RESUMEN
Pulmonary fibrosis is a formidable challenge in chronic and age-related lung diseases. Myofibroblasts secrete large amounts of extracellular matrix and induce pro-repair responses during normal wound healing. Successful tissue repair results in termination of myofibroblast activity via apoptosis; however, some myofibroblasts exhibit a senescent phenotype and escape apoptosis, causing over-repair that is characterized by pathological fibrotic scarring. Therefore, the removal of senescent myofibroblasts using senolytics is an important method for the treatment of pulmonary fibrosis. Procyanidin C1 (PCC1) has recently been discovered as a senolytic compound with very low toxicity and few side effects. This study aimed to determine whether PCC1 could improve lung fibrosis by promoting apoptosis in senescent myofibroblasts and to investigate the mechanisms involved. The results showed that PCC1 attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. In addition, we found that PCC1 inhibited extracellular matrix deposition and promoted the apoptosis of senescent myofibroblasts by increasing PUMA expression and activating the BAX signaling pathway. Our findings represent a new method of pulmonary fibrosis management and emphasize the potential of PCC1 as a senotherapeutic agent for the treatment of pulmonary fibrosis, providing hope for patients with pulmonary fibrosis worldwide. Our results advance our understanding of age-related diseases and highlight the importance of addressing cellular senescence in treatment.
Asunto(s)
Bleomicina , Catequina , Senescencia Celular , Ratones Endogámicos C57BL , Miofibroblastos , Fibrosis Pulmonar , Animales , Bleomicina/toxicidad , Miofibroblastos/metabolismo , Miofibroblastos/efectos de los fármacos , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Ratones , Senescencia Celular/efectos de los fármacos , Catequina/farmacología , Catequina/análogos & derivados , Proantocianidinas/farmacología , Apoptosis/efectos de los fármacos , Masculino , Biflavonoides/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Idiopathic pulmonary fibrosis is a progressive and age-related disease that results from impaired lung repair following injury. Targeting senescent myofibroblasts with senolytic drugs attenuates pulmonary fibrosis, revealing a detrimental role of these cells in pulmonary fibrosis. The mechanisms underlying the occurrence and persistence of senescent myofibroblasts in fibrotic lung tissue require further clarification. In this study, we demonstrated that senescent myofibroblasts are resistant to apoptosis by upregulating the proapoptotic protein BAX and antiapoptotic protein BCL-2 and BCL-XL, leading to BAX inactivation. We further showed that high levels of inactive BAX-mediated minority mitochondrial outer membrane permeabilization (minority MOMP) promoted DNA damage and myofibroblasts senescence after insult by a sublethal stimulus. Intervention of minority MOMP via the inhibition of caspase activity by quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (QVD-OPH) or BAX knockdown significantly reduced DNA damage and ultimately delayed the progression of senescence. Moreover, the BAX activator BTSA1 selectively promoted the apoptosis of senescent myofibroblasts, as BTSA1-activated BAX converted minority MOMP to complete MOMP while not injuring other cells with low levels of BAX. Furthermore, therapeutic activation of BAX with BTSA1 effectively reduced the number of senescent myofibroblasts in the lung tissue and alleviated both reversible and irreversible pulmonary fibrosis. These findings advance the understanding of apoptosis resistance and cellular senescence mechanisms in senescent myofibroblasts in pulmonary fibrosis and demonstrate a novel senolytic drug for pulmonary fibrosis treatment.
RESUMEN
OBJECTIVES: The prevalence of the co-occurrence of depressive and anxious symptoms (CO) and their influence on perceived overall health were not clear in community dwelling Chinese older adults. The aims of the study were to investigate the prevalence of CO and to explore its influence on self-rated health (SRH). METHOD: This study included 12301 individuals aged ≥65 years from the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a nationally representative survey of older adults in mainland China. Participants received face-to-face interviews and assessments of depressive symptoms and anxious symptoms via 10-item of the Center for Epidemiologic Studies Depression Scale (CES-D-10) and 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), respectively. SRH was measured by self-reported. A logistic regression model was used to examine the association between CO and SRH after adjusting for confounding variables. RESULTS: The average age was 83.4 (SD: 11.0) years and there were 6576 (53.5%) females. The age- and sex-standardized prevalence of depressive symptoms only (DSO) was 38.6%, anxious symptoms only (ASO) was 1.5%, and CO was 10.8%. Compared with those without depressive and anxious symptoms, the older adults with DSO or ASO were more likely to have significant influence on SRH. And particularly, CO was likely to produce the greatest decrement in the level of SRH. CONCLUSION: CO was not rare in Chinese older adults nationwide. The older adults having CO had increased risk for lower level of SRH than having DSO or ASO. More attention should be given to CO among the older adults.
RESUMEN
Rationale: Pulmonary fibrosis is a chronic progressive lung disease with limited therapeutic options. We previously revealed that there is iron deposition in alveolar epithelial type II cell (AECII) in pulmonary fibrosis, which can be prevented by the iron chelator deferoxamine. However, iron in the cytoplasm and the mitochondria has two relatively independent roles and regulatory systems. In this study, we aimed to investigate the role of mitochondrial iron deposition in AECII injury and pulmonary fibrosis, and to find potential therapeutic strategies. Methods: BLM-treated mice, MLE-12 cells, and primary AECII were employed to establish the mouse pulmonary fibrosis model and epithelial cells injury model, respectively. Mitochondrial transplantation, siRNA and plasmid transfection, western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), polymerase chain reaction (PCR), immunofluorescence, immunoprecipitation (IP), MitoSOX staining, JC-1 staining, oxygen consumption rate (OCR) measurement, and Cell Counting Kit-8 (CCK8) assay were utilized to elucidate the role of mitochondrial iron deposition in cell and lung fibrosis and determine its mechanism. Results: This study showed that prominent mitochondrial iron deposition occurs within AECII in bleomycin (BLM)-induced pulmonary fibrosis mouse model and in BLM-treated MLE-12 epithelial cells. Further, the study revealed that healthy mitochondria rescue BLM-damaged AECII mitochondrial iron deposition and cell damage loss. Mitoferrin-2 (MFRN2) is the main transporter that regulates mitochondrial iron metabolism by transferring cytosolic iron into mitochondria, which is upregulated in BLM-treated MLE-12 epithelial cells. Direct overexpression of MFRN2 causes mitochondrial iron deposition and cell damage. In this study, decreased ubiquitination of the ubiquitin ligase F-box/LRR-repeat protein 5 (FBXL5) degraded iron-reactive element-binding protein 2 (IREB2) and promoted MFRN2 expression as well as mitochondrial iron deposition in damaged AECII. Activation of the prostaglandin E2 receptor EP4 subtype (EP4) receptor signaling pathway counteracted mitochondrial iron deposition by downregulating IREB2-MFRN2 signaling through upregulation of FBXL5. This intervention not only reduced mitochondrial iron content but also preserved mitochondrial function and protected against AECII damage after BLM treatment. Conclusion: Our findings highlight the unexplored roles, mechanisms, and regulatory approaches of abnormal mitochondrial iron metabolism of AECII in pulmonary fibrosis. Therefore, this study deepens the understanding of the mechanisms underlying pulmonary fibrosis and offers a promising strategy for developing effective therapeutic interventions using the EP4 receptor activator.
Asunto(s)
Células Epiteliales Alveolares , Bleomicina , Modelos Animales de Enfermedad , Hierro , Mitocondrias , Fibrosis Pulmonar , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/inducido químicamente , Ratones , Hierro/metabolismo , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Ratones Endogámicos C57BL , Línea Celular , MasculinoRESUMEN
Nuclear pore complexes (NPCs) on the nuclear membrane surface have a crucial function in controlling the movement of small molecules and macromolecules between the cell nucleus and cytoplasm through their intricate core channel resembling a spiderweb with several layers. Currently, there are few methods available to accurately measure the dynamics of nuclear pores on the nuclear membranes at the nanoscale. The limitation of traditional optical imaging is due to diffraction, which prevents achieving the required resolution for observing a diverse array of organelles and proteins within cells. Super-resolution techniques have effectively addressed this constraint by enabling the observation of subcellular components on the nanoscale. Nevertheless, it is crucial to acknowledge that these methods often need the use of fixed samples. This also raises the question of how closely a static image represents the real intracellular dynamic system. High-speed atomic force microscopy (HS-AFM) is a unique technique used in the field of dynamic structural biology, enabling the study of individual molecules in motion close to their native states. Establishing a reliable and repeatable technique for imaging mammalian tissue at the nanoscale using HS-AFM remains challenging due to inadequate sample preparation. This study presents the rapid strainer microfiltration (RSM) protocol for directly preparing high-quality nuclei from the mouse brain. Subsequently, we promptly utilize HS-AFM real-time imaging and cinematography approaches to record the spatiotemporal of nuclear pore nano-dynamics from the mouse brain.
Asunto(s)
Proteínas , Imagen Individual de Molécula , Animales , Ratones , Microscopía de Fuerza Atómica/métodos , Proteínas/química , Núcleo Celular , Encéfalo/diagnóstico por imagen , MamíferosRESUMEN
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has a high mortality rate and incidence of complications. The pathophysiology of ALI/ARDS is still not fully understood. The lipopolysaccharide (LPS)-induced mouse model of ALI has been widely used to study human ALI/ARDS. Sulfasalazine (SASP) has antibacterial and anti-inflammatory effects and is used for treating inflammatory bowel and rheumatic diseases. However, the effect of SASP on LPS-induced ALI in mice has not yet been reported. Therefore, we aimed to investigate the effect of SASP on LPS-induced ALI in mice. Mice were intraperitoneally injected with SASP 2 h before or 4 h after LPS modeling. Pulmonary pathological damage was measured based on inflammatory factor expression (malondialdehyde and superoxide dismutase levels) in the lung tissue homogenate and alveolar lavage fluid. The production of inflammatory cytokines and occurrence of oxidative stress in the lungs induced by LPS were significantly mitigated after the prophylactic and long-term therapeutic administration of SASP, which ameliorated ALI caused by LPS. SASP reduced both the production of inflammatory cytokines and occurrence of oxidative stress in RAW264.7 cells, which respond to LPS. Moreover, its mechanism contributed to the suppression of NF-κB and nuclear translocation. In summary, SASP treatment ameliorates LPS-induced ALI by mediating anti-inflammatory and antioxidant effects, which may be attributed to the inhibition of NF-κB activation and promotion of antioxidant defenses. Thus, SASP may be a promising pharmacologic agent for ALI therapy.
Asunto(s)
Lesión Pulmonar Aguda , Síndrome de Dificultad Respiratoria , Ratones , Humanos , Animales , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Sulfasalazina/efectos adversos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Pulmón/patología , Estrés Oxidativo , Antiinflamatorios/farmacología , Citocinas/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patologíaRESUMEN
Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level.
RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by extensive extracellular matrix (ECM) deposition by activated myofibroblasts, which are specialized hyper-contractile cells that promote ECM remodeling and matrix stiffening. New insights on therapeutic strategies aimed at reversing fibrosis by targeting myofibroblast fate are showing promise in promoting fibrosis resolution. Previously, we showed that a novel adipocytokine, omentin-1, attenuated bleomycin (BLM)-induced lung fibrosis by reducing the number of myofibroblasts. Apoptosis, deactivation, and reprogramming of myofibroblasts are important processes in the resolution of fibrosis. Here we report that omentin-1 reverses established lung fibrosis by promoting mechanically activated myofibroblasts dedifferentiation into lipofibroblasts. Omentin-1 promotes myofibroblasts lipogenic differentiation by inhibiting dimerization and nuclear translocation of glycolytic enzymes pyruvate kinase isoform M2 (PKM2) and activation of the downstream Yes-associated protein (YAP) by increasing the cofactor fructose-1,6-bisphosphate (F1, 6BP, FBP). Moreover, omentin-1 activates proliferator-activated receptor gamma (PPARγ) signaling, the master regulator of lipogenesis, and promotes the upregulation of the lipogenic differentiation-related protein perilipin 2 (PLIN2) by suppressing the PKM2-YAP pathway. Ultimately, omentin-1 facilitates myofibroblasts transformation into the lipofibroblast phenotype, with reduced collagen synthesis and enhanced degradation properties, which are crucial mechanisms to clear the ECM deposition in fibrotic tissue, leading to fibrosis resolution. Our results indicate that omentin-1 targets mechanical signal accelerates fibrosis resolution and reverses established lung fibrosis by promoting myofibroblasts lipogenic differentiation, which is closely associated with ECM clearance in fibrotic tissue. These findings suggest that targeting mechanical force to promote myofibroblast lipogenic differentiation is a promising therapeutic strategy against persistent lung fibrosis.
Asunto(s)
Fibrosis Pulmonar Idiopática , PPAR gamma , Humanos , PPAR gamma/genética , Lipogénesis , Fibroblastos , Diferenciación CelularRESUMEN
Ferroptosis, a newly discovered type of regulated cell death, has been implicated in numerous human diseases. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease with poor prognosis and limited treatment options. Emerging evidence has linked ferroptosis and glutamate-determined cell fate which is considered a new light on the etiology of pulmonary fibrosis. Here, we observed that N-methyl d-aspartate receptor (NMDAR) activation promoted cell damage and iron deposition in MLE-12 cells in a dose-, time-, and receptor-dependent manner. This mediated substantial Ca2+ influx, upregulated the expression levels of nNOS and IRP1, and affected intracellular iron homeostasis by regulating the expression of iron transport-related proteins (i.e., TFR1, DMT1, and FPN). Excessive iron load promoted the continuous accumulation of total intracellular and mitochondrial reactive oxygen species, which ultimately led to ferroptosis. NMDAR inhibition reduced lung injury and pulmonary fibrosis in bleomycin-induced mice. Bleomycin stimulation upregulated the expression of NMDAR1, nNOS, and IRP1 in mouse lung tissues, which ultimately led to iron deposition via regulation of the expression of various iron metabolism-related genes. NMDAR activation initiated the pulmonary fibrosis process by inducing iron deposition in lung tissues and ferroptosis of alveolar type II cells. Our data suggest that NMDAR activation regulates the expression of iron metabolism-related genes by promoting calcium influx, increasing nNOS and IRP1 expression, and increasing iron deposition by affecting cellular iron homeostasis, ultimately leading to mitochondrial damage, mitochondrial dysfunction, and ferroptosis. NMDAR activation-induced ferroptosis of alveolar type II cells might be a key event to the initiation of pulmonary fibrosis.
Asunto(s)
Ferroptosis , Fibrosis Pulmonar , Ratones , Humanos , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Ferroptosis/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Pulmón/metabolismo , Bleomicina/efectos adversos , Bleomicina/metabolismo , Hierro/metabolismoRESUMEN
Anti-spike neutralizing antibodies (S NAbs) have been developed for prevention and treatment against COVID-19. The nanoscopic characterization of the dynamic interaction between spike proteins and S NAbs remains difficult. By using high-speed atomic force microscopy (HS-AFM), we elucidate the molecular property of an S NAb and its interaction with spike proteins. The S NAb appeared as monomers with a Y conformation at low density and formed hexameric oligomers at high density. The dynamic S NAb-spike protein interaction at RBD induces neither RBD opening nor S1 subunit shedding. Furthermore, the interaction was stable at endosomal pH. These findings indicated that the S NAb could have a negligible risk of antibody-dependent enhancement. Dynamic movement of spike proteins on small extracellular vesicles (S sEV) resembled that on SARS-CoV-2. The sensitivity of variant S sEVs to S NAb could be evaluated using HS-AFM. Altogether, we demonstrate a nanoscopic assessment platform for evaluating the binding property of S NAbs.
Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Anticuerpos Antivirales , Anticuerpos NeutralizantesRESUMEN
OBJECTIVE: To determine whether adverse childhood experiences (ACEs) of children of alcoholics (COA) in male were associated with their current "risky drinking". METHODS: This case-control study used the Alcohol Use Disorder Identification Test (AUDIT, cutoff is 7) to divide the participants into two groups, a "risky drinking" group (N = 53) and a "non-risky drinking" group (N = 97). Demographic data, Adverse Childhood Experiences-International Questionnaire (ACE-IQ), the Hamilton Anxiety Rating Scale (HAMA), the Hamilton Depression Rating Scale (HAMD) and the Mini-International Neuropsychiatric Interview (MINI) were used for assessment. The specific relationships between ACEs and "risky drinking" were explored. RESULTS: Respondents ranged in age from 29.70 ± 6.72 years; 74.5% were females; 94.7% were of Han nationality; 56.7% had a level of education above high school; 12% had no formal or stable job. There was difference in attitude to self-drinking between two groups (P < 0.001). The "risky drinking" group was more likely to have experienced a major depressive episode (P < 0.05), nonalcohol psychoactive substance use disorder (P < 0.01) and bulimia nervosa (P < 0.05), and they also experienced more physical abuse (P < 0.05), community violence (P < 0.001) and collective violence (P < 0.01). In a single factor logistic regression, physical abuse, community violence and collective violence were associated with a two to 11- fold increase in "risky drinking" in the adult COA, and in multiple factor logistic regression, community violence showed a graded relationship with "risky drinking". CONCLUSION: The childhood adverse experiences contribute to "risky drinking" in COA. This finding in the Chinese context have significant implications for prevention not only in China but in other cultures. There must be greater awareness of the role of ACEs in the perpetuation of alcoholism.
Asunto(s)
Experiencias Adversas de la Infancia , Alcoholismo , Trastorno Depresivo Mayor , Adulto , Niño , Femenino , Humanos , Masculino , Adulto Joven , Alcoholismo/epidemiología , Alcoholismo/psicología , Estudios de Casos y Controles , Violencia , Hijos AdultosRESUMEN
BACKGROUND: Bacteria are readily nourished in airtight environments with high humidity, such as storage cabinets, clothing closets, and corners, where ventilation is normally low and humidity is high. OBJECTIVES: We characterized the role of humidity and ventilation in bacterial growth and genus distribution at different temperatures (26 °C and 34 °C). METHODS: Fresh pork, which was used as the substrate for bacterial culture, was placed in storage cabinets. Bacterial growth and genera distribution on the surface of pork placed in a storage cabinet under different temperatures (26 °C and 34 °C); relative humidity levels (RH: 50%, 70%, 90%); and ventilation conditions (no ventilation and low, medium, and high levels of ventilation) were assessed by rDNA sequencing. RESULTS: Increased ventilation and reduced humidity significantly decreased bacterial growth at 26 °C and 34 °C. The contribution of increased ventilation to the reduction in bacterial growth exceeded that of decreased humidity. Ventilation had the greatest effect on reducing bacterial growth compared to the unventilated conditions at 70% RH. At 34 °C, medium and high levels of ventilation were required to reduce bacterial growth. High temperatures greatly increased bacterial growth, but ventilation could reduce the degree of this increase.
Asunto(s)
Respiración , Ventilación , Humedad , Temperatura , Bacterias/genéticaRESUMEN
Small extracellular vesicles (sEVs) play a crucial role in local and distant cell communication. The intrinsic properties of sEVs make them compatible biomaterials for drug delivery, vaccines, and theranostic nanoparticles. Although sEV proteomics have been robustly studied, a direct instantaneous assessment of sEV structure dynamics remains difficult. Here, we use the high-speed atomic force microscopy (HS-AFM) to evaluate nanotopological changes of sEVs with respect to different physicochemical stresses including thermal stress, pH, and osmotic stress. The sEV structure is severely altered at high-temperature, high-pH, or hypertonic conditions. Surprisingly, the spherical shape of the sEVs is maintained in acidic or hypotonic environments. Real-time observation by HS-AFM imaging reveals an irreversible structural change in the sEVs during transition of pH or osmolarity. HS-AFM imaging provides both qualitative and quantitative data at high spatiotemporal resolution (nanoscopic and millisecond levels). In summary, our study demonstrates the feasibility of HS-AFM for structural characterization and assessment of nanoparticles.
Asunto(s)
Vesículas Extracelulares , Microscopía de Fuerza Atómica/métodosRESUMEN
Aims: The aim of this study was to investigate the personality traits, and P300 component in the offspring of parents with alcohol dependence (OPAD) currently engaged in risky drinking and those not engaged in risky drinking, and to further explore the correlates of problematic alcohol use. Methods: A case-control study was conducted according to the cutoff of the Alcohol Use Disorder Identification Test (AUDIT). The frequency of the TaqIA polymorphism of the dopamine receptor D2 gene associated with alcohol dependence was compared between the two OPAD groups. Tridimensional Personality Questionnaire (TPQ), The Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), and the MINI-International Neuropsychiatric Interview (M.I.N.I.) were measured or interviewed in OPAD not engaged in risky drinking (resilient; n = 35) and those currently engaged in risky drinking (vulnerable; n = 20). P300 was measured to test the possible electrophysiological differences. The correlates of alcohol use were analyzed. Results: Vulnerable OPAD showed higher novelty seeking subscale scores (NS4; 4.45 ± 2.012 vs. 3.31 ± 1.728, P < 0.05) and harm avoidance subscale scores (HA4; 5.3 ± 2.319 vs. 3.66 ± 2.461, P < 0.05) than resilient OPAD, while the total scores of each dimension showed no significant difference. OPAD engaged in risky drinking showed more tobacco use than OPAD resistant to risky drinking. OPAD with risky drinking showed a shorter P300 latency than resilient OPAD on Fz electrodes. AUDIT scores of OPAD were correlated with P300 latency. Conclusions: P300 differed between OPAD with and without risky drinking and alcohol use was associated with P300 latency, indicating that P300 may be used in the early detection of vulnerable OPAD and early intervention in the future.
RESUMEN
Aims: To investigate the prevalence and correlates of risky drinking in Chinese elderly people aged 80 and over. Methods: Data were obtained from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) conducted in 2018. A total of 10,141 respondents aged 80 years or older were included in this analysis. Risky drinking was defined as drinking > 2 drinks per day. The participants were divided into no risky drinking, past risky drinking, and current risky drinking groups. The prevalence of risky drinking, daily dosage, and type of alcohol beverages were assessed. The correlates of risky drinking were analyzed using logistic regression. Results: The prevalence of past and current risky drinking was 6.2 and 4.4%, respectively. A total of 12.2% of males and 2.1% of females reported past risky drinking, and 8.9% of males and 1.4% of females reported current risky drinking. The median of the daily dosage of the past risky drinking group was 4.5 and 4 drinks in males and females, respectively, and were 4 and 3.3, respectively, of the current risky drinking group. Strong liquor was the most popular alcohol beverage in all groups. Men who were older or had white-collar work were less likely to be past risky drinkers, while those with smoking in past or current or heart disease were more likely to be past risky drinkers. Women who smoked in the past were more likely to be past risky drinkers. Men with older age or living in the urban areas or with heart disease were less likely to be current risky drinkers. Women with higher education or with heart disease were less likely to be current risky drinkers. Women with current smoking were more likely to have current risky drinking. Conclusions: Our findings indicated that risky drinking among the oldest-old was not rare in China. The correlates of past and current risky drinking were different. Men and women had various correlates of risky drinking as well. Those with higher socioeconomic status seemed less likely to be risky drinking. More attention should be given to risky drinking among the oldest old, and sex-specific intervention may be needed.
RESUMEN
Aims: To investigate the bidirectional longitudinal association between pain and depressive symptoms and explore whether gender modifies the association. Methods: This study used data of 17,577 participants without depressive symptoms and 15,775 without pain at baseline from waves 1-8 (2002/2003 to 2016/2017) of the English Longitudinal Study of Aging (ELSA) and waves 1 to 3 [2011-2015] of the China Health Retirement Longitudinal Study (CHARLS). Cox regression models were performed at the cohort level to evaluate the potential longitudinal associations, and then random-effect meta-analyses were conducted to pool the results. The potential modifying effect was detected by Z-test. Results: During 103,512 person-years of follow-up in participants without depressive symptoms, baseline pain intensity was associated with incident depressive symptoms. Compared with individuals who reported no pain at baseline, the pooled adjusted hazard ratio (HR) of incident depressive symptoms for participants with mild to moderate pain and for those with severe pain was 1.37 (95% CI: 1.22-1.55, p < 0.001) and 1.52 (95% CI: 1.34-1.73, p < 0.001), respectively. During 81,958 person-years of follow-up in participants without pain, baseline depressive symptoms were associated with a significantly higher incidence of pain, and the pooled adjusted HR of incident pain was 1.71 (95% CI: 1.60-1.82, p < 0.001). These associations were not modified by gender. Conclusions: A bidirectional longitudinal association between pain and depressive symptoms was demonstrated, not modified by gender. Family doctors should be aware of the bidirectional association and advice individuals with pain or depressive symptoms to be screened for both kinds of symptoms.
RESUMEN
Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic "readers" of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family.
Asunto(s)
Proteínas de Ciclo Celular , Neoplasias Colorrectales , Proteínas de Complejo Poro Nuclear , Factores de Transcripción , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Proteínas de Complejo Poro Nuclear/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
AIMS: To investigate the gender differences in neurocognitive functioning in patients with first-episode schizophrenia (FES) in China. METHODS: A total of 449 Chinese patients with FES (210 males, 239 females) were included in this study. Participants' psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). Neurocognitive functioning was assessed by 10 neuropsychological tests from a battery. Neurocognitive test scores were converted to scale scores and t-scores using normative data from Chinese populations. RESULTS: Males were younger and less likely to be married, had an earlier age of illness onset and a longer duration of untreated psychosis (DUP), and scored higher on the PANSS negative, general and total scales than females. After controlling for potential confounders, females performed better than males in the verbal learning and memory domain (p=0.016). While most neurocognitive domains were correlated with PANSS negative scores for male patients with FES, for female patients with FES, negative associations were found between scores on the PANSS general subscales and neurocognitive domains. We also performed a case-control comparison with a group of patients with clinically stable schizophrenia (CSS) (n=60) who were matched by age, sex and education years with patients with FES (n=58). After controlling for potential confounders, no significant differences were found between patients with FES and patients with CSS in all neurocognitive domains. Female patients still performed better in the verbal learning and memory domain (t=2.14, p=0.034). No interaction effects of gender and disease were found. CONCLUSIONS: Gender was an independent influence factor for the verbal learning and memory domain. Both female patients with first-episode schizophrenia and female patients with clinically stable schizophrenia performed better than male patients.