy in clinical settings, particularly in dosage control and determining the optimal therapeutic window. However, most current real-time tracking systems require a tedious synthesis and purification process. Herein, a supramolecular nano-tracker (SNT) capable of real-time tracking of drug release in vivo based on non-covalent host-guest interactions is presented. By integrating multiple cavities into a single nanoparticle, SNT achieves co-loading of drugs and probes while efficiently quenching the photophysical properties of the probe through host-guest complexation. Moreover, SNT is readily degraded under hypoxic tumor tissues, leading to the simultaneous release of drugs and probes and the fluorescence recovery of probes. With this spatial and temporal consistency in drug loading and fluorescence quenching, as well as drug release and fluorescence recovery, SNT successfully achieves real-time tracking of drug release in vivo (Pearson r = 0.9166, R2 = 0.8247). Furthermore, the released drugs can synergize effectively with fluorescent probes upon light irradiation, achieving potent chemo-photodynamic combination therapy in 4T1-bearing mice with a significantly improved survival rate (33%), providing a potential platform to significantly advance the development of nanomedicine and achieve optimal therapeutic effects in the clinic.

14.
Dermatol Ther (Heidelb) ; 14(4): 907-918, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38536616

RESUMO

INTRODUCTION: Ixekizumab, a monoclonal antibody against interleukin-17A, demonstrated effectiveness in the treatment of psoriasis in a Chinese real-world study that was consistent with previous randomized controlled trials. Here, we report further analyses from this study to explore the effectiveness of ixekizumab for treating patients with psoriasis and the involvement of special body areas (scalp, nail, joint, palmoplantar, or genital areas). METHODS: A multicenter, prospective, observational, single-arm, post-marketing surveillance study was conducted in patients aged ≥ 18 years with moderate-to-severe plaque psoriasis and prescribed with ixekizumab in 26 Chinese hospitals. Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores were compared between patients with versus without psoriasis in special body areas in the overall study population and across subgroups by body area. RESULTS: In total, 612 patients were included. At baseline, most patients (93.6%) had psoriasis involvement in at least one special body area. Overall, patients with psoriasis in special body areas reported a worse quality of life (QoL) than those without. Patients with versus without psoriasis in special body areas achieved a comparable mean reduction from baseline in PASI score (10.9 vs. 9.2 at week 2, and 16.9 vs. 14.7 at week 12, respectively) and DLQI score (6.0 vs. 4.4 at week 2, and 9.9 vs. 7.5 at week 12, respectively); a similar proportion of patients also achieved PASI 50 at week 2, and PASI 75 and PASI 90 at week 12, and a DLQI (0/1) at weeks 2 and 12. Several significantly different results were reported between subgroups, the majority of which favored patients with special body area involvement. CONCLUSION: Most patients had psoriasis involvement in a special body area which was associated with worse QoL. Ixekizumab is similarly effective in reducing disease severity and improving QoL in patients with plaque psoriasis across different special body areas.

15.
JACS Au ; 3(12): 3424-3435, 2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-38155647

RESUMO

The low intrinsic thermal conduction and high dielectric properties of epoxy resins have significantly limited their applications in electrical and electronic devices with high integration, high frequency, high power, and miniaturization. Herein, a liquid crystalline epoxy (LCE) monomer with a biphenyl mesogenic unit was first synthesized through an efficient one-step reaction. Subsequently, bisphenol AF (BPAF) containing low-polarizable -CF3 groups and 4,4'-diaminodiphenylmethane (DDM) were applied to cure the LCE and commercial diglycidyl ether of bisphenol A-type epoxy (E-51), respectively, to afford four kinds of epoxy resins with various intrinsic thermal conductivity and dielectricity values. Owing to the dual effect of microscopically stacking of mesogens and the contribution of fluorine to the formation of liquid crystallinity, ordered microstructures of the nematic liquid crystal phase were formed within the cross-linking network of LCE as confirmed by polarized optical microscopy and X-ray diffraction. Consequently, phonon scattering was suppressed, and the intrinsic thermal conductivity was improved considerably to 0.38 W/(m·K), nearly twice as high as that of E-51 cured with DDM (0.20 W/(m·K)). Additionally, the ordered microstructure and ultralow polar -CF3 groups within LCE cured with BPAF enabled the epoxy resin to exhibit a remarkably lower and stable dielectric constant (ε) and dielectric loss tangent (tan δ) over both low and high frequencies compared to E-51 cured with DDM. The ε decreased from 3.40 to 2.72 while the tan δ decreased from 0.044 to 0.038 at 10 GHz. This work presents a scalable and facile strategy for breaking the bottleneck of making epoxy resins simultaneously with high inherent thermal conduction and low dielectric performance.

16.
Bioengineered ; 13(3): 4744-4756, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35138218

RESUMO

Sperm-associated antigen 5 (SPAG5) has been identified as a driver in several type of cancers. In this study, we aimed to reveal the role of SPAG5 in melanoma and clarify whether FOXM1 (forkhead box protein M1) /ADAM17 (A disintegrin and metalloproteinase 17) /NOTCH1 signaling was involved. The expression of SPAG5 in malignant melanoma (MM) tissues and matched normal tissues was detected using qRT-PCR, immunohistochemistry and Western blotting. Cell viability was tested using CCK-8 (Cell Count Kit-8), colony formation and EdU staining. Cell migration and epithelial to mesenchymal transition (EMT) were measured using transwell chambers and immunofluorescent staining. Cell cycle distribution and tumorigenesis were assessed by flow cytometry and in vivo tumor-bearing experiments, respectively. The results demonstrated that the expression of SPAG5 was increased in MM tissues and cells. Downregulation of SPAG5 inhibited cell viability, migration, invasion and EMT, and induced a G1-phase arrest. In addition, downregulation of SPAG5 decreased the expression of FOXM1, thereafter inhibiting the expression of ADAM17, NOTCH1 and HES1. Furthermore, deletion of SPAG5 expression decreased the tumorigenesis of MM A375 cells. In conclusion, this study demonstrated that SPAG5 was overexpressed in MM. Downregulation of SPAG5 repressed MM cell growth and EMT, which might be induced by inactivation of the FOXM1/ADAM17/NOTCH1 signaling.


Assuntos
Proteína ADAM17 , Proteínas de Ciclo Celular , Proteína Forkhead Box M1 , Melanoma , Humanos , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Carcinogênese , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Melanoma/genética , Metaloproteases/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo
17.
Eur J Dermatol ; 32(2): 259-268, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35866908

RESUMO

Background: Psoriasis is a systemic inflammatory disease. The autoimmune response plays a role in the pathogenesis of psoriasis. The long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) can regulate the immune response and participate in the pathogenesis of immune-related diseases, however, the role of ANRIL in the pathogenesis of psoriasis requires further clarification. Objectives: To study the association between ANRIL polymorphisms and psoriasis in the northern Chinese population. Materials & Methods: We genotyped six SNPs in ANRIL in 270 psoriasis vulgaris patients and 271 healthy controls in the northern Chinese population using an improved multiplexed ligation detection reaction method, in order to identify the role of ANRIL in psoriasis. Results: The C allele of rs3217992 and the T allele of rs2518723 were more prevalent in the case group than in the control group. The haplotypes, CTATAA, CCCCGG, and CTCCGG, were associated with risk of psoriasis, while the TCCCGG, TCATAA and CCATAA haplotypes were protective against psoriasis. Based on subgroup analysis, patients with the CT genotype at the rs3217992 and rs2518723 loci had a higher probability of a family history of psoriasis, and patients with the AA genotype had a higher mean age in the rs1333048 and rs10757278 groups, while those with the TT genotype had a higher mean age in the rs1333045 group. Conclusion: Our study identifies an association between ANRIL genetic variants and risk of psoriasis in northern China.


Assuntos
Polimorfismo de Nucleotídeo Único , Psoríase , RNA Longo não Codificante/genética , Alelos , Povo Asiático/genética , China , Predisposição Genética para Doença , Haplótipos , Humanos , Psoríase/genética
18.
Adv Sci (Weinh) ; 9(10): e2104578, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35037420

RESUMO

Formation of biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signal transduction and gene activation through condensate formation, and how dysregulation of these mechanisms contributes to disease progression, remain elusive. Here, the authors report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase-separated condensates upon activation of cAMP signaling. They show that intranuclear CRTC2 interacts with positive transcription elongation factor b (P-TEFb) and activates P-TEFb by disrupting the inhibitory 7SK snRNP complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). They find that CRTC2 localizes to the nucleus and forms condensates in cystic epithelial cells of both mouse and human ADPKD kidneys. Genetic depletion of CRTC2 suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, they identify CRTC2-regulated cystogenesis-associated genes, whose activation depends on CRTC2 condensate-facilitated P-TEFb recruitment and the release of paused RNA polymerase II. Together, their findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD.


Assuntos
Rim Policístico Autossômico Dominante , Animais , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/metabolismo , Fator B de Elongação Transcricional Positiva/genética , Fator B de Elongação Transcricional Positiva/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional
19.
J Clin Invest ; 132(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35166240

RESUMO

The chromosomal t(4;14) (p16;q32) translocation drives high expression of histone methyltransferase nuclear SET domain-containing 2 (NSD2) and plays vital roles in multiple myeloma (MM) evolution and progression. However, the mechanisms of NSD2-driven epigenomic alterations in chemoresistance to proteasome inhibitors (PIs) are not fully understood. Using a CRISPR/Cas9 sgRNA library in a bone marrow-bearing MM model, we found that hepatoma-derived growth factor 2 (HRP2) was a suppressor of chemoresistance to PIs and that its downregulation correlated with a poor response and worse outcomes in the clinic. We observed suppression of HRP2 in bortezomib-resistant MM cells, and knockdown of HRP2 induced a marked tolerance to PIs. Moreover, knockdown of HRP2 augmented H3K27me3 levels, consequentially intensifying transcriptome alterations promoting cell survival and restriction of ER stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylase MYC-induced nuclear antigen (MINA) to remove H3K27me3. Tazemetostat, a highly selective epigenetic inhibitor that reduces H3K27me3 levels, synergistically sensitized the anti-MM effects of bortezomib both in vitro and in vivo. Collectively, these results provide a better understanding of the origin of chemoresistance in patients with MM with the t(4;14) translocation and a rationale for managing patients with MM who have different genomic backgrounds.


Assuntos
Reprogramação Celular , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 4/genética , Dioxigenases , Epigênese Genética/efeitos dos fármacos , Histona Desmetilases , Mieloma Múltiplo , Proteínas de Neoplasias , Proteínas Nucleares , Inibidores de Proteassoma/farmacologia , Translocação Genética , Linhagem Celular Tumoral , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Dioxigenases/genética , Dioxigenases/metabolismo , Epigenômica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo
20.
Bioengineered ; 12(1): 1874-1889, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34076564

RESUMO

Excessive activation of signal transducer and activator of transcription 3 (STAT3) is implicated in breast cancer (BC) chemoresistance, but its underlying mechanism is not fully understood. There are STAT3 binding sites in fat mass and obesity-associated protein (FTO) promoter region, thus STAT3 may regulate the transcription of FTO. This study aimed to investigate the correlation between FTO and STAT3 in BC chemoresistance. Herein, FTO and STAT3 were highly expressed in doxorubicin-resistant BC (BC-DoxR) cells. CHIP assay verified the binding between STAT3 and FTO promoter in BC-DoxR cells. Dual luciferase reporter assay showed that FTO promoter activity was inhibited by S3I-201 (STAT3 inhibitor) but enhanced by epidermal growth factor (EGF, STAT3 activator) in BC-DoxR and BC cells. FTO mRNA and protein expression were suppressed by S3I-201 in BC-DoxR cells and EGF-stimulated BC cells. Notably, FTO regulated total N6-methyladenosine (m6A) levels in BC-DoxR and BC cells but could not affect STAT3 mRNA expression, indicating that FTO was not involved in the m6A modification of STAT3. However, FTO could activate STAT3 signaling in BC-DoxR and BC cells. Besides, FTO knockdown inhibited the doxorubicin resistance of BC-DoxR cells, while FTO overexpression enhanced the doxorubicin resistance and weakened the doxorubicin sensitivity of BC cells. Moreover, decreased doxorubicin resistance by STAT3 knockdown was abolished by FTO overexpression and decreased doxorubicin sensitivity by STAT3 overexpression was reversed by FTO knockdown, indicating that FTO was implicated in STAT3-mediated doxorubicin resistance and impairment of doxorubicin sensitivity of BC cells. Altogether, our findings provide a mechanism underlying BC doxorubicin resistance.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Neoplasias da Mama/patologia , Doxorrubicina/farmacologia , Fator de Transcrição STAT3/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Fator de Transcrição STAT3/genética , Neoplasias de Mama Triplo Negativas/patologia
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