RESUMEN
The α7 nicotinic acetylcholine receptor (nAChR), a potential drug target for treating cognitive disorders, mediates communication between neuronal and non-neuronal cells. Although many competitive antagonists, agonists, and partial-agonists have been found and synthesized, they have not led to effective therapeutic treatments. In this context, small molecules acting as positive allosteric modulators binding outside the orthosteric, acetylcholine, site have attracted considerable interest. Two single-domain antibody fragments, C4 and E3, against the extracellular domain of the human α7-nAChR were generated through alpaca immunization with cells expressing a human α7-nAChR/mouse 5-HT3A chimera, and are herein described. They bind to the α7-nAChR but not to the other major nAChR subtypes, α4ß2 and α3ß4. E3 acts as a slowly associating positive allosteric modulator, strongly potentiating the acetylcholine-elicited currents, while not precluding the desensitization of the receptor. An E3-E3 bivalent construct shows similar potentiating properties but displays very slow dissociation kinetics conferring quasi-irreversible properties. Whereas, C4 does not alter the receptor function, but fully inhibits the E3-evoked potentiation, showing it is a silent allosteric modulator competing with E3 binding. Both nanobodies do not compete with α-bungarotoxin, localizing at an allosteric extracellular binding site away from the orthosteric site. The functional differences of each nanobody, as well as the alteration of functional properties through nanobody modifications indicate the importance of this extracellular site. The nanobodies will be useful for pharmacological and structural investigations; moreover, they, along with the extracellular site, have a direct potential for clinical applications.
Asunto(s)
Receptores Nicotínicos , Anticuerpos de Dominio Único , Humanos , Ratones , Animales , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Anticuerpos de Dominio Único/farmacología , Regulación Alostérica , Acetilcolina/farmacología , Receptores Nicotínicos/metabolismoRESUMEN
Rotational Raman lidar is an important technique for detecting atmospheric temperature. However, in cloud regions with strong elastic scattering conditions, elastic scattering crosstalk (ESC) is prevalent due to insufficient out-of-band suppression of the optical filter, resulting significant deviations in temperature retrieval. To address this challenge, a temperature correction technique for optically-thin clouds based on the backscatter ratio is proposed. Using the least-squares method, a temperature correction function is formulated based on the relationship between the ESC and backscatter ratio of clouds. Subsequently, the backscatter ratio is used to correct the rotational Raman ratio of clouds, thereby obtaining the vertical distribution of atmospheric temperature within the cloud layer. The feasibility of this method was assessed through numerical simulations and experimentally validated using a temperature and aerosol detection lidar at the Xi'an University of Technology (XUT). The results indicate that the difference between the retrieved temperature profile under high signal-to-noise ratio conditions and radiosonde data is less than 1.5â K. This correction technique enables atmospheric temperature measurements under elastic scattering conditions with a backscatter ratio less than 115, advancing research on atmospheric structure and cloud microphysics.
RESUMEN
Burn patients are at high risk of central line-associated bloodstream infection (CLABSI). However, the diagnosis of such infections is complex, resource-intensive, and often delayed. This study aimed to investigate the epidemiology of CLABSI and develop a prediction model for the infection in burn patients. The study analysed the infection profiles, clinical epidemiology, and central venous catheter (CVC) management of patients in a large burn centre in China from January 2018 to December 2021. In total, 222 burn patients with a cumulative 630 CVCs and 5,431 line-days were included. The CLABSI rate was 23.02 CVCs per 1000 line-days. The three most common bacterial species were Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa; 76.09% of isolates were multidrug resistant. Compared with a non-CLABSI cohort, CLABSI patients were significantly older, with more severe burns, more CVC insertion times, and longer total line-days, as well as higher mortality. Regression analysis found longer line-days, more catheterisation times, and higher burn wounds index to be independent risk factors for CLABSI. A novel nomogram based on three risk factors was constructed with an area under the receiver operating characteristic curve (AUROC) value of 0.84 (95% CI: 0.782-0.898) with a mean absolute error of calibration curve of 0.023. The nomogram showed excellent predictive ability and clinical applicability, and provided a simple, practical, and quantitative strategy to predict CLABSI in burn patients.
Asunto(s)
Bacteriemia , Quemaduras , Infecciones Relacionadas con Catéteres , Catéteres Venosos Centrales , Humanos , Bacteriemia/complicaciones , Bacteriemia/epidemiología , Quemaduras/complicaciones , Infecciones Relacionadas con Catéteres/epidemiología , Catéteres Venosos Centrales/efectos adversos , Catéteres Venosos Centrales/microbiología , Nomogramas , Estudios RetrospectivosRESUMEN
Long noncoding RNAs (lncRNAs) are transcripts with lengths of more than 200 nt and limited protein-coding potential. They were found to play important roles in plant stress responses. In this study, the maize drought-tolerant inbred line AC7643 and drought-sensitive inbred line AC7729/TZSRW, as well as their recombinant inbred lines (RILs) were selected to identify drought-responsive lncRNAs in roots. Compared with non-responsive lncRNAs, drought-responsive lncRNAs had different sequence characteristics in length of genes and number of exons. The ratio of down-regulated lncRNAs induced by drought was significantly higher than that of coding genes; and lncRNAs were more widespread expressed in recombination sites in the RILs. Additionally, by integration of the modifications of DNA 5-methylcytidine (5mC), histones, and RNA N6-methyladenosine (m6A), it was found that the enrichment of histone modifications associated with transcriptional activation in the genes generated lncRNAs was lower that coding genes. The lncRNAs-mRNAs co-expression network, containing 15,340 coding genes and 953 lncRNAs, was constructed to investigate the molecular functions of lncRNAs. There are 13 modules found to be associated with survival rate under drought. We found nine SNPs located in lncRNAs among the modules associated with plant survival under drought. In conclusion, we revealed the characteristics of lncRNAs responding to drought in maize roots based on multiomics studies. These findings enrich our understanding of lncRNAs under drought and shed light on the complex regulatory networks that are orchestrated by the noncoding RNAs in response to drought stress.
Asunto(s)
ARN Largo no Codificante , Zea mays , Zea mays/genética , ARN Largo no Codificante/genética , Sequías , Exones , Regulación de la Expresión Génica de las Plantas , Perfilación de la Expresión GénicaRESUMEN
Pure rotational Raman lidar is often used for atmospheric temperature profile measurements. However, high elastic scattering suppression ratios (>107) are required for temperature measurement in clouds and haze, which imposes stringent requirements on spectral separation techniques. To solve this problem, a lidar measurement technique based on vibrational and rotational Raman spectra is proposed. Using nitrogen vibrational and rotational Raman scattering to obtain temperature profiles under strong elastic scattering, combined with the dual-rotational Raman temperature measurements under weak elastic scattering, a vertical distribution of atmospheric temperature including cloud and haze layers, can be obtained. The feasibility of the method was verified by numerical simulation. The Raman lidar for temperature measurements was established in Xi'an University of Technology, and the obtained temperature results show good agreement with the radiosonde measurements. The proposed method combines the high sensitivity of the dual-rotational Raman method and the high Mie-scattering suppression of the vibrational Raman method, thus further improving the adaptability of Raman lidar to cloudy and hazy air conditions and supporting atmospheric and cloud physics research.
RESUMEN
Due to its biological activity, carvacrol (CAR) is widely used in medicine, agriculture, and forestry. Our previous studies showed that in Lymantria dispar larvae, CAR treatment can induce the production of antifeedants and lead to growth inhibition and death of larvae. However, the effect CAR exerts on RNA levels in L. dispar larvae remains unclear. In this study, the Illumina HiSeq4000 sequencing platform was used to sequence the total RNA of L. dispar larvae. A total of six cDNA libraries (three treatments and three controls) were established and 39,807 genes were generated. Compared with the control group, 296 differentially expressed genes (DEGs) (142 up-regulated and 154 down-regulated) were identified after CAR treatment. GO and KEGG enrichment analyses showed that these DEGs mainly clustered in the metabolism of xenobiotics, carbohydrates, and lipids. Furthermore, 12 DEGs were found to be involved in detoxification, including six cytochrome P450s, two esterases, one glutathione peroxidase, one UDP-glycosyltransferase gene, and two genes encoding heat shock proteins. The expression levels of detoxification genes changed under CAR treatment (especially P450s), which further yielded candidate genes for explorations of the insecticidal mechanism of CAR. The reliability of transcriptome data was verified by qRT-PCR. The enzyme activities of CYP450 and acid phosphatase significantly increased (by 38.52 U/mg·prot and 0.12 µmol/min·mg, respectively) 72 h after CAR treatment. However, the activity of alkaline phosphatase did not change significantly. These changes in enzyme activity corroborated the reliability of the transcriptome data at the protein level. The results of GO enrichment analysis of DEGs indicated that CAR influenced the oxidation-reduction process in L. dispar larvae. Furthermore, CAR can cause oxidative stress in L. dispar larvae, identified through the determination of peroxidase and polyphenol oxidase activities, total antioxidant capacity, and hydrogen peroxide content. This study provides useful insight into the insecticidal mechanism of CAR.
Asunto(s)
Mariposas Nocturnas , Transcriptoma , Animales , Cimenos , Perfilación de la Expresión Génica , Larva/genética , Mariposas Nocturnas/genética , Reproducibilidad de los ResultadosRESUMEN
Maize (Zea mays) is an important multi-functional crop. The growth and yield of maize are severely affected by drought stress. Previous studies have shown that microRNAs (miRNAs) in maize play important roles in response to abiotic stress; however, their roles in response to drought stress in maize roots is unclear. In our study, we found 375 miRNAs in the roots of 16 inbred lines. Of the 16 lines, zma-MIR168, zma-MIR156, and zma-MIR166 were highly expressed, whereas zma-MIR399, zma-MIR2218, and zma-MIR2275 exhibited low expression levels. The expression patterns of miRNA in parental lines and their derived RILs are different. Over 50% of miRNAs exhibited a lower expression in recombinant inbred lines than in parents. The expression of 50 miRNAs was significantly altered under water stress (WS) in at least three inbred lines, and the expression of miRNAs in drought-tolerant lines changed markedly. To better understand the reasons for miRNA response to drought, the degree of histone modifications for miRNA genes was estimated. The methylation level of H3K4 and H3K9 in miRNA precursor regions changed more noticeably after WS, but no such phenomenon was seen for DNA methylation and m6A modification. After the prediction of miRNA targets using psRNATarget and psRobot, we used correlation analysis and qRT-PCR to further investigate the relationship between miRNAs and target genes. We found that 87 miRNA-target pairs were significantly negatively correlated. In addition, a weighted gene co-expression network analysis using miRNAs, as well as their predicted targets, was conducted to reveal that miR159, miR394, and miR319 may be related to maize root growth. The results demonstrated that miRNAs might play essential roles in the response to drought stress.
Asunto(s)
MicroARNs , Zea mays , Sequías , Regulación de la Expresión Génica de las Plantas , MicroARNs/genética , MicroARNs/metabolismo , Hojas de la Planta/metabolismo , Estrés Fisiológico/genética , Zea mays/genética , Zea mays/metabolismoRESUMEN
The purpose of this study was to examine the combination of magnetic anion-exchange microbeads (MAM) and magnetic cation-exchange microbeads (MCM) to remove crystal violet (CV; a basic dye) and acid green 9 (AG9; an acidic dye) from their individual and combined solutions. Adsorption kinetics and isotherms experiments were performed in batch mode. CV and AG9 displayed superior affinity towards MCM and MAM, respectively, and their combined solution was efficiently adsorbed by combining MCM and MAM. The pseudo-first-order, pseudo-second-order, Elovich and intra-particle diffusion models well described the adsorption kinetic data, and the pseudo-second-order model appeared a better fit for the two-component CV/AG9 system. The better fit of the Langmuir isotherm for CV adsorption indicated that CV adsorption occurred on active sites with equal affinity in the monolayer. In contrast, AG9 adsorption onto the heterogeneous MAM surface appeared to be multilayered adsorption. The adsorption capacities of the two dyes decreased with the increase in the co-existing salt concentration and increased only slightly at the high salt level due to the salting-out effect. Moreover, these microbeads maintained most of their initial capacity during five reuse cycles, indicating the great potential of MCM and MAM to remove basic and acidic dyes in practical applications.
Asunto(s)
Colorantes , Contaminantes Químicos del Agua , Adsorción , Concentración de Iones de Hidrógeno , Intercambio Iónico , Cinética , Fenómenos Magnéticos , Microesferas , TermodinámicaRESUMEN
Nuclear export protein 1 (XPO1), a member of the nuclear export protein-p (Karyopherin-P) superfamily, regulates the transport of "cargo" proteins. To facilitate this important process, which is essential for cellular homeostasis, XPO1 must first recognize and bind the cargo proteins. To inhibit this process, small molecule inhibitors have been designed that inhibit XPO1 activity through covalent binding. However, the scaffolds for these inhibitors are very limited. While virtual screening may be used to expand the diversity of the XPO1 inhibitor skeleton, enormous computational resources would be required to accomplish this using traditional screening methods. In the present study, we report the development of a hybrid virtual screening workflow and its application in XPO1 covalent inhibitor screening. After screening, several promising XPO1 covalent molecules were obtained. Of these, compound 8 performed well in both tumor cell proliferation assays and a nuclear export inhibition assay. In addition, molecular dynamics simulations were performed to provide information on the mode of interaction of compound 8 with XPO1. This research has identified a promising new scaffold for XPO1 inhibitors, and it demonstrates an effective and resource-saving workflow for identifying new covalent inhibitors.
Asunto(s)
Neoplasias , Receptores Citoplasmáticos y Nucleares , Transporte Activo de Núcleo Celular , Humanos , Carioferinas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
N6-methyladenosine (m6A) is an abundant mRNA modification that affects multiple biological processes, including those involved in the cell stress response and viral infection. YTH domain family 2 (YTHDF2) is an m6A-binding protein that affects the localization and stability of targeted mRNA. RNA-binding proteins (RBPs) can regulate the stability of inflammatory gene mRNA transcripts, thus participating in the regulation of inflammatory processes. As an RBP, the role of YTHDF2 in the LPS-induced inflammatory reaction has not been reported. To elucidate the function of YTHDF2 in the inflammatory response of macrophages, we first detected the expression level of YTHDF2 in RAW 264.7 cells, and found that it was upregulated after LPS stimulation. YTHDF2 knockdown significantly increased the LPS-induced IL-6, TNF-α, IL-1ß, and IL-12 expression and the phosphorylation of p65, p38, and ERK1/2 in NF-κB and MAPK signaling. Moreover, the upregulated expression of TNF-α and IL-6 in cells with silenced YTHDF2 expression was downregulated by the NF-κB, p38, and ERK inhibitors. YTHDF2 depletion increased the expression and stability of MAP2K4 and MAP4K4 mRNAs. All of these results suggest that YTHDF2 knockdown increases mRNA expression levels of MAP2K4 and MAP4K4 via stabilizing the mRNA transcripts, which activate MAPK and NF-κB signaling pathways, which promote the expression of proinflammatory cytokines and aggravate the inflammatory response in LPS-stimulated RAW 264.7 cells.
Asunto(s)
Adenosina/análogos & derivados , Inflamación/inducido químicamente , Lipopolisacáridos/efectos adversos , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Adenosina/metabolismo , Animales , Citocinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/genética , Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , MAP Quinasa Quinasa 4/genética , Ratones , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Células RAW 264.7 , Transducción de Señal , Regulación hacia ArribaRESUMEN
Bone mesenchymal stem cells (BMSCs) can be a useful cell resource for developing biological treatment strategies for bone repair and regeneration, and their therapeutic applications hinge on an understanding of their physiological characteristics. N6-methyl-adenosine (m6A) is the most prevalent internal chemical modification of mRNAs and has recently been reported to play important roles in cell lineage differentiation and development. However, little is known about the role of m6A modification in the cell differentiation of BMSCs. To address this issue, we investigated the expression of N6-adenosine methyltransferases (Mettl3 and Mettl14) and demethylases (Fto and Alkbh5) and found that Mettl3 was upregulated in BMSCs undergoing osteogenic induction. Furthermore, we knocked down Mettl3 and demonstrated that Mettl3 knockdown decreased the expression of bone formation-related genes, such as Runx2 and Osterix. The alkaline phosphatase (ALP) activity and the formation of mineralized nodules also decreased after Mettl3 knockdown. RNA sequencing analysis revealed that a vast number of genes affected by Mettl3 knockdown were associated with osteogenic differentiation and bone mineralization. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that the phosphatidylinositol 3-kinase/AKT (PI3K-Akt) signaling pathway appeared to be one of the most enriched pathways, and Western blotting results showed that Akt phosphorylation was significantly reduced after Mettl3 knockdown. Mettl3 has been reported to play an important role in regulating alternative splicing of mRNA in previous research. In this study, we found that Mettl3 knockdown not only reduced the expression of Vegfa but also decreased the level of its splice variants, vegfa-164 and vegfa-188, in Mettl3-deficient BMSCs. These findings might contribute to novel progress in understanding the role of epitranscriptomic regulation in the osteogenic differentiation of BMSCs and provide a promising perspective for new therapeutic strategies for bone regeneration.
Asunto(s)
Empalme Alternativo/genética , Células de la Médula Ósea/metabolismo , Diferenciación Celular , Células Madre Mesenquimatosas/metabolismo , Metiltransferasas/metabolismo , Osteogénesis , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-DawleyRESUMEN
Tet-eleven translocation 1 (TET1) is a dioxygenase that plays an important role in decreasing the abundance of DNA methylation and changing the expression levels of specific genes related to inflammation. Porphyromonas gingivalis (Pg.) lipopolysaccharide (LPS) can induce periodontal diseases that present with severe bone loss and collagen fiber destruction accompanied by a high number of M1 macrophages. M1-polarized macrophages are pivotal immune cells that promote the progression of the periodontal inflammatory response, but the function of TET1 during M1 macrophage activation is still unknown. Our results showed that the mRNA and protein expression levels of TET1 decreased in THP-1 cells during M1 macrophage differentiation. TET1 knockdown resulted in a significant decrease in the production of proinflammatory markers such as IL-6, TNF-α, CCL2, and HLA-DR in Pg. LPS/IFN-γ- and Escherichia coli (E. coli) LPS/IFN-γ-induced M1 macrophages. Mechanistically, TET1 knockdown downregulated the activity of the NF-κB signaling pathway. After treatment with the NF-κB inhibitor BAY 11-7082, M1 marker expression showed no significant difference between the TET1 knockdown group and the control group. Taken together, these results suggest that TET1 depletion inhibited Pg. LPS/IFN-γ-induced M1 macrophage polarization through the NF-κB pathway in THP-1 cells.
Asunto(s)
Interferón gamma/inmunología , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Oxigenasas de Función Mixta/genética , FN-kappa B/inmunología , Porphyromonas gingivalis/inmunología , Proteínas Proto-Oncogénicas/genética , Técnicas de Silenciamiento del Gen , Humanos , Inflamación/inmunología , Inflamación/microbiología , Activación de Macrófagos , Macrófagos/microbiología , Oxigenasas de Función Mixta/inmunología , Proteínas Proto-Oncogénicas/inmunología , Transducción de Señal , Células THP-1RESUMEN
Dental pulp inflammation is a widespread public health problem caused by oral bacterial infections and can progress to pulp necrosis and periapical diseases. N6-methyladenosine (m6A) is a prevalent epitranscriptomic modification in mRNA. Previous studies have demonstrated that m6A methylation plays important roles in cell differentiation, embryonic development and stress responses. However, whether m6A modification affects dental pulp inflammation remains unknown. To address this issue, we investigated the expression of m6A and N6-adenosine methyltransferase (METTL3, METTL14) as well as demethylases (FTO, ALKBH5) and found that the levels of m6A and METTL3 were up-regulated in human dental pulp cells (HDPCs) stimulated by lipopolysaccharide (LPS). Furthermore, we knocked down METTL3 and demonstrated that METTL3 depletion decreased the expression of inflammatory cytokines and the phosphorylation of IKKα/ß, p65 and IκBα in the NF-κB signalling pathway as well as p38, ERK and JNK in the MAPK signalling pathway in LPS-induced HDPCs. The RNA sequencing analysis revealed that the vast number of genes affected by METTL3 depletion was associated with the inflammatory response. Previous research has shown that METTL3-dependent N6-adenosine methylation plays an important role in mRNA splicing. In this study, we found that METTL3 knockdown facilitated the expression of MyD88S, a splice variant of MyD88 that inhibits inflammatory cytokine production, suggesting that METTL3 might inhibit the LPS-induced inflammatory response of HDPCs by regulating alternative splicing of MyD88. These data shed light on new findings in epitranscriptomic regulation of the inflammatory response and open new avenues for research into the molecular mechanisms of dental pulp inflammation.
Asunto(s)
Empalme Alternativo/genética , Pulpa Dental/metabolismo , Pulpa Dental/patología , Inflamación/genética , Inflamación/patología , Metiltransferasas/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Adolescente , Adulto , Citocinas/metabolismo , Regulación hacia Abajo/genética , Humanos , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Sistema de Señalización de MAP Quinasas , Metiltransferasas/genética , FN-kappa B/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación hacia Arriba/genética , Adulto JovenRESUMEN
Dental pulp inflammation is a bacterially driven inflammation process characterized by the local accumulation of cytokines/chemokines that participate in destructive processes in the pulp. Multiple mechanisms are involved in dental pulp inflammation, including epigenetic events, such as DNA methylation/demethylation. Ten-eleven translocation 2 (TET2) is a recently discovered DNA methylcytosine dioxygenase that plays important roles in inflammatory disease. However, its role in the inflammatory response of dental pulp is unknown. We observed elevated mRNA and protein levels of TET2 after lipopolysaccharide (LPS) stimulation in human dental pulp cells (hDPCs). To identify the effects of TET2 on cytokine expression, TET2 was knocked down and cytokines were detected using a cytokine antibody array after LPS stimulation. The protein expression of GM-CSF, IL-6, IL-8 and RANTES decreased in the LPS-induced hDPCs following TET2 knockdown. The downregulated expression levels of IL-6 and IL-8 were further confirmed by real-time quantitative polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Additionally, the phosphorylation levels of IKK-α/ß, p65 and IκBα of the NF-κB signaling pathway were decreased in the TET2-silenced group. Furthermore, the global 5-hydroxymethylcytosine (5hmC) level was significantly decreased and the genomic 5-methylcytosine (5mC) level was increased in the TET2-deficient hDPCs; TET2 depletion resulted in a decrease in the 5hmC level of the MyD88 promoter following LPS stimulation. These findings indicate that TET2 knockdown inhibits LPS-induced inflammatory response in hDPCs by downregulating MyD88 hydroxymethylation. Thus, TET2-dependent DNA demethylation might play an important role in dental pulp inflammation as an epigenetic regulator.
Asunto(s)
Citocinas/metabolismo , Proteínas de Unión al ADN/metabolismo , Pulpa Dental/metabolismo , Dioxigenasas/metabolismo , Inflamación/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Citocinas/efectos de los fármacos , Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Pulpa Dental/citología , Pulpa Dental/efectos de los fármacos , Pulpa Dental/inmunología , Dioxigenasas/genética , Epigénesis Genética/genética , Técnicas de Silenciamiento del Gen , Humanos , Inflamación/inmunología , Lipopolisacáridos/farmacología , Factor 88 de Diferenciación Mieloide/genética , Cultivo Primario de Células , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismoRESUMEN
As a sedentary lifestyle leads to numerous health problems, it is important to keep constant motivation for a more active lifestyle. A large majority of the worldwide population, such as office workers, long journey vehicle drivers and wheelchair users, spends several hours every day in sedentary activities. The postures that sedentary lifestyle users assume during daily activities hide valuable information that can reveal their wellness and general health condition. Aiming at mining such underlying information, we developed a cushion-based system to assess their activity levels and recognize the activity from the information hidden in sitting postures. By placing the smart cushion on the chair, we can monitor users' postures and body swings, using the sensors deployed in the cushion. Specifically, we construct a body posture analysis model to recognize sitting behaviors. In addition, we provided a smart cushion that effectively combine pressure and inertial sensors. Finally, we propose a method to assess the activity levels based on the evaluation of the activity assessment index (AAI) in time sliding windows. Activity level assessment can be used to provide statistical results in a defined period and deliver recommendation exercise to the users. For practical implications and actual significance of results, we selected wheelchair users among the participants to our experiments. Features in terms of standard deviation and approximate entropy were compared to recognize the activities and activity levels. The results showed that, using the novel designed smart cushion and the standard deviation features, we are able to achieve an accuracy of (>89%) for activity recognition and (>98%) for activity level recognition.
Asunto(s)
Conducta Sedentaria , Ejercicio Físico , Artículos Domésticos , Humanos , Postura , Úlcera por Presión , Silla de RuedasRESUMEN
Prostate cancer (PCa) is the second most common cancer in males worldwide. Androgen deprivation therapy (ADT) is the primary treatment method used for PCa. Although more effective androgen synthesis and antiandrogen inhibitors have been developed for clinical practice, hormone resistance increases the incidence of ADT-insensitive prostate cancer and poor prognoses. The tumor microenvironment (TME) has become a research hotspot with efforts to identify treatment targets based on the characteristics of the TME to improve prognosis. Herein, we introduce the basic characteristics of the PCa TME and the side effects of traditional prostate cancer treatments. We further highlight the emergence of novel nanotherapy strategies, their therapeutic mechanisms, and their effects on the PCa microenvironment. With further research, clinical applications of nanotherapy for PCa are expected in the near future. Collectively, this Review provides a valuable resource regarding the various nanotherapy types, demonstrating their broad clinical prospects to improve the quality of life in patients with PCa.
RESUMEN
Silicosis is a systemic disease with predominantly diffuse fibrosis of the lungs due to prolonged inhalation of free SiO2 dust during the manufacturing process, for which there is no effective treatment. In this study, we used a combined epigenetic and transcriptomic approach to reveal the chromatin-opening features of silicosis and identify the key transcription factor activator protein 1 (AP-1) that responds to silicosis fibrosis. Therapeutic administration of an AP-1 inhibitor inhibits the PI3K/AKT signaling pathway, reduces fibrosis marker proteins, and significantly ameliorates lung fibrosis in a mouse model of silicosis. In addition, it was observed that the expression of Jun and JunB was significantly up-regulated in a TGF-ß1-induced in vitro transdifferentiation model of NIH/3T3 cells, and Co-IP confirmed that a protein complex could be formed between Jun and JunB. Mechanistically, silencing of Jun and JunB expression reversed the activation of the PI3K/AKT signaling pathway and the upregulation of fibrosis marker proteins in NIH/3 T3 cells after TGF-ß1 stimulation. Taken together, Jun/JunB is expected to be a potential therapeutic target for silicosis fibrosis.
Asunto(s)
Proteínas Proto-Oncogénicas c-jun , Transducción de Señal , Silicosis , Factor de Transcripción AP-1 , Silicosis/metabolismo , Silicosis/tratamiento farmacológico , Silicosis/patología , Animales , Ratones , Factor de Transcripción AP-1/metabolismo , Células 3T3 NIH , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Humanos , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Modelos Animales de Enfermedad , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Ratones Endogámicos C57BLRESUMEN
Acute lung injury (ALI) is a serious disorder characterized by the release of pro-inflammatory cytokines and cascade activation of macrophages. Ferroptosis, a form of iron-dependent cell death triggered by intracellular phospholipid peroxidation, has been implicated as an internal mechanism underlying ALI. In this study, we investigated the effects of m6A demethylase fat mass and obesity-associated protein (FTO) on the inhibition of macrophage ferroptosis in ALI. Using a mouse model of lipopolysaccharide (LPS)-induced ALI, we observed the induction of ferroptosis and its co-localization with the macrophage marker F4/80, suggesting that ferroptosis might be induced in macrophages. Ferroptosis was promoted during LPS-induced inflammation in macrophages in vitro, and the inflammation was counteracted by the ferroptosis inhibitor ferrostatin-1 (fer-1). Given that FTO showed lower expression levels in the lung tissue of mice with ALI and inflammatory macrophages, we further dissected the regulatory capacity of FTO in ferroptosis. The results demonstrated that FTO alleviated macrophage inflammation by inhibiting ferroptosis. Mechanistically, FTO decreased the stability of ACSL4 mRNA via YTHDF1, subsequently inhibiting ferroptosis and inflammation by interrupting polyunsaturated fatty acid consumption. Moreover, FTO downregulated the synthesis and secretion of prostaglandin E2, thereby reducing ferroptosis and inflammation. In vivo, the FTO inhibitor FB23-2 aggravated lung injury, the inflammatory response, and ferroptosis in mice with ALI; however, fer-1 therapy mitigated these effects. Overall, our findings revealed that FTO may function as an inhibitor of the inflammatory response driven by ferroptosis, emphasizing its potential as a target for ALI treatment.
Asunto(s)
Lesión Pulmonar Aguda , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Coenzima A Ligasas , Ferroptosis , Inflamación , Macrófagos , Animales , Masculino , Ratones , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Ciclohexilaminas , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Lipopolisacáridos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones Endogámicos C57BL , Fenilendiaminas/farmacología , Células RAW 264.7RESUMEN
Di (2-ethyl-hexyl) phthalate (DEHP) mainly enters the human body through the digestive tract, respiratory tract, and skin. At the same time, it has reproductive and developmental toxicity, neurotoxicity, and so on, which can cause the decrease of sperm motility. Asthenospermia is also known as low sperm motility, and the semen quality of men in some areas of China is declining year by year. Interestingly, previous studies have shown that sleep disorders can also lead to asthenospermia. However, the relationship between sleep, DEHP, and asthenospermia is still unclear. Analysis of the National Health and Nutrition Examination Survey (NHANES) population database showed that DEHP was associated with sleep disorders, and subsequent experiments in mice and Drosophila indicated that DEHP exposure had certain effects on sleep and asthenospermia. Furthermore, we analyzed the Comparative Toxicogenomics Database (CTD) to find out the common signaling pathway among the three: hypoxia-inducible factor 1(HIF-1). Then Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to screen out the proteins that DEHP affected the HIF-1 pathway: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR), and finally Western blot analysis was used to detect the expression levels of the three proteins. Compared with the control group, DEHP decreased the protein expression levels of GAPDH and AKT1 in the HIF-1 pathway, and caused sleep disorders and decreased sperm motility. This study provides preliminary evidence for exploring the mechanism among DEHP, sleep disorders, and asthenospermia.
Asunto(s)
Dietilhexil Ftalato , Ácidos Ftálicos , Trastornos del Sueño-Vigilia , Humanos , Masculino , Animales , Ratones , Dietilhexil Ftalato/toxicidad , Análisis de Semen , Encuestas Nutricionales , Motilidad Espermática , SueñoRESUMEN
PURPOSE: The objective of this study was to investigate the influence of high dietary iodine supply and different iodine sources on thyroid status and oxidative stress in target tissues of the thyroid hormones in fattening pigs. METHODS: Eighty castrates (body weight: 33.3 ± 0.4 kg) were randomly allotted into five different treatments: The control diet contained 150 µg I/kg as KI, the other feeding groups were supplemented with 4,000 µg I/kg (as KI and KIO(3)) and 10,000 µg I/kg (as KI and KIO(3)), respectively. The mRNA expression levels of sodium/iodide symporter (NIS) and key antioxidant enzymes (Cu/Zn SOD, CAT, GPx) were analyzed in thyroid gland, liver, kidney, muscle, and adipose tissue sampled during slaughter. Furthermore, antioxidant enzyme activities and the effect on lipid peroxidation (MDA) were determined in liver and muscle. RESULTS: In thyroid gland, a significant downregulation of NIS and Cu/Zn SOD mRNA expression was observed in high-iodine groups. In liver, a source effect on the mRNA expression of Cu/Zn SOD between KI and KIO(3) at 4,000 µg I/kg was shown. In contrast, not SOD but GPx activity was affected by iodine source with strongest downregulation in high KIO(3) group. In muscle, GPx activity was affected by both iodine source and dose, showing stronger downregulation in KI groups. In kidney and adipose tissue, oxidative stress parameters showed no or only unsystematic changes. However, variation in iodine supply had no effect on MDA concentrations. CONCLUSIONS: NIS expression was significantly decreased with increased iodine supplementation, which is to ensure the thyroid gland function. However, the alleviating effect of iodine supplementation observed in antioxidant enzyme mRNA expression and activity did not reflect on the lipid peroxide level.