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Phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) is involved in many biological functions. However, the mechanisms of PIP2 in collective cell migration remain elusive. This study highlights the regulatory role of cytidine triphosphate synthase (CTPsyn) in collective border cell migration through regulating the asymmetrical distribution of PIP2. We demonstrated that border cell clusters containing mutant CTPsyn cells suppressed migration. CTPsyn was co-enriched with Actin at the leading edge of the Drosophila border cell cluster where PIP2 was enriched, and this enrichment depended on the CTPsyn activity. Genetic interactions of border cell migration were found between CTPsyn mutant and genes in PI biosynthesis. The CTPsyn reduction resulted in loss of the asymmetric activity of endocytosis recycling. Also, genetic interactions were revealed between components of the exocyst complex and CTPsyn mutant, indicating that CTPsyn activity regulates the PIP2-related asymmetrical exocytosis activity. Furthermore, CTPsyn activity is essential for RTK-polarized distribution in the border cell cluster. We propose a model in which CTPsyn activity is required for the asymmetrical generation of PIP2 to enrich RTK signaling through endocytic recycling in collective cell migration.
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Proteínas de Drosophila , Drosophila , Animales , Ligasas de Carbono-Nitrógeno , Movimiento Celular/genética , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismoRESUMEN
AIMS: Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo. METHODS: Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo. RESULTS: Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. CONCLUSIONS: These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.
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Subfamilia B de Transportador de Casetes de Unión a ATP , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Lansoprazol , Lisosomas , Ratones Desnudos , Inhibidores de la Bomba de Protones , Ensayos Antitumor por Modelo de Xenoinjerto , Lansoprazol/farmacología , Animales , Humanos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones , Inhibidores de la Bomba de Protones/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Simulación del Acoplamiento Molecular , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Proteínas de NeoplasiasRESUMEN
Arthropods maintain ecosystem balance while also contributing to the spread of disease. Plant-derived natural repellents represent an ecological method of pest control, but their direct molecular targets in arthropods remain to be further elucidated. Occupying a critical phylogenetic niche in arthropod evolution, scorpions retain an ancestral genetic profile. Here, using a behavior-guided screening of the Mesobuthus martensii genome, we identified a scorpion transient receptor potential (sTRP1) channel that senses Cymbopogon-derived natural repellents, while remaining insensitive to the synthetic chemical pesticide DEET. Scrutinizing orthologs of sTRP1 in Drosophila melanogaster, we further demonstrated dTRPγ ion channel as a chemosensory receptor of natural repellents to mediate avoidance behavior. This study sheds light on arthropod molecular targets of natural repellents, exemplifying the arthropodplant adaptation. It should also help the rational design of insect control strategy and in conserving biodiversity.
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Artrópodos , Repelentes de Insectos , Venenos de Escorpión , Animales , Artrópodos/genética , Drosophila melanogaster/genética , Biblioteca de Genes , Repelentes de Insectos/farmacología , Venenos de Escorpión/química , EscorpionesRESUMEN
Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue.
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BACKGROUND: Neoadjuvant chemo-immunotherapy combination has shown remarkable advances in the management of esophageal squamous cell carcinoma (ESCC). However, the identification of a reliable biomarker for predicting the response to this chemo-immunotherapy regimen remains elusive. While computed tomography (CT) is widely utilized for response evaluation, its inherent limitations in terms of accuracy are well recognized. Therefore, in this study, we present a novel technique to predict the response of ESCC patients before receiving chemo-immunotherapy by testing volatile organic compounds (VOCs) in exhaled breath. METHODS: This study employed a prospective-specimen-collection, retrospective-blinded-evaluation design. Patients' baseline breath samples were collected and analyzed using high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). Subsequently, patients were categorized as responders or non-responders based on the evaluation of therapeutic response using pathology (for patients who underwent surgery) or CT images (for patients who did not receive surgery). RESULTS: A total of 133 patients were included in this study, with 91 responders who achieved either a complete response (CR) or a partial response (PR), and 42 non-responders who had stable disease (SD) or progressive disease (PD). Among 83 participants who underwent both evaluations with CT and pathology, the paired t-test revealed significant differences between the two methods (p < 0.05). For the breath test prediction model using breath test data from all participants, the validation set demonstrated mean area under the curve (AUC) of 0.86 ± 0.06. For 83 patients with pathological reports, the breath test achieved mean AUC of 0.845 ± 0.123. CONCLUSIONS: Since CT has inherent weakness in hollow organ assessment and no other ideal biomarker has been found, our study provided a noninvasive, feasible, and inexpensive tool that could precisely predict ESCC patients' response to neoadjuvant chemo-immunotherapy combination using breath test based on HPPI-TOFMS.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/terapia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamiento farmacológico , Estudios Retrospectivos , Estudios Prospectivos , Terapia Neoadyuvante , Pruebas Respiratorias/métodos , BiomarcadoresRESUMEN
Organotins have been widely used in various industrial applications. This study investigated the structure-activity relationship as inhibitors of human, pig, and rat gonadal 3ß-hydroxysteroid dehydrogenases (3ß-HSD). Human KGN cell, pig, and rat testis microsomes were utilized to assess the inhibitory effects of 18 organotins on the conversion of pregnenolone to progesterone. Among them, diphenyltin, triethyltin, and triphenyltin exhibited significant inhibitory activity against human 3ß-HSD2 with IC50 values of 114.79, 106.98, and 5.40 µM, respectively. For pig 3ß-HSD, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin demonstrated inhibitory effects with IC50 values of 172.00, 100.19, 87.00, 5.75, and 1.65 µM, respectively. Similarly, for rat 3ß-HSD1, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin displayed inhibitory activity with IC50 values of 81.35, 43.56, 55.55, 4.09, and 0.035 µM, respectively. They were mixed inhibitors of pig and rat 3ß-HSD, while triphenyltin was identified as a competitive inhibitor of human 3ß-HSD2. The mechanism underlying the inhibition of organotins on 3ß-HSD was explored, revealing that they may disrupt the enzyme activity by binding to cysteine residues in the catalytic sites. This proposition was supported by the observation that the addition of dithiothreitol reversed the inhibition caused by all organotins except for triethyltin, which was partially reversed. In conclusion, this study provides valuable insights into the structure-activity relationship of organotins as inhibitors of human, pig, and rat gonadal 3ß-HSD. The mechanistic investigation suggests that these compounds likely exert their inhibitory effects through binding to cysteine residues in the catalytic sites.
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Inhibidores Enzimáticos , Compuestos Orgánicos de Estaño , Testículo , Animales , Humanos , Relación Estructura-Actividad , Compuestos Orgánicos de Estaño/farmacología , Compuestos Orgánicos de Estaño/química , Ratas , Masculino , Testículo/enzimología , Testículo/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Porcinos , 3-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Simulación del Acoplamiento Molecular , Progesterona/farmacología , Progesterona/metabolismo , Microsomas/enzimología , Microsomas/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND PURPOSE: The aim was to investigate the neurological complications associated with coronavirus disease 19 (COVID-19) during the 2022 Omicron wave. METHODS AND ANALYSIS: The medical records of a cohort of people admitted to neurological wards of three participating tertiary centres in Sichuan from 12 December 2022 to 12 January 2023 were reviewed. Demographics and clinical data were obtained and analysed with an interest in COVID-19-related new-onset or worse neurological symptoms. The current data were also compared in two centres with similar data from the same period 12 months earlier. RESULTS: In all, 790 people were enrolled, of whom 436 were positive for COVID-19. Ninety-nine had new onset COVID-related neurological problems, or their known neurological condition deteriorated during the wave. There was a significant difference in demographics from the findings amongst admissions 12 months earlier as there was an increase in the average age, the incidence of encephalitis and encephalopathy, and mortality rates. One hundred and one received COVID-specific antivirals, intravenous glucocorticoids and intravenous immunoglobulin therapy. No differences were seen between these and those who did not use them. CONCLUSION: New-onset neurological conditions, particularly encephalitis and encephalopathy, increased significantly during this period. Deterioration of existing neurological conditions, such as seizure exacerbation, was also observed. A large-scale treatment trial of people with COVID-19 infection presenting with neurological disorders is still needed.
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Encefalopatías , COVID-19 , Encefalitis , Humanos , Estudios de Cohortes , COVID-19/complicaciones , COVID-19/epidemiología , China/epidemiología , ConvulsionesRESUMEN
BACKGROUND: In recent years, triglyceride glucose (TyG) index, as a popular metabolic index, has been proposed as an alternative index of insulin resistance, and it has been proved to be associated with many cardiovascular diseases, but the relationship between it and aortic valve calcification is still unknown. METHODS: A total of 450 aortic valve disease patients were enrolled in this study, including 361 patients with aortic valve calcification (AVC) (calcification group) and 89 patients without (control group). According to the severity of AVC, patients with AVC included severe calcification, moderate calcification and low calcification. The TyG index was calculated based on fasting triglyceride and fasting blood glucose levels. RESULTS: The TyG index in the calcification group was significantly higher than that in the control group (P < .05), and with the increase of the degree of calcification, the TyG index showed an increasing trend. The univariate and multivariate logistic regression analysis showed TyG index has a high predictive value for the presence of AVC (OR (95% CI): 1.743 (1.036-2.933)) and severe AVC (OR (95% CI): 1.608 (1.143-2.262)). In assessing the predictive value of the TyG index distribution width for AVC, with the first quartile as a reference, the last quartile of the TyG index had significant predictive value for the presence of AVC and severe AVC. CONCLUSIONS: TyG index was significantly associated with the presence and severity of AVC, suggesting that TyG index may be a valid predictor of AVC.
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Activated carbon has an excellent porous structure and is considered a promising adsorbent and electrode material. In this study, activated carbon fibers (ACFs) with abundant microporous structures, derived from natural cotton fibers, were successfully synthesized at a certain temperature in an Ar atmosphere and then activated with KOH. The obtained ACFs were characterized by field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), elemental analysis, nitrogen and carbon dioxide adsorption-desorption analysis, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and N2 adsorption-desorption measurement. The obtained ACFs showed high porous qualities and had a surface area from 673 to 1597 m2/g and a pore volume from 0.33 to 0.79 cm3/g. The CO2 capture capacities of prepared ACFs were measured and the maximum capture capacity for CO2 up to 6.9 mmol/g or 4.6 mmol/g could be achieved at 0 °C or 25 °C and 1 standard atmospheric pressure (1 atm). Furthermore, the electrochemical capacitive properties of as-prepared ACFs in KOH aqueous electrolyte were also studied. It is important to note that the pore volume of the pores below 0.90 nm plays key roles to determine both the CO2 capture ability and the electrochemical capacitance. This study provides guidance for designing porous carbon materials with high CO2 capture capacity or excellent capacitance performance.
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Beyond lithium-ion technologies, lithium-sulfur batteries stand out because of their multielectron redox reactions and high theoretical specific energy (2500 Wh kg-1). However, the intrinsic irreversible transformation of soluble lithium polysulfides to solid short-chain sulfur species (Li2S2 and Li2S) and the associated large volume change of electrode materials significantly impair the long-term stability of the battery. Here we present a liquid sulfur electrode consisting of lithium thiophosphate complexes dissolved in organic solvents that enable the bonding and storage of discharge reaction products without precipitation. Insights garnered from coupled spectroscopic and density functional theory studies guide the complex molecular design, complexation mechanism, and associated electrochemical reaction mechanism. With the novel complexes as cathode materials, high specific capacity (1425 mAh g-1 at 0.2 C) and excellent cycling stability (80% retention after 400 cycles at 0.5 C) are achieved at room temperature. Moreover, the highly reversible all-liquid electrochemical conversion enables excellent low-temperature battery operability (>400 mAh g-1 at -40 °C and >200 mAh g-1 at -60 °C). This work opens new avenues to design and tailor the sulfur electrode for enhanced electrochemical performance across a wide operating temperature range.
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The impact of host condition on prognosis of non-small cell lung cancer (NSCLC) and the interaction between host and NSCLC remain unclear. This study investigated the association between systemic inflammation and prognosis and characteristics of radically resected NSCLC. This study consisted of a cohort study and an exploratory study of institutional prospective databases. All participants underwent video-assisted thoracoscopic lobectomy as the primary treatment. Systemic inflammation was assessed before surgery using the advanced lung cancer inflammation index and the systemic inflammation response index. Next-generation sequencing and multiplex immunofluorescence analysis were conducted to delineate tumor characteristics. In the cohort study including 1507 participants, high inflammation was associated with poor disease-free survival and overall survival before and after propensity score matching and in multivariable analysis. Systemic inflammation showed good prognostic value for stage IA-IB NSCLC, and the prognostic value diminished with upstaging of NSCLC. In the exploratory study including 217 adenocarcinomas, tumor microenvironment of high inflammation group showed a greater abundance of PDL1+ tumor cells and immune cells, which were independent from driver gene mutations and clinicopathological characteristics. Spatial analysis demonstrated a higher frequency of immune-suppressed cellular neighborhood, increased avoidance between immune cells and PDL1- tumor cells and compromised immune killing and presentation in tumor microenvironment of high inflammation group. Systemic inflammation showed limited association with genomic mutations. Systemic inflammation may influence the prognosis of NSCLC at both the systematic level and the local immune response. The correlation between high inflammation and immunosuppressive microenvironment indicates a novel thread for anticancer treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Estudios de Cohortes , Pronóstico , Inflamación , Estudios Retrospectivos , Microambiente TumoralRESUMEN
RESEARCH QUESTION: Does follicular stimulation using human menopausal gonadotrophin (HMG) after pituitary down-regulation by a GnRH agonist improve endometrial thickness (EMT) and clinical outcomes of frozen-thawed embryo transfer (FET; using vitrified-warmed embryos) in women with thin endometrium after intensified oestrogen administration (IOA)? DESIGN: This was a retrospective study. A total of 627 patients attempted 683 FET cycles with at least one previous history of thin endometrium. None of the cycles reached over 7 mm EMT after using oral and vaginal oestradiol for more than 21 days (IOA protocol). A total of 129 cycles proceeded with FET, 305 cycles were cancelled, and 249 cycles involved administration of HMG following GnRH agonist pituitary down-regulation (GnRH agonistâ¯+â¯HMG protocol) for further endometrial preparation. RESULTS: EMT became significantly greater (7.18 ± 1.14 mm versus 6.13 ± 0.63 mm, P < 0.001) using GnRH agonistâ¯+â¯HMG compared with previous IOA cycles, but this was not related to serum oestrogen concentrations. A total of 213 cycles after the GnRH agonistâ¯+â¯HMG protocol proceeded with FET, showing a significantly increased clinical pregnancy rate, implantation rate and live birth rate compared with those after IOA. CONCLUSIONS: The GnRH agonistâ¯+â¯HMG protocol for endometrial preparation in FET cycles improves EMT in women with a thin endometrium after IOA and showed significantly better clinical outcomes than IOA. The authors suggest that the GnRH agonistâ¯+â¯HMG protocol should be used for EMT that is less than 7 mm after there has been no optimal response to IOA.
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Criopreservación , Transferencia de Embrión , Embarazo , Humanos , Femenino , Estudios Retrospectivos , Transferencia de Embrión/métodos , Índice de Embarazo , Estrógenos , Menotropinas , Hormona Liberadora de Gonadotropina , Endometrio/fisiología , Inducción de la Ovulación/métodosRESUMEN
Non-alcoholic fatty liver disease is associated with ageing, and impaired mitochondrial homeostasis is the main cause for hepatic ageing. Caloric restriction (CR) is a promising therapeutic approach for fatty liver. The purpose of the present study was to investigate the possibility of early-onset CR in decelerating the progression of ageing-related steatohepatitis. The putative mechanism associated with mitochondria was further determined. C57BL/6 male mice at 8 weeks of age were randomly assigned to one of three treatments: Young-AL (AL, ad libitum), Aged-AL, or Aged-CR (60% intake of AL). Mice were sacrificed when they were 7 months old (Young) or 20 months old (Aged). Aged-AL mice displayed the greatest body weight, liver weight, and liver relative weight among treatments. Steatosis, lipid peroxidation, inflammation, and fibrosis coexisted in the aged liver. Mega mitochondria with short, randomly organized crista were noticed in the aged liver. The CR ameliorated these unfavourable outcomes. The level of hepatic ATP decreased with ageing, but this was reversed by CR. Ageing caused a decrease in mitochondrial-related protein expressions of respiratory chain complexes (NDUFB8 and SDHB) and fission (DRP1), but an increase in proteins related to mitochondrial biogenesis (TFAM), and fusion (MFN2). CR reversed the expression of these proteins in the aged liver. Both Aged-CR and Young-AL revealed a comparable pattern of protein expression. To summarize, this study demonstrated the potential of early-onset CR in preventing ageing-associated steatohepatitis, and maintaining mitochondrial functions may contribute to CR's protection during hepatic ageing.
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Restricción Calórica , Hígado Graso , Ratones , Masculino , Animales , Ratones Endogámicos C57BL , Mitocondrias , Hígado Graso/prevención & control , Envejecimiento/metabolismo , HomeostasisRESUMEN
BACKGROUND: Red blood cell (RBC) indices such as RBC count and RBC distribution width (RDW) are associated with heart failure and coronary artery disease, but the relationship between RBC indices and coronary artery calcification (CAC) is unclear. This study aimed to investigate RBC indices' correlation with, and predictive value for, the presence and severity of CAC. METHODS: In this study, 1257 hospitalized patients who received a coronary computed tomography angiography examination were finally selected. Patients were classified into a control group (without CAC, n = 655) and a calcification group (with CAC, n = 602) according to their CAC score. The calcification group was further divided into a low calcification group, medium calcification group, and high calcification group. RESULTS: In the calcification group, the RBC count was lower, and the RDW-standard deviation (SD) and RDW-coefficient of variation (CV) were higher, than those in the control group (P < .05). In the high calcification group, the RBC count was significantly lower, and the RDW-SD and RDW-CV were significantly higher, than those in the low calcification group (P < .05). Multivariate logistic regression analysis showed that RBC count, RDW-SD, and RDW-CV were independent predictors of CAC presence. Furthermore, multivariate logistic regression analysis also showed that RBC count and RDW-SD were independent predictors of severe CAC. CONCLUSIONS: RBC indices were significantly associated with the presence and severity of CAC, indicating that these RBC indices have the potential to be predictors of CAC.
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Calcinosis , Enfermedad de la Arteria Coronaria , Humanos , Índices de Eritrocitos , Calcinosis/diagnóstico por imagen , Eritrocitos , Factores de RiesgoRESUMEN
This study aimed to screen factors related to live birth outcomes of women with first frozen embryo transfer (FET). The enrolled women were divided into training and validation cohorts. The least absolute shrinkage and selection operator (Lasso) regression algorithm of machine learning and the multiple regression model were then used to screen factors relevant to live birth failure (LBF) for the training dataset. A nomogram risk prediction model was established on the basis of the screened factors, and the consistency index (C-index) and calibration curve were derived for evaluating the model. The validation cohort was utilized to validate the nomogram model further. In total, 2083 women who accepted the first FET in our hospital were included and 44 factors were initially screened in this study. On the basis of the training cohort, the screened risk factors via multiple regression analysis with odds ratio (OR) values were female age (OR: 3.092, 95%CI: 1.065-4.852), body mass index (BMI; OR: 1.106, 95%CI: 1.015-1.546), caesarean section (OR: 1.909, 95%CI: 1.318-2.814), number of high-quality embryos (OR: 0.698, 95%CI: 0.599-0.812), and endometrial thickness (OR: 0.957, CI: 0.904-0.980). The nomogram model was generated based on five predictors. Furthermore, favourable results with C-indexes and calibration curves close to ideal curves indicated the accurate predictive ability of the nomogram. Female age, BMI, caesarean section, number of high-quality embryos, and endometrial thickness were independent predictors for LBF. The five factors of the risk assessment model may help to identify LBF with high accuracy in women who accept FET.
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Cesárea , Nacimiento Vivo , Embarazo , Humanos , Femenino , Masculino , Estudios Retrospectivos , Índice de Embarazo , Transferencia de Embrión/métodosRESUMEN
Sodium (Na) metal batteries are promising as next-generation energy storage systems due to the high specific capacity of the Na metal anode as well as rich natural abundance and low cost of Na resources. Nevertheless, uncontrolled growth of dendritic/mossy Na arising from the unstable solid-electrolyte interphase (SEI) leads to rapid electrode degradation and severe safety issues. In this work, we introduce cetyltrimethylammonium bromide (CTAB) as an electrolyte additive that enables a synergistic effect from both the CTA+ cation and Br- anion in stabilizing the Na metal anode. Notably, cryogenic transmission electron microscopy is utilized to investigate the effect of the additive, revealing the critical morphology and structure of the SEIs and Na electrodes at the nano/atomic scale. Benefiting fromthe additive, a stable Na anode can be realized at an ultrahigh capacity of 30 mAh cm-2 at 10 mA cm-2 over 400 h.
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Kidney ischemia reperfusion injury (IRI) is a common and inevitable pathological condition in routine urological practices, especially during transplantation. Severe kidney IRI may even induce systemic damage to peripheral organs, and lead to multisystem organ failure. However, no standard clinical treatment option is currently available. It has been reported that kidney IRI is predominantly associated with abnormally increased endogenous reactive oxygen species (ROS). Scavenging excessive ROS may reduce the damage caused by oxidative stress and subsequently alleviate kidney IRI. Here, we reported a simple and efficient one-step synthesis of gold-platinum nanoparticles (AuPt NPs) with a gold core having a loose and branched outer platinum shell with superior ROS scavenging capacity to possibly treat kidney IRI. These AuPt NPs exhibited multiple enzyme-like anti-oxidative properties simultaneously possessing catalase- and peroxidase-like activity. These particles showed excellent cell protective capability, and alleviated kidney IRI both in vitro and in vivo without obvious toxicity, by suppressing cell apoptosis, inflammatory cytokine release, and inflammasome formation. Meanwhile, AuPt NPs also had an effect on inhibiting the transition to chronic kidney disease by reducing kidney fibrosis in the long term. Thus, AuPt NPs might be a good therapeutic agent for kidney IRI management and may be helpful for the development of clinical treatments for kidney IRI.
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Enfermedades Renales , Nanopartículas del Metal , Daño por Reperfusión , Humanos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Especies Reactivas de Oxígeno , Catalasa , Platino (Metal)/uso terapéutico , Oro/uso terapéutico , Inflamasomas , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , Riñón/patología , Estrés Oxidativo , Enfermedades Renales/patología , Fibrosis , CitocinasRESUMEN
Under metabolic stress, cellular components can assemble into distinct membraneless organelles for adaptation. One such example is cytidine 5'-triphosphate synthase (CTPS, for which there are CTPS1 and CTPS2 forms in mammals), which forms filamentous structures under glutamine deprivation. We have previously demonstrated that histidine (His)-mediated methylation regulates the formation of CTPS filaments to suppress enzymatic activity and preserve the CTPS protein under glutamine deprivation, which promotes cancer cell growth after stress alleviation. However, it remains unclear where and how these enigmatic structures are assembled. Using CTPS-APEX2-mediated in vivo proximity labeling, we found that synaptosome-associated protein 29 (SNAP29) regulates the spatiotemporal filament assembly of CTPS along the cytokeratin network in a keratin 8 (KRT8)-dependent manner. Knockdown of SNAP29 interfered with assembly and relaxed the filament-induced suppression of CTPS enzymatic activity. Furthermore, APEX2 proximity labeling of keratin 18 (KRT18) revealed a spatiotemporal association of SNAP29 with cytokeratin in response to stress. Super-resolution imaging suggests that during CTPS filament formation, SNAP29 interacts with CTPS along the cytokeratin network. This study links the cytokeratin network to the regulation of metabolism by compartmentalization of metabolic enzymes during nutrient deprivation.
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Ligasas de Carbono-Nitrógeno , Histidina , Animales , Citidina Trifosfato , Histidina/genética , QueratinasRESUMEN
Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake.
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Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Memoria/fisiología , Receptores de Serotonina/metabolismo , Ácido 3-Hidroxibutírico/sangre , Animales , Western Blotting , Corticosterona/sangre , Electrofisiología , Prueba de Tolerancia a la Glucosa , Hipocampo/citología , Hipocampo/metabolismo , Potenciación a Largo Plazo/fisiología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Ratones , Ratones Endogámicos C57BL , Neuronas/citología , Neuronas/metabolismo , ARN Mensajero/metabolismo , Receptores de Serotonina/genética , Serotonina/sangre , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Dendrobium is a genus of plants used as traditional Chinese herbal medicines, with high economic and medicinal value. METHODS AND RESULTS: To reveal the mechanism of flavonoid biosynthesis in Dendrobium, the metabolites and transcriptomes of four Dendrobium species (D. chrysotoxum, D. nobile, D. fimbriatum, and D. denneanum) were analyzed comprehensively. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis revealed ten flavonoid compounds in Dendrobium. In total, 100,096 unigenes were obtained from the transcript database of the four Dendrobium species. Among the identified differentially expressed genes, 51 were associated with flavonoid biosynthesis, and 670 differentially expressed transcription factors were predicted, including 194 MYB, 87 bHLH, and 100 WRKY family transcription factors, respectively. Transcriptome analysis showed that the expression levels of structural genes such as chalcone synthase (CHS), cinnamate-4-hydroxylase (C4H), and flavonoid 3'-hydroxylase (F3'H) were lower in D. chrysotoxum, D. nobile, and D. fimbriatum than those in D. denneanum, which may be the main reason for the low flavonoid contents in D. chrysotoxum, D. nobile, and D. fimbriatum. CONCLUSIONS: The expression level of structural genes corresponded to the accumulation level of flavonols in the different Dendrobium species. The results deepen the understanding of the molecular mechanism of flavonoid biosynthesis in Dendrobium and provide novel insights into the synthesis and accumulation of flavonoids in Dendrobium.