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1.
Nucleic Acids Res ; 51(15): 7914-7935, 2023 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-37351599

RESUMEN

During the repair of DNA double-strand breaks (DSBs), de novo synthesized DNA strands can displace the parental strand to generate single-strand DNAs (ssDNAs). Many programmed DSBs and thus many ssDNAs occur during meiosis. However, it is unclear how these ssDNAs are removed for the complete repair of meiotic DSBs. Here, we show that meiosis-specific depletion of Dna2 (dna2-md) results in an abundant accumulation of RPA and an expansion of RPA from DSBs to broader regions in Saccharomyces cerevisiae. As a result, DSB repair is defective and spores are inviable, although the levels of crossovers/non-crossovers seem to be unaffected. Furthermore, Dna2 induction at pachytene is highly effective in removing accumulated RPA and restoring spore viability. Moreover, the depletion of Pif1, an activator of polymerase δ required for meiotic recombination-associated DNA synthesis, and Pif1 inhibitor Mlh2 decreases and increases RPA accumulation in dna2-md, respectively. In addition, blocking DNA synthesis during meiotic recombination dramatically decreases RPA accumulation in dna2-md. Together, our findings show that meiotic DSB repair requires Dna2 to remove ssDNA-RPA filaments generated from meiotic recombination-associated DNA synthesis. Additionally, we showed that Dna2 also regulates DSB-independent RPA distribution.


Asunto(s)
Proteínas de Unión al ADN , Proteínas de Saccharomyces cerevisiae , ADN , Reparación del ADN , ADN de Cadena Simple/genética , Proteínas de Unión al ADN/genética , Meiosis/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
2.
J Cell Sci ; 135(6)2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35142363

RESUMEN

TDP-43 (also known as TARDBP) is a nuclear splicing factor functioning in pre-mRNA processing. Its C-terminal 35-kDa fragment (TDP-35) forms inclusions or aggregates in cytoplasm, and sequesters full-length TDP-43 into the inclusions through binding with RNA. We extended the research to investigate whether TDP-35 inclusions sequester other RNA-binding proteins (RBPs) and how RNA-binding specificity has a role in this sequestration process. We have characterized T-cell restricted intracellular antigen-1 (TIA1) and other RBPs that can be sequestered into the TDP-35 inclusions through specific RNA binding, and found that this sequestration leads to the dysfunction of TIA1 in maturation of target pre-mRNA. Moreover, we directly visualized the dynamic sequestration of TDP-43 by the cytoplasmic TDP-35 inclusions by live-cell imaging. Our results demonstrate that TDP-35 sequesters some specific RBPs and this sequestration is assisted by binding with RNA in a sequence-specific manner. This study provides further evidence in supporting the hijacking hypothesis for RNA-assisted sequestration and will be beneficial to further understanding of the TDP-43 proteinopathies.


Asunto(s)
Esclerosis Amiotrófica Lateral , Proteinopatías TDP-43 , Esclerosis Amiotrófica Lateral/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Cuerpos de Inclusión/metabolismo , ARN/genética , ARN/metabolismo , Precursores del ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteinopatías TDP-43/metabolismo
3.
BMC Cancer ; 24(1): 354, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38504172

RESUMEN

Colorectal cancer (CRC) is a worldwide health concern. Chronic inflammation is a risk factor for CRC, and interleukin-6 (IL-6) plays a pivotal role in this process. Arginine-specific mono-ADP-ribosyltransferase-1 (ART1) positively regulates inflammatory cytokines. ART1 knockdown reduces the level of glycoprotein 130 (gp130), a key transducer in the IL-6 signalling pathway. However, the relationship between ART1 and IL-6 and the resulting effects on IL-6-induced proliferation in CRC cells remain unclear. The aims of this study were to investigate the effects of ART1 knockdown on IL-6-induced cell proliferation in vitro and use an in vivo murine model to observe the growth of transplanted tumours. The results showed that compared with the control, ART1-sh cancer cells induced by IL-6 exhibited reduced viability, a lower rate of colony formation, less DNA synthesis, decreased protein levels of gp130, c-Myc, cyclin D1, Bcl-xL, and a reduced p-STAT3/STAT3 ratio (P < 0.05). Moreover, mice transplanted with ART1-sh CT26 cells that had high levels of IL-6 displayed tumours with smaller volumes (P < 0.05). ART1 and gp130 were colocalized in CT26, LoVo and HCT116 cells, and their expression was positively correlated in human CRC tissues. Overall, ART1 may serve as a promising regulatory factor for IL-6 signalling and a potential therapeutic target for human CRC.


Asunto(s)
Neoplasias Colorrectales , Interleucina-6 , Humanos , Animales , Ratones , Interleucina-6/genética , ADP Ribosa Transferasas/genética , ADP Ribosa Transferasas/metabolismo , Receptor gp130 de Citocinas/genética , Línea Celular Tumoral , Poli(ADP-Ribosa) Polimerasas/genética , Proliferación Celular , Neoplasias Colorrectales/patología , Proteínas Ligadas a GPI/metabolismo
4.
Environ Sci Technol ; 58(19): 8215-8227, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38687897

RESUMEN

Per- and polyfluoroalkyl substances (PFAS) are extensively utilized in varieties of products and tend to accumulate in the human body including umbilical cord blood and embryos/fetuses. In this study, we conducted an assessment and comparison of the potential early developmental toxicity of perfluorooctanoic acid (PFOA), undecafluorohexanoic acid (PFHxA), heptafluorobutyric acid, perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate, and perfluorobutyric acid at noncytotoxic concentrations relevant to human exposure using models based on human embryonic stem cells in both three-dimensional embryoid body (EB) and monolayer differentiation configurations. All six compounds influenced the determination of cell fate by disrupting the expression of associated markers in both models and, in some instances, even led to alterations in the formation of cystic EBs. The expression of cilia-related gene IFT122 was significantly inhibited. Additionally, PFOS and PFOA inhibited ciliogenesis, while PFOA specifically reduced the cilia length. Transcriptome analysis revealed that PFOS altered 1054 genes and disrupted crucial signaling pathways such as WNT and TGF-ß, which play integral roles in cilia transduction and are critical for early embryonic development. These results provide precise and comprehensive insights into the potential adverse health effects of these six PFAS compounds directly concerning early human embryonic development.


Asunto(s)
Fluorocarburos , Células Madre Embrionarias Humanas , Humanos , Células Madre Embrionarias Humanas/efectos de los fármacos , Fluorocarburos/toxicidad , Diferenciación Celular/efectos de los fármacos
5.
Cell Mol Biol (Noisy-le-grand) ; 70(7): 206-211, 2024 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-39097873

RESUMEN

The objective of this study was to investigate the impact of ethyl pyruvate (EP), an HMGB1 inhibitor, on ESCC cells both in vitro and in vivo. The viability of ESCC cells was assessed using the MTT method to evaluate the correlation between EP and cell viability. A scratch test was used to investigate the relationship between EP and cell migration and invasion. The effects of EP on tumor growth and survival in cancerous nude mice were examined using a tumor formation model. Immunohistochemical staining was performed to evaluate the expression levels of HMGB1, TLR4, and MyD88 in tumor tissues. EP, an anti-HMGB1 inhibitor, inhibited ESCC cell proliferation and metastasis in vitro and in vivo. Furthermore, compared with the control treatment, EP improved the activity, diet, and drinking behaviour of nude mice; inhibited tumour growth; and led to lower protein expression levels of HMGB1, TLR4, and MyD88. EP has the potential to regulate the HMGB1/TLR4-MyD88 signaling pathway, thereby inhibiting the proliferation and metastasis of ESCC, suppressing tumor growth, improving quality of life, and serving as an effective drug for ESCC treatment.


Asunto(s)
Carcinoma de Células Escamosas , Proliferación Celular , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteína HMGB1 , Ratones Desnudos , Factor 88 de Diferenciación Mieloide , Piruvatos , Receptor Toll-Like 4 , Animales , Piruvatos/farmacología , Humanos , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Línea Celular Tumoral , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Proliferación Celular/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacos , Ratones , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos BALB C , Supervivencia Celular/efectos de los fármacos , Masculino
6.
Nucleic Acids Res ; 50(18): 10418-10435, 2022 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-36107772

RESUMEN

Interference exists ubiquitously in many biological processes. Crossover interference patterns meiotic crossovers, which are required for faithful chromosome segregation and evolutionary adaption. However, what the interference signal is and how it is generated and regulated is unknown. We show that yeast top2 alleles which cannot bind or cleave DNA accumulate a higher level of negative supercoils and show weaker interference. However, top2 alleles which cannot religate the cleaved DNA or release the religated DNA accumulate less negative supercoils and show stronger interference. Moreover, the level of negative supercoils is negatively correlated with crossover interference strength. Furthermore, negative supercoils preferentially enrich at crossover-associated Zip3 regions before the formation of meiotic DNA double-strand breaks, and regions with more negative supercoils tend to have more Zip3. Additionally, the strength of crossover interference and homeostasis change coordinately in mutants. These findings suggest that the accumulation and relief of negative supercoils pattern meiotic crossovers.


Asunto(s)
ADN Superhelicoidal , Meiosis , Saccharomyces cerevisiae/citología , Segregación Cromosómica , Intercambio Genético , Roturas del ADN de Doble Cadena , ADN-Topoisomerasas de Tipo II , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Ubiquitina-Proteína Ligasas/genética
7.
Artículo en Inglés | MEDLINE | ID: mdl-38836741

RESUMEN

Objective: To investigate the influence of preoperative detrusor muscle activity on the short-term prognosis of elderly patients diagnosed with benign prostatic hyperplasia (BPH) undergoing 1470 nm semiconductor laser surgery. Methods: A retrospective study was conducted on clinical data from 165 elderly BPH patients who underwent 1470 nm semiconductor laser surgery between May 2019 and April 2023. Patients were stratified based on preoperative urodynamic study findings, specifically their bladder contractility index (BCI). Patients with a BCI ≤100 constituted the detrusor underactivity (DU) group (n=64), while those with a BCI >100 formed the non-DU group (n=101). Surgical parameters, including duration, intraoperative blood loss, postoperative hospital stay, bladder irrigation, and catheterization duration, were compared. Additionally, changes in International Prostate Symptom Score (IPSS), Quality of Life (QOL) score, residual urine volume, and peak urinary flow rate (Qmax) were assessed before and three months after surgery in both groups. Results: There were no statistically significant differences observed between the DU and non-DU groups concerning surgical duration, intraoperative blood loss, postoperative hospitalization duration, bladder irrigation duration, and postoperative catheterization duration (P > .05). Similarly, no significant disparities were noted in the IPSS and QOL scores preoperatively and at the three-month follow-up in both groups (P > .05). Both cohorts exhibited no significant differences in residual urine volume before surgery and at the three-month mark postoperatively (P > .05). However, the postoperative Qmax was significantly reduced in the DU group compared to the non-DU group (P < .05). Conclusions: Detrusor muscle activity does not exert a significant impact on clinical symptom improvement and quality of life in elderly BPH patients treated with 1470 nm semiconductor laser surgery. However, patients with DU exhibited inferior postoperative recovery in Qmax, underscoring the importance of preoperative urodynamic studies for early intervention and enhanced surgical outcomes in this patient population.

8.
Aesthetic Plast Surg ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39046484

RESUMEN

OBJECTIVE: The aim of this study was to further guide the diagnosis and treatment programs for clinical facial contouring with injectable fillers by studying the facial contour parameters and proportion preferences consistent with Asian aesthetics. METHODS: A total of 89 subjects (42 males and 47 females aged 20-60 years) who met the inclusion criteria were enrolled in this study. The subjects were grouped by age, sex, and external contour attractiveness score, and the external contour aesthetic parameters and proportions of the subjects in different groups were measured and analysed. RESULTS: The upper facial breadth and lower facial breadth decreased with age, with significant differences between the 50-60-year age group and other age groups (P < 0.01). The nasomental angle showed a decreasing trend with age, with significant differences between the 40-49-year age group and the 20-29-year and 30-39-year age groups (P < 0.05). Males and females were significantly different in calva height, total head height, lower facial height, and calva height to total head height ratio (P < 0.05). With increasing age, the external contour attractiveness scores of males and females both showed decreasing trends, with significant differences between the 50-60-year age group and other age groups (P < 0.05). CONCLUSION: The calva height and the cranioauricular angle have a significant impact on external contour attractiveness. In general, temporal depression, cheek sagging, lateral cheek depression, and an ill-defined mandibular border will occur due to ageing, collagen loss, ligament laxity and sagging, and soft tissue atrophy and sagging, reducing the attractiveness of the external contour. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

9.
Aesthetic Plast Surg ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38995348

RESUMEN

BACKGROUND: In Asia, the demand for cosmetic facial treatments has surged due to technological advancements, increased social acceptability, and affordability. Poly-L-lactic acid (PLLA) fillers, known for their biocompatibility and biodegradability, have emerged as a popular choice for facial contouring, yet studies specifically addressing their use in Asian populations are scarce. METHODS: This retrospective study examined 30 Chinese patients who underwent facial contouring with PLLA fillers, focusing on product composition, injection techniques, and safety measures. A comprehensive clinical evaluation was performed, including the Global Aesthetic Improvement Scale (GAIS) and Global Impression of Change Scale (GICS) for effectiveness and patient satisfaction, respectively. RESULTS: No significant difference in GAIS scores was observed between injectors and blinded evaluators over a 12-month period, indicating consistent effectiveness. Patient satisfaction remained high, with GICS scores reflecting positive outcomes. The safety profile was favorable, with no serious adverse events reported. The study highlighted the importance of anatomical knowledge to avoid complications, particularly in areas prone to blindness. CONCLUSIONS: PLLA fillers offer a safe, effective option for facial contour correction in the Asian population, achieving high patient satisfaction and maintaining results over time. The study underscores the need for tailored approaches in cosmetic procedures for Asians, considering their unique facial structures and aesthetic goals. Further research with larger, multicenter cohorts is recommended to validate these findings and explore long-term effects. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

10.
Mol Carcinog ; 62(6): 786-802, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36929853

RESUMEN

Dynamin 1 Like (DNM1L), a member of dynamin superfamily capable of mediating mitochondrial outer membrane division, plays a key role in the progression of different types of tumors. However, the prognostic value, clinical significance of DNM1L and its specific mechanism involved in tumorigenesis of hepatocellular carcinoma (HCC) have not been investigated clearly. In this study, we found that the expression of DNM1L were significantly higher in HCC tissues than adjacent/normal liver tissues based on multiple data sets obtained from TCGA, GEO and ONCOMINE database, also its protein expression form Drp1 is significantly higher in HCC tissues than adjacent tissues, and is related to the degree of differentiation. Kaplan-Meier curves suggested that high DNM1L expression prominently correlated with poorer overall survival, progression-free survival, relapse-free survival and disease-specific survival. Multivariate analysis showed that higher DNM1L expression was independent prognostic factors of shorter overall survival and disease-free survival. Kyoto Encyclopedia of Genes and Genomes and Gene set enrichment analysis analysis combined with validation experiments revealed the regulatory role of DNM1L on key molecules in the metabolism of xenobiotics by cytochrome p450 pathway, and DNM1L may also affects invasion and metastasis capability of HCC by mediating extracellular matrix -receptor interaction pathway. Moreover, analysis showed that higher DNM1L, CYP2C9, CYP3A4, CYP1A2 expression were associated with the resistance to sorafenib therapy. TIMER and CIBERSORT analysis indicated that the increase of DNM1L expression may affect the infiltration of immune cells in the tumor microenvironment. Taken together, the above results indicated that DNM1L could be able to serve as a promising independent predictor and therapeutic target for HCC patients.


Asunto(s)
Carcinoma Hepatocelular , Dinaminas , Neoplasias Hepáticas , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/genética , Pronóstico , Microambiente Tumoral , Dinaminas/genética
11.
Nucleic Acids Res ; 49(16): 9353-9373, 2021 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-34417612

RESUMEN

Meiotic recombination is integrated into and regulated by meiotic chromosomes, which is organized as loop/axis architecture. However, the regulation of chromosome organization is poorly understood. Here, we show Esa1, the NuA4 complex catalytic subunit, is constitutively expressed and localizes on chromatin loops during meiosis. Esa1 plays multiple roles including homolog synapsis, sporulation efficiency, spore viability, and chromosome segregation in meiosis. Detailed analyses show the meiosis-specific depletion of Esa1 results in decreased chromosome axis length independent of another axis length regulator Pds5, which further leads to a decreased number of Mer2 foci, and consequently a decreased number of DNA double-strand breaks, recombination intermediates, and crossover frequency. However, Esa1 depletion does not impair the occurrence of the obligatory crossover required for faithful chromosome segregation, or the strength of crossover interference. Further investigations demonstrate Esa1 regulates chromosome axis length via acetylating the N-terminal tail of histone H4 but not altering transcription program. Therefore, we firstly show a non-chromosome axis component, Esa1, acetylates histone H4 on chromatin loops to regulate chromosome axis length and consequently recombination frequency but does not affect the basic meiotic recombination process. Additionally, Esa1 depletion downregulates middle induced meiotic genes, which probably causing defects in sporulation and chromosome segregation.


Asunto(s)
Proteínas de Ciclo Celular/genética , Histona Acetiltransferasas/genética , Histonas/genética , Meiosis/genética , Proteínas de Saccharomyces cerevisiae/genética , Acetilación , Animales , Caenorhabditis elegans/genética , Cromatina/genética , Emparejamiento Cromosómico/genética , Segregación Cromosómica/genética , Intercambio Genético/genética , Roturas del ADN de Doble Cadena , Recombinación Homóloga/genética , Saccharomyces cerevisiae/genética , Esporas Fúngicas/genética , Esporas Fúngicas/crecimiento & desarrollo , Complejo Sinaptonémico/genética
12.
Ophthalmic Physiol Opt ; 43(6): 1462-1468, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37574762

RESUMEN

PURPOSE: In order to improve the efficiency of orthokeratology (OK) lens fitting and predict the axial length after 1 year of OK lens wear, machine learning models were proposed. METHODS: Clinical data from 1302 myopic subjects were collected retrospectively, and two machine learning models were implemented. Demographic and corneal topographic data were collected as input variables. The output variables were the parameters of the OK lens and the axial length after 1 year. Eighty percent of input variables was used as the training set and the remaining 20% was used as the validation set. The first alignment curve (AC1) of the OK lenses, deduced using machine learning models and formula calculation, were compared. Multiple regression models (support vector machine, Gaussian process, decision tree and random forest) were used to predict the axial length after 1 year. In addition, we classified data based on lens brand, and carried out more detailed parameter fitting and analysis for spherical and toric OK lenses. RESULTS: The OK lens fitting model showed higher (R2 = 0.93) and lower errors (mean absolute error [MAE] = 0.19, mean square error [MSE] = 0.09) when predicting AC1, compared with the formula calculation (R2 = 0.66, MAE = 0.44, MSE = 0.25). The machine learning model still had high R2 values ranging from 0.91 to 0.96 when considering the brand and design of the OK lenses. Further, the R2 value for the axial length prediction model was 0.94, which indicated that the machine learning model had high accuracy and good robustness. CONCLUSION: The OK lens fitting model and the axial length prediction model played an important role in guiding OK lens fitting, with high accuracy and robustness in prediction performance.

13.
Postgrad Med J ; 99(1173): 708-714, 2023 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-37117041

RESUMEN

PURPOSE: The present study aimed to assess the association of elevated serum uric acid (SUA) and hypouricemia with all-cause mortality and cardiovascular mortality in Chinese hypertensive patients. METHODS: In the present prospective cohort, 9325 hypertensive patients from Dongguan, China were enrolled from 2014 to 2018 for analysis. Participants were categorised by quintiles of SUA. The HRs and 95% CIs for the association between SUA, all-cause and cardiovascular mortality were evaluated using the multivariate Cox regression model. After adjusting for multiple confounders, restricted cubic spline analysis was conducted to demonstrate the shape of relationship. RESULTS: After a median follow-up of 4.18 years for 9325 participants, there were 409 (4.4%) and 151 (1.6%) reported cases of all-cause and cardiovascular mortality, respectively. By using the third quintile of SUA (6.68 mg/dL to <7.55 mg/dL for men, 5.63 mg/dL to <6.42 mg/dL for women) as reference, the highest quintiles of SUA were associated with an elevated risk of all cause (HR: 1.34, 95% CI 1.00 to 1.80) in the crude model, but the association was not significant after adjusting for multiple comparisons. The association between low SUA and mortality and the dose-response analysis on the non-linearity of SUA-mortality relationship were not statistically significant. CONCLUSIONS: Although the association between SUA levels, all-cause and cardiovascular disease mortality did not appear to be significant among Chinese hypertensive patients, the findings might be confounded by their medical conditions. Further studies are needed to verify the optimal SUA levels for hypertensive patients.


Asunto(s)
Enfermedades Cardiovasculares , Hipertensión , Masculino , Humanos , Femenino , Estudios de Cohortes , Ácido Úrico , Estudios Prospectivos , Factores de Riesgo , Hipertensión/epidemiología , China/epidemiología
14.
Acta Biochim Biophys Sin (Shanghai) ; 55(5): 736-748, 2023 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-37171184

RESUMEN

Nine polyglutamine (polyQ) proteins have already been identified that are considered to be associated with the pathologies of neurodegenerative disorders called polyQ diseases, but whether these polyQ proteins mutually interact and synergize in proteinopathies remains to be elucidated. In this study, 4 polyQ-containing proteins, androgen receptor (AR), ataxin-7 (Atx7), huntingtin (Htt) and ataxin-3 (Atx3), are used as model molecules to investigate their heterologous coaggregation and consequent impact on cellular proteostasis. Our data indicate that the N-terminal fragment of polyQ-expanded (PQE) Atx7 or Htt can coaggregate with and sequester AR and Atx3 into insoluble aggregates or inclusions through their respective polyQ tracts. In vitro coprecipitation and NMR titration experiments suggest that this specific coaggregation depends on polyQ lengths and is probably mediated by polyQ-tract interactions. Luciferase reporter assay shows that these coaggregation and sequestration effects can deplete the cellular availability of AR and consequently impair its transactivation function. This study provides valid evidence supporting the viewpoint that coaggregation of polyQ proteins is mediated by polyQ-tract interactions and benefits our understanding of the molecular mechanism underlying the accumulation of different polyQ proteins in inclusions and their copathological causes of polyQ diseases.


Asunto(s)
Enfermedades Neurodegenerativas , Proteostasis , Humanos , Péptidos/química , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Ataxina-3/genética , Ataxina-3/metabolismo
15.
Chem Biodivers ; 20(8): e202300841, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37462846

RESUMEN

Three undescribed glycoside constituents, macrophyllosides E-G and a pair of iridoid glycosides genticrasides A/B, together with eleven known glycoside compounds were isolated from the roots of Gentiana crassicaulis Duthie ex Burk. Their structures were identified by means of spectra analysis and data comparison with previous literatures. Interestingly, the glucose moieties in macrophylloside E and F possess free anomeric hydroxy groups. Genticrasides A/B, identified as a pair of iridoid originated lactones, have not been reported from Gentianaceae family up to now. The anti-inflammatory effects of selected compounds were also evaluated through the nitric oxide (NO) production inhibition in lipopolysaccharides (LPS)-induced RAW264.7 macrophage cells. In which, macrophyllosides G and D showed NO inhibitory activities with rates of 76.14±4.02 % and 52.44±8.29 % at 100 µg/mL.


Asunto(s)
Gentiana , Gentiana/química , Raíces de Plantas/química , Glicósidos Iridoides/farmacología , Iridoides/análisis , Macrófagos , Óxido Nítrico
16.
Int J Mol Sci ; 24(12)2023 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-37373438

RESUMEN

Fibroblast growth factors (FGFs) have been widely studied by virtue of their ability to regulate many essential cellular activities, including proliferation, survival, migration, differentiation and metabolism. Recently, these molecules have emerged as the key components in forming the intricate connections within the nervous system. FGF and FGF receptor (FGFR) signaling pathways play important roles in axon guidance as axons navigate toward their synaptic targets. This review offers a current account of axonal navigation functions performed by FGFs, which operate as chemoattractants and/or chemorepellents in different circumstances. Meanwhile, detailed mechanisms behind the axon guidance process are elaborated, which are related to intracellular signaling integration and cytoskeleton dynamics.


Asunto(s)
Factores de Crecimiento de Fibroblastos , Receptores de Factores de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Orientación del Axón , Transducción de Señal/fisiología , Axones/metabolismo
17.
Cutan Ocul Toxicol ; 42(4): 264-272, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37602871

RESUMEN

OBJECTIVE: To explore the retinal toxicity of pharmaceuticals and personal care products (PPCPs), flame retardants, bisphenols, phthalates, and polycyclic aromatic hydrocarbons (PAHs) on human retinal progenitor cells (RPCs) and retinal pigment epithelial (RPE) cells, which are the primary cell types at the early stages of retinal development, vital for subsequent functional cell type differentiation, and closely related to retinal diseases. MATERIALS AND METHODS: After 23 days of differentiation, human embryonic stem cell (hESC)-based retinal pre-organoids, containing RPCs and RPE cells, were exposed to 10, 100, and 1000 nM pesticides (butachlor, terbutryn, imidacloprid, deltamethrin, pendimethalin, and carbaryl), flame retardants (PFOS, TBBPA, DBDPE, and TDCIPP), PPCPs (climbazole and BHT), and other typical pollutants (phenanthrene, DCHP, and BPA) for seven days. Then, mRNA expression changes were monitored and compared. RESULTS: (1) The selected pollutants did not show strong effects at environmental and human-relevant concentrations, although the effects of flame retardants were more potent than those of other categories of chemicals. Surprisingly, some pollutants with distinct structures showed similar adverse effects. (2) Exposure to pollutants induced different degrees of cell detachment, probably due to alterations in extracellular matrix and/or cell adhesion. CONCLUSIONS: In this study, we established a retinal pre-organoid model suitable for evaluating multiple pollutants' effects, and pointed out the potential retinal toxicity of flame retardants, among other pollutants. Nevertheless, the potential mechanisms of toxicity and the effects on cell detachment are still unclear and deserve further exploration. Additionally, this model holds promise for screening interventions aimed at mitigating the detrimental effects of these pollutants.


Asunto(s)
Contaminantes Ambientales , Retardadores de Llama , Células Madre Embrionarias Humanas , Humanos , Células Madre Embrionarias Humanas/metabolismo , Contaminantes Ambientales/toxicidad , Retardadores de Llama/farmacología , Retardadores de Llama/toxicidad , Retina/metabolismo , Organoides , Diferenciación Celular
18.
J Environ Sci (China) ; 127: 753-766, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36522103

RESUMEN

Beijing faces the challenge of high levels of ozone (O3) pollution. In this study, the Weather Research and Forecasting model and Community Multiscale Air Quality model (CMAQ) were used to simulate atmospheric O3 concentrations in Beijing. To investigate the formation mechanisms and source contributions of O3 pollution in different regions of Beijing, process analysis and the integrated source apportionment method within the CMAQ were applied to O3 concentrations in the summer of 2018. The process analysis results showed that vertical diffusion was the major contributor to O3 concentrations at all receptor sites in Beijing, at > 65.94 µg/(m3·hr). Gas-phase chemical reactions consumed a significant amount of O3 in urban and inner suburban areas (> -5.57 µg/(m3·hr)), while near-surface chemical reactions made positive contributions in outer suburban areas (> 4.72 µg/(m3·hr)). The O3 formation chemical reactions indicated that NO titration, which removes O3 at night-time, mainly occurred in urban areas. The weaker chemical reactions occurring near the surface in outer suburbs suggested that suburban-area O3 was produced in the upper atmospheric layers and was transported vertically to the lower layers. The O3 source apportionment results showed that boundary contributions were the dominant contributor to O3 pollution in Beijing (> 40%). The contribution of non-local emissions to O3 levels was significantly greater in the outer suburbs than in urban and inner suburban areas due to topography. This study increases the understanding of the complex processes of O3 formation in different areas of Beijing and informs the implementation of O3 control plans.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Ozono , Ozono/análisis , Contaminantes Atmosféricos/análisis , Beijing , Monitoreo del Ambiente/métodos , Contaminación del Aire/análisis , China
19.
Zhonghua Nan Ke Xue ; 29(2): 131-137, 2023 Feb.
Artículo en Zh | MEDLINE | ID: mdl-37847084

RESUMEN

OBJECTIVE: To evaluate the effect of transurethral plasmakinetic enucleation of the prostate (PKEP) with complete preservation of the urethral mucosa in the 11-1 o'clock position on urinary continence and erectile function in BPH patients. METHODS: We retrospectively analyzed the clinical data on 84 cases of BPH treated by traditional PKEP (group A, n = 48) or modified PKEP with complete preservation of the urethral mucosa in the 11-1 o'clock position (group B, n = 36) from January 2017 to December 2021. All the patients had sexual activities within three months preoperatively. We followed up the patients for 12 months after surgery and compared the baseline, surgery-related and follow-up data between the two groups of patients. RESULTS: There were no statistically significant differences between the two groups of patients in age, disease duration, prostate volume, preoperative postvoid residual urine (PVR), preoperative maximum urinary flow rate (Qmax), IPSS, PSA level, QOL scores or IIEF-5 scores, nor in the operation time, intraoperative hemoglobin decrease, volume of resected tissue, bladder flushing time, postoperative hospital stay, or postoperative improvement of Qmax and IPSS. The rate of urinary continence was significantly higher in group B than in A at 1 month postoperatively (66.67% ï¼»24/36ï¼½ vs 43.25% ï¼»20/48ï¼½, P = 0.025) and so were IIEF-5 scores at 6 months (16.69 ± 3.21 vs 15.27 ± 2.74, P = 0.032) and 12 months (18.04 ± 2.04 vs 16.96 ± 2.54, P = 0.039), while the incidence rate of retrograde ejaculation markedly lower in the former than in the latter group at 6 months (33.33% ï¼»12/36ï¼½ vs 56.25% ï¼»28/48ï¼½, P = 0.018) and 12 months (25% ï¼»9/36ï¼½ vs 47.92% ï¼»23/48ï¼½, P = 0.027). At 1, 3, 6 and 12 months after surgery, the patients in group B also showed remarkably higher QOL scores than those in group B (2.61 ± 0.81 vs 2.12 ± 0.69, P = 0.005; 2.24 ± 0.66 vs 1.94 ± 0.51,P = 0.026; 2.12 ± 0.83 vs 1.80 ± 0.53,P = 0.047; and 1.94 ± 0.65 vs 1.72 ± 0.58, P = 0.038). CONCLUSION: Modified PKEP with complete preservation of the urethral mucosa in the 11-1 o'clock position can improve urinary continence, protect erectile function and ameliorate QOL in patients with BPH.


Asunto(s)
Disfunción Eréctil , Hiperplasia Prostática , Resección Transuretral de la Próstata , Masculino , Humanos , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/cirugía , Disfunción Eréctil/cirugía , Calidad de Vida , Estudios Retrospectivos , Membrana Mucosa , Resultado del Tratamiento
20.
Zhongguo Yi Liao Qi Xie Za Zhi ; 47(5): 582-586, 2023 Sep 30.
Artículo en Zh | MEDLINE | ID: mdl-37753902

RESUMEN

In recent years, with the rapid development of Chinese domestic surgical robot technology and the expansion of the application market, the "industry-university-research-medicine" collaborative innovation transformation mode has gradually developed and formed. Medical institutions play an important role in multi-party cooperation with enterprises, universities, and research institutes, as well as in product planning, technology research and development, achievement transformation, and personnel training. On the basis of reviewing the current situation of the development of the "industry-university-research-medicine" collaborative innovation transformation mode of domestic surgical robots, this study explores the multiple roles played by medical institutions in this mode and challenges, further putting forward corresponding recommendations.


Asunto(s)
Medicina , Robótica , Humanos , Universidades , Industrias , Tecnología
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