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1.
Children (Basel) ; 11(5)2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38790593

RESUMEN

Recently, there has been a shift in smoking patterns among adolescents, with a decrease in the prevalence of conventional cigarette smoking and an increase in the use of electronic cigarettes (e-cigarettes). The harmful effects of e-cigarettes are remarkable, highlighting the need for proactive interventions for adolescent users and smoking cessation that consider the characteristics of both conventional cigarette smokers and e-cigarette users. This study aims to investigate the smoking status of adolescent conventional cigarette and e-cigarette smokers and to analyze the predictors of their smoking cessation plans (SCPs) based on the transtheoretical model. Self-rated health, prior smoking cessation education, consciousness-raising, and dramatic relief as types of experiential processes of change, and formation of helping relationships as a type of behavioral process of change significantly differed according to the type of cigarette behavior among adolescents. The predictors of SCP among adolescents were perceived pros of smoking and academic performance among conventional cigarette smokers and behavioral process of change, perceived pros of smoking, and economic status among e-cigarette users. This study identified differences in the characteristics and predictors of SCP. Strategies tailored to each specific adolescent smoking population are further required to promote smoking cessation.

2.
ACS Nano ; 18(20): 12885-12896, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38709870

RESUMEN

In Li metal batteries (LMBs), which boast the highest theoretical capacity, the chemical structure of the solid electrolyte interphase (SEI) serves as the key component that governs the growth of reactive Li. Various types of additives have been developed for electrolyte optimization, representing one of the most effective strategies to enhance the SEI properties for stable Li plating. However, as advanced electrolyte systems become more chemically complicated, the use of additives is empirically optimized. Indeed, their role in SEI formation and the resulting cycle life of LMBs are not well-understood. In this study, we employed cryogenic transmission electron microscopy combined with Raman spectroscopy, theoretical studies including molecular dynamics (MD) simulations and density functional theory (DFT) calculations, and electrochemical measurements to explore the nanoscale architecture of SEI modified by the most representative additives, lithium nitrate (LiNO3) and vinylene carbonate (VC), applied in a localized high-concentration electrolyte. We found that LiNO3 and VC play distinct roles in forming the SEI, governing the solvation structure, and influencing the kinetics of electrochemical reduction. Their collaboration leads to the desired SEI, ensuring prolonged cycle performance for LMBs. Moreover, we propose mechanisms for different Li growth and cycling behaviors that are determined by the physicochemical properties of SEI, such as uniformity, elasticity, and ionic conductivity. Our findings provide critical insights into the appropriate use of additives, particularly regarding their chemical compatibility.

3.
Exp Mol Med ; 56(4): 763-771, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38658704

RESUMEN

Recent studies have demonstrated that the three-dimensional conformation of the chromatin plays a crucial role in gene regulation, with aberrations potentially leading to various diseases. Advanced methodologies have revealed a link between the chromatin conformation and biological function. This review divides these methodologies into sequencing-based and imaging-based methodologies, tracing their development over time. We particularly highlight innovative techniques that facilitate the simultaneous mapping of RNAs, histone modifications, and proteins within the context of the 3D architecture of chromatin. This multimodal integration substantially improves our ability to establish a robust connection between the spatial arrangement of molecular components in the nucleus and their functional roles. Achieving a comprehensive understanding of gene regulation requires capturing diverse data modalities within individual cells, enabling the direct inference of functional relationships between these components. In this context, imaging-based technologies have emerged as an especially promising approach for gathering spatial information across multiple components in the same cell.


Asunto(s)
Cromatina , Regulación de la Expresión Génica , Cromatina/metabolismo , Cromatina/genética , Cromatina/química , Humanos , Animales , Histonas/metabolismo , Histonas/genética
4.
BMB Rep ; 56(12): 633-644, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38052424

RESUMEN

Epigenetic mechanisms, primarily mediated through histone and DNA modifications, play a pivotal role in orchestrating the functional identity of a cell and its response to environmental cues. Similarly, the spatial arrangement of chromatin within the threedimensional (3D) nucleus has been recognized as a significant factor influencing genomic function. Investigating the relationship between epigenetic regulation and 3D chromatin structure has revealed correlation and causality between these processes, from the global alignment of average chromatin structure with chromatin marks to the nuanced correlations at smaller scales. This review aims to dissect the biological significance and the interplay between the epigenome and 3D chromatin structure, while also exploring the underlying molecular mechanisms. By synthesizing insights from both experimental and modeling perspectives, we seek to provide a comprehensive understanding of cellular functions. [BMB Reports 2023; 56(12): 633-644].


Asunto(s)
Epigénesis Genética , Epigenoma , Cromatina/genética , Histonas/genética , Histonas/metabolismo , Genoma
5.
Healthcare (Basel) ; 11(18)2023 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-37761722

RESUMEN

We present a secondary data analysis of the raw data from the eighth Korea National Health and Nutrition Examination Survey (KNHANES). A total of 827 current smokers who responded that they had smoked >5 packs (100 cigarettes) of cigarettes in their lifetime and were currently smoking traditional cigarettes were selected. This study was conducted to identify sociodemographic, smoking-related, and health-related characteristics that influence the use of e-cigarettes in adult smokers. To examine these factors, general characteristics such as age, marital status, education level, and occupation were included in Model 1, while health-related characteristics such as the level of smoking and depression were included in Model 2. In Model 1, age, a high level of education, and working in an office were found to be significantly correlated with e-cigarette use among smokers, while age and working in the office were found to be significantly correlated with e-cigarette use in Model 2. Therefore, e-cigarette use was high among adult smokers of young ages who were office workers. Although evidence is lacking regarding its safety and use as smoking cessation aids, many smokers have been reported to use e-cigarettes as smoking cessation aids, making it necessary to provide accurate information on e-cigarettes.

6.
Mol Cell ; 83(9): 1377-1392.e6, 2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-37146570

RESUMEN

Although population-level analyses revealed significant roles for CTCF and cohesin in mammalian genome organization, their contributions at the single-cell level remain incompletely understood. Here, we used a super-resolution microscopy approach to measure the effects of removal of CTCF or cohesin in mouse embryonic stem cells. Single-chromosome traces revealed cohesin-dependent loops, frequently stacked at their loop anchors forming multi-way contacts (hubs), bridging across TAD boundaries. Despite these bridging interactions, chromatin in intervening TADs was not intermixed, remaining separated in distinct loops around the hub. At the multi-TAD scale, steric effects from loop stacking insulated local chromatin from ultra-long range (>4 Mb) contacts. Upon cohesin removal, the chromosomes were more disordered and increased cell-cell variability in gene expression. Our data revise the TAD-centric understanding of CTCF and cohesin and provide a multi-scale, structural picture of how they organize the genome on the single-cell level through distinct contributions to loop stacking.


Asunto(s)
Cromatina , Cromosomas , Animales , Ratones , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Cromosomas/genética , Cromosomas/metabolismo , Cromatina/genética , Cromatina/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Mamíferos/metabolismo
7.
Vaccines (Basel) ; 11(5)2023 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-37243069

RESUMEN

Newborn piglets are susceptible to a highly contagious enteritis caused by the porcine epidemic diarrhea virus (PEDV), associated with high levels of mortality worldwide. There is pressing need for a rapid, safe, and cost-effective vaccine to safeguard pigs from getting infected by PEDV. PEDV belongs to the coronavirus family and is characterized by high levels of mutability. The primary goal of a PEDV vaccine is to provide immunity to newborn piglets through vaccination of sows. Plant-based vaccines are becoming more popular because they have low manufacturing costs, are easily scalable, have high thermostability, and a long shelf life. This is in contrast to conventional vaccines which include inactivated, live, and/or recombinant types that can be expensive and have limited ability to respond to rapidly mutating viruses. The binding of the virus to host cell receptors is primarily facilitated by the N-terminal subunit of the viral spike protein (S1), which also contains several epitopes that are recognized by virus-neutralizing antibodies. As a result, we generated a recombinant S1 protein using a plant-based vaccine platform. We found that the recombinant protein was highly glycosylated, comparable to the native viral antigen. Vaccination of pregnant sows at four and two weeks before farrowing led to the development of humoral immunity specific to S1 in the suckling piglets. In addition, we noted significant viral neutralization titers in both vaccinated sows and piglets. When challenged with PEDV, piglets born from vaccinated sows displayed less severe clinical symptoms and significantly lower mortality rates compared to piglets born from non-vaccinated sows.

8.
Cell Syst ; 14(4): 324-339.e7, 2023 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-37080164

RESUMEN

Transcription factors (TFs) control gene expression, often acting synergistically. Classical thermodynamic models offer a biophysical explanation for synergy based on binding cooperativity and regulated recruitment of RNA polymerase. Because transcription requires polymerase to transition through multiple states, recent work suggests that "kinetic synergy" can arise through TFs acting on distinct steps of the transcription cycle. These types of synergy are not mutually exclusive and are difficult to disentangle conceptually and experimentally. Here, we model and build a synthetic circuit in which TFs bind to a single shared site on DNA, such that TFs cannot synergize by simultaneous binding. We model mRNA production as a function of both TF binding and regulation of the transcription cycle, revealing a complex landscape dependent on TF concentration, DNA binding affinity, and regulatory activity. We use synthetic TFs to confirm that the transcription cycle must be integrated with recruitment for a quantitative understanding of gene regulation.


Asunto(s)
Regulación de la Expresión Génica , Biología Sintética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Unión Proteica , ADN/metabolismo
9.
Mol Cell ; 83(9): 1446-1461.e6, 2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-36996812

RESUMEN

Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.


Asunto(s)
Cromatina , Secuencias Reguladoras de Ácidos Nucleicos , Humanos , Cromatina/genética , Regiones Promotoras Genéticas , Regulación de la Expresión Génica , Genoma , Proteínas de Ciclo Celular/metabolismo , Elementos de Facilitación Genéticos , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo
10.
Adv Mater ; 35(17): e2211497, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36762586

RESUMEN

Design of bifunctional multimetallic alloy catalysts, which are one of the most promising candidates for water splitting, is a significant issue for the efficient production of renewable energy. Owing to large dimensions of the components and composition of multimetallic alloys, as well as the trade-off behavior in terms of the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) overpotentials for bifunctional catalysts, it is difficult to search for high-performance bifunctional catalysts with multimetallic alloys using conventional trial-and-error experiments. Here, an optimal bifunctional catalyst for water splitting is obtained by combining Pareto active learning and experiments, where 110 experimental data points out of 77946 possible points lead to effective model development. The as-obtained bifunctional catalysts for HER and OER exhibit high performance, which is revealed by model development using Pareto active learning; among the catalysts, an optimal catalyst (Pt0.15 Pd0.30 Ru0.30 Cu0.25 ) exhibits a water splitting behavior of 1.56 V at a current density of 10 mA cm-2 . This study opens avenues for the efficient exploration of multimetallic alloys, which can be applied in multifunctional catalysts as well as in other applications.

11.
Int J Mol Sci ; 24(2)2023 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-36674667

RESUMEN

Regular exercise, especially aerobic exercise, is beneficial for increasing serum high-density lipoprotein-cholesterol (HDL-C) levels in the general population. In addition to the HDL-C quantity, exercise enhances HDL functionality, antioxidants, and cholesterol efflux. On the other hand, the optimal intensity and frequency of exercise to increase HDL quantity and enhance HDL quality in middle-aged women need to be determined. The current study was designed to compare the changes in HDL quantity and quality among middle-aged women depending on exercise intensity, frequency, and duration; participants were divided into a sedentary group (group 1), a middle-intensity group (group 2), and a high-intensity group (group 3). There were no differences in anthropometric parameters among the groups, including blood pressure, muscle mass, and handgrip strength. Although there was no difference in serum total cholesterol (TC) among the groups, the serum HDL-C and apolipoprotein (apo)A-I levels remarkably increased to 17% and 12%, respectively, in group 3. Serum low-density lipoprotein-cholesterol (LDL-C), glucose, triglyceride, and the apo-B/apoA-I ratio were remarkably decreased in the exercise groups depending on the exercise intensity; group 3 showed 13%, 10%, and 45% lower LDL-C, glucose, and triglyceride (TG), respectively, than group 1. The hepatic and muscle damage parameter, aspartate aminotransferase (AST), was significantly decreased in the exercise groups, but high-sensitivity C-reactive protein (CRP), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GTP) were similar in the three groups. In LDL, the particle size was increased 1.5-fold (p < 0.001), and the oxidation extent was decreased by 40% with a 23% lower TG content in group 3 than in group 1. In the exercise groups (groups 2 and 3), LDL showed the slowest electromobility with a distinct band intensity compared to the sedentary group (group 1). In HDL2, the particle size was 2.1-fold increased (p < 0.001) in the exercise group (group 3) with a 1.5-fold increase in TC content compared to that in group 1, as well as significantly enhanced antioxidant abilities, paraoxonase (PON) activity, and ferric ion reduction ability (FRA). In HDL3, the particle size was increased 1.2-fold with a 45% reduction in TG in group 3 compared to group 1. With increasing exercise intensity, apoA-I expression was increased in HDL2 and HDL3, and PON activity and FRA were enhanced (p < 0.001). In conclusion, regular exercise in middle-aged women is associated with the elevation of serum HDL-C and apoA-I with the enhancement of HDL quality and functionality and an increase in the TC content, particle size, and antioxidant abilities. With the reduction in TG and oxidized products in LDL and HDL, lipoproteins could have more anti-atherogenic properties through regular exercise in an intensity-dependent manner.


Asunto(s)
Antioxidantes , Lipoproteínas HDL , Persona de Mediana Edad , Humanos , Femenino , Lipoproteínas HDL/metabolismo , Antioxidantes/metabolismo , Apolipoproteína A-I , LDL-Colesterol , Tamaño de la Partícula , Fuerza de la Mano , Apolipoproteínas , Triglicéridos , Lipoproteínas HDL3 , Ejercicio Físico , HDL-Colesterol , Lipoproteínas LDL/metabolismo
12.
Clin Exp Vaccine Res ; 11(3): 285-289, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36451664

RESUMEN

Various vaccines have been developed to fight severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 pandemic. However, new variants of SARS-CoV-2 undermine the effort to fight SARS-CoV-2. Here, we produced S proteins harboring the receptor-binding domain (RBD) of the Omicron variant in plants. Plant-produced S proteins together with adjuvant CIA09A triggered strong immune responses in mice. Antibodies in serum inhibited interaction of recombinant human angiotensin-converting enzyme 2 with RBD of the Omicron variant, but not RBD of other variants. These results suggest that antibodies induced by RBD of the Omicron variant are highly specific for the Omicron RBD, but not for that of other variants.

13.
Healthcare (Basel) ; 10(11)2022 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-36360479

RESUMEN

The aim of this study is to understand the effects of self-control and social networks of friends on the amount of smoking among out-of-school adolescents. The subjects of this study were 187 out-of-school adolescent smokers from the J-province Youth Counseling Welfare Center as of 2020. Data were collected through self-report questionnaires that contained questions about sociodemographic characteristics, self-control, social networks of friends, and amount of smoking. The dependent variable was smoking amount. Descriptive statistics, χ2 tests, correlation analyses, and regression analysis were performed. The predictors of smoking in OSY (out-of-school youth) were analyzed with respect to self-control and social networks of friends. The significant variables in model 3 were age, living with parents, and average allowance. The smoking rate of friends (ß = 0.256) and the degree of penetration of friends smoking (ß = 0.341) were significant variables. The higher the percentage of friends smoking and the higher the degree of penetration of smoking among the members of social networks, the higher the amount of smoking.

14.
World J Gastroenterol ; 28(27): 3422-3434, 2022 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-36158271

RESUMEN

BACKGROUND: The biochemical phenomenon defined as poly adenosine diphosphate (ADP)-ribosylation (PARylation) is essential for the progression of pancreatic cancer. However, the excessive accumulation of poly ADP-ribose (PAR) induces apoptosis-inducing factor (AIF) release from mitochondria and energy deprivation resulting in the caspase-independent death of cancer cells. AIM: To investigate whether sustained calcium supply could induce an anticancer effect on pancreatic cancer by PAR accumulation. METHODS: Two pancreatic cancer cell lines, AsPC-1 and CFPAC-1 were used for the study. Calcium influx and mitochondrial reactive oxygen species (ROS) were observed by fluorescence staining. Changes in enzyme levels, as well as PAR accumulation and energy metabolism, were measured using assay kits. AIF-dependent cell death was investigated followed by confirming in vivo anticancer effects by sustained calcium administration. RESULTS: Mitochondrial ROS levels were elevated with increasing calcium influx into pancreatic cancer cells. Then, excess PAR accumulation, decreased PAR glycohydrolase and ADP-ribosyl hydrolase 3 levels, and energy deprivation were observed. In vitro and in vivo antitumor effects were confirmed to accompany elevated AIF levels. CONCLUSION: This study visualized the potential anticancer effects of excessive PAR accumulation by sustained calcium supply on pancreatic cancer, however elucidating a clear mode of action remains a challenge, and it should be accompanied by further studies to assess its potential for clinical application.


Asunto(s)
Neoplasias Pancreáticas , Poli Adenosina Difosfato Ribosa , Adenosina Difosfato , Factor Inductor de la Apoptosis/metabolismo , Calcio/metabolismo , Caspasas/metabolismo , Glicósido Hidrolasas/metabolismo , Humanos , Mitocondrias/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Poli Adenosina Difosfato Ribosa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ribosa/metabolismo
15.
Int J Mol Sci ; 23(15)2022 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-35955766

RESUMEN

Light-to-moderate alcohol drinking is associated with a low incidence of cardiovascular disease (CVD) via an elevation of high-density lipoproteins-cholesterol (HDL-C), particularly with the short-term supplementation of alcohol. However, there is no information on the change in the HDL qualities and functionalities between non-drinkers and mild drinkers in the long-term consumption of alcohol. This study analyzed the lipid and lipoprotein profiles of middle-aged Korean female non-drinkers, mild-drinkers, and binge-drinkers, who consumed alcohol for at least 10 years. Unexpectedly, the serum levels of HDL-C and apolipoprotein A-I (apoA-I) were decreased significantly depending on the alcohol amount; the binge-drinker group showed 18% and 13% lower HDL-C (p = 0.011) and apoA-I levels (p = 0.024), respectively, than the non-drinker group. Triglyceride (TG) and oxidized species, malondialdehyde (MDA), and low-density lipoproteins (LDL) levels were significantly elevated in the drinker groups. Interestingly, the binge-drinker group showed 1.4-fold higher (p = 0.020) cholesterol contents in HDL2 and 1.7-fold higher (p < 0.001) TG contents in HDL3 than those of the non-drinker group. The mild-drinker group also showed higher TG contents in HDL3 (p = 0.032) than the non-drinker group, while cholesterol contents were similar in the HDL3 of all groups. Transmission electron microscopy (TEM) showed that the non-drinker group showed a more distinct and clear particle shape of the LDL and HDL image with a larger particle size than the drinker group. Electrophoresis of LDL showed that the drinker group had faster electromobility with a higher smear band intensity and aggregation in the loading position than the non-drinker group. The HDL level of binge drinkers showed the lowest paraoxonase activity, the highest glycated extent, and the most smear band intensity of HDL and apoA-I, indicating that HDL quality and functionality were impaired by alcohol consumption. In conclusion, long-term alcohol consumption in middle-aged women, even in small amounts, caused a significant decrease in the serum HDL-C and apoA-I with atherogenic changes in LDL and HDL, such as an increase in TG and MDA content with a loss of paraoxonase activity.


Asunto(s)
Apolipoproteína A-I , Aterosclerosis , Consumo de Bebidas Alcohólicas , Arildialquilfosfatasa , Aterosclerosis/etiología , Colesterol , HDL-Colesterol , Etanol , Femenino , Humanos , Persona de Mediana Edad , República de Corea , Triglicéridos
16.
Vaccines (Basel) ; 11(1)2022 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-36679898

RESUMEN

Porcine parvovirus (PPV) causes reproductive failure in sows, and vaccination remains the most effective means of preventing infection. The NADL-2 strain has been used as a vaccine for ~50 years; however, it does not protect animals against genetically heterologous PPV strains. Thus, new effective and safe vaccines are needed. In this study, we aimed to identify novel PPV1 strains, and to develop PPV1 subunit vaccines. We isolated and sequenced PPV1 VP2 genes from 926 pigs and identified ten PPV1 strains (belonging to Groups C, D and E). We selected the Group D PPV1-82 strain as a vaccine candidate because it was close to the highly pathogenic 27a strain. The PPV1-82 VP2 protein was produced in Nicotiana benthamiana. It formed virus-like particles and exhibited a 211 agglutination value. The PPV1-190313 strain (Group E), isolated from an aborted fetus, was used as the challenging strain because it was pathogenic. The unvaccinated sow miscarried at 8 days postchallenge, and mummified fetuses were all PPV1-positive. By contrast, pregnant sows vaccinated with PPV1-82 VP2 had 9-11 Log2 antibody titers and produced normal fetuses after PPV1-190313 challenge. These results suggest the PPV1-82 VP2 subunit vaccine protects pregnant sows against a genetically heterologous PPV1 strain by inducing neutralizing antibodies.

17.
World J Gastrointest Oncol ; 13(6): 574-588, 2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-34163574

RESUMEN

The development of colorectal cancer (CRC) can result from changes in a variety of cellular systems within the tumor microenvironment. Particularly, it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression. Based on this background, the potential to focus on poly [adenosine diphosphate (ADP)-ribose] polymerase (PARP)-1 and poly-ADP ribosylation (PARylation) as the main causes of malignant formation of CRC may be considered. One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid (DNA) repair function, which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide. PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes. Given the high importance of these processes in CRC, it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles; furthermore, it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC. This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC, which may present the potential to identify various research topics that can be challenged both non-clinically and clinically.

18.
Sci Transl Med ; 13(591)2021 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-33910981

RESUMEN

The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening "on-target/off-tumor" toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells.


Asunto(s)
Receptores Quiméricos de Antígenos , Línea Celular Tumoral , Femenino , Humanos , Inmunoterapia Adoptiva , Mesotelina , Ratones , Placenta , Embarazo , Receptores de Antígenos de Linfocitos T , Ensayos Antitumor por Modelo de Xenoinjerto
19.
N Biotechnol ; 63: 29-36, 2021 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-33667631

RESUMEN

Porcine circovirus type 2 (PCV2) is a non-enveloped, icosahedral virus of the Circoviridae family, with a small, circular, single-stranded DNA genome. PCV2 infections cause substantial economic losses in the pig industry worldwide. Currently, commercially produced PCV2 vaccines are expensive, whereas plant-based expression systems can produce recombinant proteins at low cost for use as vaccines. In this study, recombinant PCV2 capsid protein (rCap) was transiently expressed in Nicotiana benthamiana and purified by metal affinity chromatography, with a yield of 102 mg from 1 kg plant leaves. Electron microscopy confirmed that purified rCap self-assembled into virus-like particles (VLPs) at neutral pH. It was shown to provoke a strong immune response in guinea pigs. The results indicate that plant systems can enable production of large amounts of proteins to serve as candidates for subunit vaccines.


Asunto(s)
Anticuerpos Neutralizantes/biosíntesis , Proteínas de la Cápside/biosíntesis , Circovirus/química , Nicotiana/metabolismo , Vacunas de Partículas Similares a Virus/biosíntesis , Animales , Anticuerpos Neutralizantes/química , Proteínas de la Cápside/química , Cobayas , Nicotiana/química , Vacunas de Partículas Similares a Virus/química
20.
Molecules ; 25(22)2020 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-33202899

RESUMEN

Sorafenib has been recently used for the treatment of patients with advanced colorectal cancer (CRC) and is recognized for its therapeutic value. However, the continuous use of sorafenib may cause resistance in the treatment of cancer patients. In this study, we investigated whether sorafenib exerts an enhanced anticancer effect on CRC cells via the calcium-mediated deactivation of the focal adhesion kinase (FAK) signaling pathways. The appropriate dose of sorafenib and lactate calcium salt (CaLa) for a combination treatment were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Then, cell cycle analysis was performed following treatment with 2.5 µM sorafenib and/or 2.5 mM CaLa. CRC cells were found to be in the G1 phase by sorafenib treatment, and they accumulated in the sub-G1 phase with CaLa treatment. Western blots and enzyme-linked immunosorbent assays were performed to analyze the elements of the recombinant activated factor (RAF) and focal adhesion kinase (FAK) signaling cascades. Sorafenib-inhibited RAF-dependent signaling in CRC cells, however, either did not affect the expression of Akt or increased it. As the upstream signaling of FAK was suppressed by CaLa, we observed that the expression of the sub-signaling phospho (p) AKT and p-mammalian target of rapamycin was also suppressed. Treatment with a combination of sorafenib and CaLa enhanced the antitumor activity of CRC cells. The % viability of CRC cells was significantly decreased compared to the single treatment with sorafenib or CaLa, and the accumulation of Sub G1 of CRC cells was clearly confirmed. The migration ability of CRC cells was significantly reduced. The findings of this study indicate that sorafenib will show further improved antitumor efficacy against CRC due to overcoming resistance through the use of CaLa.


Asunto(s)
Antineoplásicos/farmacología , Calcio/farmacología , Neoplasias Colorrectales/enzimología , Quinasa 1 de Adhesión Focal/metabolismo , Ácido Láctico/farmacología , Sorafenib/farmacología , Ciclo Celular , Línea Celular Tumoral , Supervivencia Celular , Neoplasias Colorrectales/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Células HCT116 , Células HT29 , Humanos , Transducción de Señal
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