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With the rapid development of the global economy and the continuous consumption of fossil resources, sustainable and biodegradable natural biomass has garnered extensive attention as a promising substitute for synthetic polymers. Due to their hierarchical and nanoscale structures, natural biopolymers exhibit remarkable mechanical properties, along with excellent innate biocompatibility and biodegradability, demonstrating significant potential in various application scenarios. Among these biopolymers, proteins and polysaccharides are the most commonly studied due to their low cost, abundance, and ease of use. However, the direct processing/conversion of proteins and polysaccharides into their final products has been a long-standing challenge due to their natural morphology and compositions. In this review, we emphasize the importance of processing natural biopolymers into high-value-added products through sustainable and cost-effective methods. We begin with the extraction of four types of natural biopolymers: cellulose, chitosan, eggshell membrane, and silk fibroin. The processing and post-functionalization strategies for these natural biopolymers are then highlighted. Alongside their unique structures, the versatile potential applications of these processable natural biopolymers in biomedical engineering, biosensors, environmental engineering, and energy applications are illustrated. Finally, we provide a summary and future outlook on processable natural biopolymers, underscoring the significance of converting natural biopolymers into valuable biomaterial platforms.

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Background: Understanding how disability progresses with ageing is important for shaping policies aimed at improving older adults' quality of life, especially when considering the global trends in ageing, life expectancy (LE), and gender disparity. We aimed to assess the health transition probabilities of daily living activities and their implications on LE and gender gaps in global middle-aged and elderly populations. Methods: In this multi-cohort study with a sample of 74 101 individuals aged ≥50 years, we analysed data from six international cohorts: the China Health and Retirement Longitudinal Study (CHARLS), the English Longitudinal Study of Ageing (ELSA), the Health and Retirement Study (HRS) in the USA, the Mexican Longitudinal Study of Ageing (MHAS), the Korean Longitudinal Study of Ageing (KLoSA), and the Survey of Health, Ageing and Retirement in Europe (SHARE). We estimated probabilities between robust health; disabilities related to instrumental activities of daily living (IADL) and basic activities of daily living (BADL); and mortality through multi-state Markov models. We included gender as a covariate in the models to calculate hazard ratios (HRs), while we calculated LE within the distinct health states of robust health, IADL disabilities, BADL disabilities, and mortality using the stochastic population analysis for complex events (SPACE) microsimulation. Results: Women had higher progressions to disability (IADL: HR = 1.392; BADL: HR = 1.356) compared to men, who conversely showed lesser progression from IADL to BADL disability (HR = 0.856) and lower mortality rates (span of HRs = 0.232-0.692). LE at age 50 favoured women (32.16-38.22 years) over men (28.99-33.58 years), yet they spent more time in states of disability. We otherwise observed significant regional and gender disparities in healthy LE. Conclusions: We identified ageing patterns in which longer lives are often coupled with extended periods of disability. Pronounced gender and regional differences indicate a need for targeted health interventions to address inequities and improve seniors' quality of life. Our findings highlight the necessity for policy interventions focussed on health equity to more completely respond to the demographic shift towards older populations.

Asunto(s)

Actividades Cotidianas , Disparidades en el Estado de Salud , Esperanza de Vida , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Estudios de Cohortes , Estudios Longitudinales , Transición de la Salud , Factores Sexuales , Personas con Discapacidad/estadística & datos numéricos , Anciano de 80 o más Años

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Skin damage caused by chemical corrosion is currently one of the common skin diseases and poisoning symptoms, with nitrogen mustard compounds causing the most persistent and severe damage. These chemicals penetrate the top layer of the skin, enter the dermis, and cause DNA damage, oxidative stress, and inflammation. However, to date, no effective drug treatment has been found. Even the potential antidotes could not effectively penetrate the top layer of the skin to exert their effects due to the skin barrier. To address this problem, an innovative transdermal drug delivery strategy based on aspirin microneedles was proposed. The classic medicine aspirin was first discovered not only to reduce inflammation and oxidative stress but also to promote DNA repair and reduce DNA damage. The aspirin microneedles directly delivered the drug to the damaged area, released aspirin through the skin barrier, and exhibited good biocompatibility. These findings indicate that aspirin microneedles have great potential for promoting wound healing and broad application prospects.

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Deep vein thrombosis (DVT) is a serious health issue that often leads to considerable morbidity and mortality. Diagnosis of DVT in a clinical setting, however, presents considerable challenges. The fusion of metabolomics techniques and machine learning methods has led to high diagnostic and prognostic accuracy for various pathological conditions. This study explored the synergistic potential of dual-platform metabolomics (specifically, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)) to expand the detection of metabolites and improve the precision of DVT diagnosis. Sixty-one differential metabolites were identified in serum from DVT patients: 22 from GC-MS and 39 from LC-MS. Among these, five key metabolites were highlighted by SHapley Additive exPlanations (SHAP)-guided feature engineering and then used to develop a stacking diagnostic model. Additionally, a user-friendly interface application system was developed to streamline and automate the application of the diagnostic model, enhancing its practicality and accessibility for clinical use. This work showed that the integration of dual-platform metabolomics with a stacking machine learning model enables faster and more accurate diagnosis of DVT in clinical environments.

Asunto(s)

Aprendizaje Automático , Metabolómica , Trombosis de la Vena , Humanos , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/metabolismo , Trombosis de la Vena/sangre , Metabolómica/métodos , Cromatografía de Gases y Espectrometría de Masas , Cromatografía Liquida , Masculino , Persona de Mediana Edad , Femenino

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The development of an efficient palladium probe holds significant application value, considering the detrimental impact of palladium contaminants on human health. Thus, it is critical to create a sensitive detection method. To this end, a fluorescent probe TM-TPA-Pd based on benzothianone structure was designed, using allyl carbonate as the Pd0 recognition unit. TM-TPA-Pd exhibited high sensitivity (1.4 eq), selectivity, near-infrared (NIR) fluorescence (798 nm), and low detection limit (0.46 µM) for Pd0 with a rapid "turn-on" fluorescence signal (5 min). Furthermore, TM-TPA-Pd has extremely low cytotoxicity and has been successfully applied to detecting cells and zebrafish, which has great potential for palladium detection in biological systems.

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Colorantes Fluorescentes , Paladio , Pez Cebra , Animales , Colorantes Fluorescentes/química , Paladio/química , Paladio/análisis , Humanos , Espectrometría de Fluorescencia , Límite de Detección , Espectroscopía Infrarroja Corta/métodos

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The delay of diabetic wound healing puts a huge burden on the society. The key factors hindering wound healing include bacterial infection, unresolved inflammation and poorly generated blood vessels. In this paper, glycidyl trimethyl ammonium chloride (GTA) was grafted to chitosan (CS) to obtain quaternary ammonium grafted chitosan (QCS) with enhanced antibacterial performance, and then cross-linked by dialdehyde terminated poly(ethylene oxide) (PEO DA) to construct QCS/PEO DA hydrogel with tissue adhesion, biodegradation and self-healing properties. The QCS/PEO DA hydrogel is loaded with tannin acid (TA) and deferoxamine (DFO) to enhance antioxidant property and angiogenesis. At the same time, the TA and DFO loaded TA@DFO/hydrogel preserved the biocompatibility and biodegradability of chitosan. Moreover, the multifunctional hydrogel behaved excellent hemostatic properties in mice model and significantly promoted the healing efficacy of diabetic wounds. Overall, the TA@DFO/hydrogel is promising anti-infection dressing material for diabetic wound healing.

Asunto(s)

Antibacterianos , Quitosano , Deferoxamina , Diabetes Mellitus Experimental , Hidrogeles , Compuestos de Amonio Cuaternario , Taninos , Cicatrización de Heridas , Quitosano/química , Quitosano/farmacología , Cicatrización de Heridas/efectos de los fármacos , Taninos/química , Taninos/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Animales , Hidrogeles/química , Hidrogeles/farmacología , Ratones , Deferoxamina/farmacología , Deferoxamina/química , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Masculino , Portadores de Fármacos/química , Staphylococcus aureus/efectos de los fármacos , Humanos , Escherichia coli/efectos de los fármacos

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Antifreeze proteins (AFPs) can inhibit ice crystal growth. The ice-binding mechanism of AFPs remains unclear, yet the hydration shells of AFPs are thought to play an important role in modulating the binding of AFPs and ice. Here, we performed all-atom molecular dynamics simulations of an AFP from Choristoneura fumiferana (CfAFP) at four different temperatures, with a focus on analysis at 240 and 300 K, to investigate the dynamic and thermodynamic characteristics of hydration shells around ice-binding surfaces (IBS) and non-ice-binding surfaces (NIBS). Our results revealed that the dynamics of CfAFP hydration shells were highly heterogeneous, with its IBS favoring a less dense and more tetrahedral solvation shell, and NIBS hydration shells having opposite features to those of the IBS. The IBS of nine typical hyperactive AFPs were found to be in pure low-entropy hydration shell region, indicating that low-entropy hydration shell region of IBS and the tetrahedral arrangements of water molecules around them mediate the ice-binding mechanism of AFPs. It is because the entropy increase of the low-entropy hydration shell around IBS, while the higher entropy water molecules at NIBS most likely prevent ice crystal growth. These findings provide new mechanistic insights into the ice-binding of AFPs.

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Proteínas Anticongelantes , Proteínas de Insectos , Mariposas Nocturnas , Proteínas Anticongelantes/química , Proteínas Anticongelantes/metabolismo , Mariposas Nocturnas/química , Mariposas Nocturnas/metabolismo , Proteínas de Insectos/química , Proteínas de Insectos/metabolismo , Hielo , Entropía , Animales , Adsorción , Simulación por Computador

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The efficacy of single chemotherapy drugs in cancer treatment is often limited. Combining administration targeting multiple targets has emerged as an effective strategy to improve cancer treatment. Ursolic acid, a triterpenoid compound in various natural foods, was identified as a novel inhibitor of lung cancer specific target TMEM16A. The IC50 of ursolic acid on the whole-cell current of TMEM16A was 13.85 ± 1.64 µM. Molecular dynamics simulations and site-directed mutagenesis experiments indicated the binding sites of ursolic acid on TMEM16A as L381, R535, E623, and C625. Ursolic acid significantly inhibited the proliferation and migration of LA795 cells, while promoting cancer cell apoptosis. Mechanistic studies revealed that ursolic acid inhibited lung cancer through the MAPK and EMT pathways, and induced DNA and membrane damage. Next, a degradable and self-repairing hydrogel drug-loading system was designed to enhance the targeting effect of the ursolic acid and cisplatin drug combination. In vivo experiments showed that the hydrogel-loaded ursolic acid and cisplatin enhanced the antitumor activity and reduced the toxicity. This study presents a novel approach of multi-target combination therapy using ursolic acid and cisplatin, combined with the targeted delivery capability of the hydrogel system, which significantly improves the therapeutic efficacy in lung cancer.

Asunto(s)

Cisplatino , Hidrogeles , Neoplasias Pulmonares , Triterpenos , Ácido Ursólico , Triterpenos/farmacología , Triterpenos/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Cisplatino/farmacología , Humanos , Hidrogeles/química , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ratones , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Simulación de Dinámica Molecular , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacos

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Monolayer MXenes are a novel class of two-dimensional transition metal carbides/nitrides with fascinating physicochemical properties. Despite recent advances in the study of MXenes' mechanical properties, a comprehensive understanding of the fundamental physical mechanisms that affect fracture due to surface terminations and vacancy defects in MXenes under nanoindentation remains largely unexplored. Here, we address this gap using molecular dynamics simulations and nanoindentation theory to investigate the effects of surface terminations and vacancy defects on the fracture behavior of Ti3C2Tx MXenes. By inducing the rupture of monolayer MXenes through nanoindentation, we find that bare Ti3C2 exhibits brittle fracture behavior. The presence of surface terminations and vacancy defects reduces the load-carrying capacity and flexibility of MXenes. Interestingly, surface terminations increase the stiffness of the structure, while vacancy defects have the opposite effect. We also find that high concentrations of surface oxidation impart ductile fracture characteristics to MXenes and increase the maximum crack length at failure. Additionally, defects exceeding the critical concentration can effectively prevent brittle crack propagation by causing frequent crack deflection and blunting crack tips. Combining these findings, we propose a new strategy to synergistically enhance the fracture toughness of MXenes through high concentrations of surface oxidation and vacancy defects exceeding the critical concentration without significantly affecting strength and stiffness, thereby avoiding catastrophic failure in MXene monolayers due to brittle fracture. This work provides fundamental insights into the mechanical properties and fracture mechanisms of monolayer MXenes.

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Chronic diarrhea has a considerable impact on quality of life. This randomized, double-blind, placebo-controlled crossover intervention trial was conducted with 69 participants (36 in Group A, 33 in Group B), aiming to investigate the potential of postbiotics in alleviating diarrhea-associated symptoms. Participants received postbiotic Probio-Eco® and placebo for 21 days each in alternating order, with a 14-day washout period between interventions. The results showed that postbiotic intake resulted in significant improvements in Bristol stool scale score, defecation frequency, urgency, and anxiety. Moreover, the postbiotic intervention increased beneficial intestinal bacteria, including Dysosmobacter welbionis and Faecalibacterium prausnitzii, while reducing potential pathogens like Megamonas funiformis. The levels of gut Microviridae notably increased. Non-targeted metabolomics analysis revealed postbiotic-driven enrichment of beneficial metabolites, including α-linolenic acid and p-methoxycinnamic acid, and reduction of diarrhea-associated metabolites, including theophylline, piperine, capsaicin, and phenylalanine. Targeted metabolomics confirmed a significant increase in fecal butyric acid after postbiotic intervention. The levels of aromatic amino acids, phenylalanine and tryptophan, and their related metabolites, 5-hydroxytryptophan and kynurenine, decreased after the postbiotic intervention, suggesting diarrhea alleviation was through modulating the tryptophan-5-hydroxytryptamine and tryptophan-kynurenine pathways. Additionally, chenodeoxycholic acid, a diarrhea-linked primary bile acid, decreased substantially. In conclusion, postbiotics have shown promise in relieving chronic diarrhea.

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Estudios Cruzados , Diarrea , Heces , Microbioma Gastrointestinal , Humanos , Diarrea/microbiología , Diarrea/metabolismo , Diarrea/terapia , Método Doble Ciego , Masculino , Femenino , Adulto Joven , Adulto , Enfermedad Crónica , Heces/microbiología , Heces/química , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/aislamiento & purificación , Probióticos/administración & dosificación , Calidad de Vida

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Designing hydrogel dressing with intrinsic antibacterial property to promote skin injury recovery remains a significant challenge. In this research, poly(aspartic hydrazide) with grafted betaine (PAHB) was designed and reacted with oxidized dextran (OD) to fabricate biodegradable PAHB/OD hydrogel and its application as wound dressing was systematically investigated. The PAHB/OD hydrogels exhibited fast gelation, strong tissue adhesion, preferable mechanical properties and biocompatibility. The grafted betaine endowed the hydrogel with antibacterial property and antibacterial rate enhanced through photothermal performance of composited CuS nanoparticles under near infrared (NIR) radiation. The CuS composited PAHB/OD hydrogel (CuS/hydrogel) with microporous morphology was used as burn wound dressing with loaded anti-inflammatory drug diclofenac sodium (DS) in mouse model. The results showed the DS loaded CuS/hydrogel (CuS@DS/hydrogel) promoted the tissue regeneration and suppressed the inflammatory response. The histological analysis and immunohistochemical expression confirmed the CuS@DS/hydrogel promote angiogenesis of the burn wound by regulating the expression of inflammatory cytokines (IL-6 and CD68) and vascular endothelial growth factor (VEGF). Overall, the CuS@DS/hydrogel hydrogel is a promising candidate as wound dressing due to its tissue adhesive, antioxidant, antibacterial and anti-inflammatory activities.

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In this study, we conducted a thorough investigation into the mechanisms by which miR-29 influences lipid metabolism. Thirty-two cows were selected and categorized into distinct groups based on their liver triglyceride (TG) content: healthy, mild fatty liver, and moderate fatty liver groups. Dairy cows with moderate fatty liver showed higher levels of hepatic lipid accumulation, MDA content and serum AST, ALT and ALP contents and lower hepatic catalase CAT and SOD activities. Subsequently, hepatocytes isolated from healthy calves were exposed to sodium oleate (SO) in the presence or absence of pre-incubation with miR-29 inhibitor or inhibitor NC. Pre-transfection with miR-29 inhibitor resulted in reduced hepatocyte lipid accumulation and MDA levels, as well as decreased levels of AST, ALT, and ALP in the supernatant. In the miR-29 inhibitor + SO group, there was an increase in the expression of SREBP-1, FAS, SCD1, and Sirt1. Meanwhile, the expression of PPARα, CPT1, CPT2, PGC-1α, NRF-1, UCP2, and miR-29 were observed to be decreased. In comparison to the miR-29 inhibitor + SO group, some of the measured indicators showed partial reversal in the miR-29 inhibitor + siSirt1 + SO group. Collectively, these findings provide evidence that miR-29 may play a crucial role in the pathogenesis of fatty liver in dairy cows.

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BACKGROUND: Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in CALM1, CALM2, or CALM3, which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function. METHODS: We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of CALM1 pathogenic variants. RESULTS: Human CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1 knockout or CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization duration of CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine Calm1 depleted Calm1 transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in CalmN98S/+ mice without a deleterious effect on cardiac electrical or contractile function. CONCLUSIONS: These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.

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Aromatic components of C8-C15 are playing indispensable roles in multi-functional properties of jet fuel. Here, we reported the controllable alkylation of benzene with mixed olefins of ethylene and propylene toward C8-C15 aromatic hydrocarbons for jet fuels over the bifunctional Ga/ZSM-5 catalyst. The resultant 2Ga/ZSM-5 exhibited a superior selectivity of 86.4% (yield of 55.5%) to C8-C15 range aromatics, at benzene conversion of 40.3%, ethylene and propylene conversion of 99.5% and 99.2%, respectively. The incorporation of Ga species could effectively weaken the strong acid sites of ZSM-5 and endow 2Ga/ZSM-5 catalyst with appropriate acidity, therefore facilitating the benzene alkylation process and suppressing the undesired hydrogen transfer or aromatization side reactions as well, thus improving the yield of desired C8-C15aromatics for jet fuels. This work provided insight into the development of promising bifunctional catalyst for the oriented transformation of biomass-derived chemicals to aviation fuels.

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PURPOSE: Depression is one of the most common mental disorders and substantially decreases socioemotional well-being and health-related quality of life. Analyzing temporal patterns in depressive symptoms can reveal emerging risks that require attention and have implications for mental health promotion. The present study disentangled age, period, and cohort (APC) effects on trends in depressive symptoms and their gender disparities among China's nationally representative samples of middle-aged and older adults. METHODS: Using four-wave data (2011, 2013, 2015, and 2018) from the China Health and Retirement Longitudinal Study (N = 65455), APC effects were quantified based on the hierarchical APC model. The 10-item Center for Epidemiologic Studies Depression Scale (CES-D-10) was used to measure depressive symptoms. RESULTS: Depressive symptoms increased during late life and stabilized after reaching an advanced age. After further adjusting for individual characteristics, depressive symptoms exhibited a negative trend with advancing age. The mean levels of depressive symptoms remained stable during the study period. Depressive symptoms varied significantly across cohorts, with those born in 1949-1951 having the most severe depressive symptoms. Significant life-course and cohort variations existed in the gender gaps in depressive symptoms. Although women had higher mean scores on the CES-D-10 scale throughout the life course, the gender gaps in depressive symptoms gradually narrowed with age, as depressive symptoms decreased more rapidly among women. A widening trend in gender gaps in depressive symptoms was found among those born after the mid-1950s, mainly driven by a notable decline in depressive symptoms among men CONCLUSIONS: The convergence of living conditions between genders in late life, as a result of traditional Chinese culture, may have narrowed the gender gap in depressive symptoms. However, given the widening gender disparities in depressive symptoms among younger cohorts, more attention should be paid to women's mental health in the context of China's rapid socioeconomic development.

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BACKGROUND: Lung cancer is a highly malignant disease with limited treatment options and significant adverse effects. It is urgent to develop novel treatment strategies for lung cancer. In recent years, TMEM16A has been confirmed as a specific drug target for lung cancer. The development of TMEM16A-targeting drugs and combined administration for the treatment of lung cancer has become a research hotspot. METHODS: Fluorescence screening and electrophysiological experiments were conducted to confirm the inhibitory effect of CCA on TMEM16A. Molecular dynamics simulation and site-directed mutagenesis were employed to analyze the binding mode of CCA and TMEM16A. CCK-8, colony formation, wound healing, transwell, and annexin-V experiments were conducted to explore the regulatory effects and mechanisms of CCA on the proliferation, migration, and apoptosis of lung cancer cells. Tumor model mice and pharmacokinetic experiments were used to examine the efficacy and safety of CCA and cisplatin in vivo. RESULTS: This study firstly confirmed that CCA effectively inhibits TMEM16A to exert anticancer effects and analyzed the pharmacological mechanism. CCA bound to S517/N546/E623/E633/Q637 of TMEM16A through hydrogen bonding and electrostatic interactions. It inhibited the proliferation and migration, and induced apoptosis of lung cancer cells by targeting TMEM16A. In addition, the combined administration of CCA and cisplatin exhibited a synergistic effect, enhancing the efficacy of lung cancer treatment while reducing side effects. CONCLUSION: CCA is an effective novel inhibitor of TMEM16A, and it synergizes with cisplatin in anticancer treatment. These findings will provide new research ideas and lead compound for the combination therapy of lung cancer.

Asunto(s)

Anoctamina-1 , Apoptosis , Proliferación Celular , Cisplatino , Neoplasias Pulmonares , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Humanos , Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Proliferación Celular/efectos de los fármacos , Anoctamina-1/metabolismo , Ratones , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Ratones Endogámicos BALB C , Ratones Desnudos , Masculino , Simulación de Dinámica Molecular , Células A549

RESUMEN

Ion channels play a crucial role in the electrophysiological activities of organisms. The calcium-activated chloride channel TMEM16A is involved in various physiological processes. Therefore, inhibitors of TMEM16A are used to treat diseases caused by TMEM16A dysfunction. However, the unclear inhibition mechanism hinders the progress of drug development. Based on our previous study, we found that the molecular structures of TMEM16A inhibitors tracheloside, matairesinoside and arctigenin are similar. In this study, we conducted a structure-based virtual screening of tracheloside analogs from the PubChem database. The six tracheloside analogs with the highest affinity to TMEM16A were selected, and their inhibitory effects were detected by fluorescence and electrophysiological experiments. Subsequently, the interaction between the tracheloside analogs and TMEM16A was investigated through molecular docking and site-directed mutagenesis. Based on the above results, the mechanism of inhibition of TMEM16A gated conformation by tracheloside analogs was proposed. These findings provide a structural and theoretical basis for drug development targeting TMEM16A.

Asunto(s)

Anoctamina-1 , Humanos , Anoctamina-1/antagonistas & inhibidores , Anoctamina-1/química , Desarrollo de Medicamentos , Células HEK293 , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Relación Estructura-Actividad

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Flexible polyurethane foam (FPUF) is a ubiquitous material utilized in furniture cushions, mattresses, and various technical applications. Despite the widespread use, FPUF faces challenges in maintaining long-lasting flame retardancy and aging resistance, particularly in harsh environments, while retaining mechanical robustness. Here, we present a novel approach to address these issues by enhancing FPUF through multiple free-radical-trapping and hydrogen-bonding mechanisms. A hindered amine phosphorus-containing polyol (DTAP) was designed and chemically introduced into FPUF. The distinctive synergy between hindered amine and phosphorus-containing structures enables the formation of multiple hydrogen bonds with urethane, while also effectively capturing free radicals across a broad temperature spectrum. As a result, incorporating only 5.1 wt% of DTAP led to the material successfully passing vertical burning tests and witnessing notable enhancements in tensile strength, elongation at break, and tear strength. Even after enduring accelerated thermal aging for 168 hours, the foam maintained exceptional flame retardancy and mechanical properties. This study offers novel insights into material enhancement, simultaneously achieving outstanding long-lasting flame retardancy, toughness, and anti-aging performance.

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In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

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The ovary in mammals has developed specialized mechanisms for protection against pathogen infections; however, the understanding of the innate immune system in the ovary of crustaceans is still limited. To elucidate the ovary's defense mechanisms in response to viral challenges, we subjected oriental river prawns (Macrobrachium nipponense) to poly I:C, a double-stranded RNA analog that emulates viral dsRNA, and analyzed the ovary's transcriptome profiles. Concurrently, RNA-seq analysis was performed on the hepatopancreas, a well-recognized immune-related tissue, following poly I:C challenge to investigate the distinct response mechanisms of the ovary and hepatopancreas and to gain a comprehensive understanding of the immune responses in both tissues. The results indicate that 1368 genes are differentially expressed in the ovary, with 903 genes upregulated and 465 genes downregulated. Subsequent analysis reveals that these differentially expressed genes (DEGs) include numerous genes associated with innate immunity, such as members of the C-type lectin, fibrinogen-related protein (Frep), Toll-like receptor, and NOD-like receptor (NLR) gene families, as well as acid phosphatase, scavenger receptor, crustin, Down syndrome cell adhesion molecule (Dscam), hemocyanin, and lipopolysaccharide and beta-1,3-glucan binding protein (LGBP). Furthermore, the DEGs include several genes related to ovary development, such as sox8, vitellogenin, progranulin, cyclin-dependent kinase, ecdysone receptor, frizzled, and members of the Fox gene family. In the hepatopancreas, a total of 729 DEGs were identified. Comparison of the DEGs in both tissues indicates that only 91 genes are common to both groups, highlighting significant tissue-specific responses to poly I:C stimulation. This study aims to enhance our understanding of the immune protective mechanisms employed by the ovary in response to pathogen exposure and establishes a foundation for investigating ovarian reproductive immunity in crustaceans.