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With the global population continuously rising, efficient bioconversion of inedible agricultural by-products is crucial for human food and energy sustainability. We here propose solid-state fermentation approaches to efficiently convert biopolymers into oligomers/monomers by accelerating the natural degradation process of the versatile Streptomyces sp. strain SCUT-3. Using fish skin as a representative by-product, 54.3 g amino acids and 14.7 g peptides (91 % < 2500 Da) were recovered from 89.0 g protein in 100 g tilapia skin sample by collagenase-overexpressed SCUT-3 for seven days at a 1:4 substrate:liquid ratio. Fish skin collagen hydrolysates exhibited excellent anti-oxidation, anti-hypertension, scratch-repairing, anti-aging, anti-ultraviolet radiation, and anti-inflammation effects on human skin fibroblasts In vitro and zebrafish larvae in vivo, indicating their potential applications in healthcare/skincare and anti-atopic dermatitis. As Laozi said, the divine law follows nature. This study underscores the efficacy of genetically engineered SCUT-3 according to its natural biomass utilization laws in large-scale biopolymer conversion.
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The emerging tumor microenvironment (TME) is a complex and constantly evolving entity. Cancer-associated fibroblasts (CAFs) are a vital component of the TME with diverse functions. They interact closely with cancer cells through reciprocal signaling and play a crucial role in tumor progression. Exosomes, which contain diverse biological information, are identified as an important mediator of cell-cell communication. This study aimed to investigate how CAF-derived exosomes promote metastasis of endometrial cancer (EC). Our findings revealed that CAF-derived exosomes significantly enhanced EC cell proliferation and migration compared to normal fibroblast-derived exosomes. Quantitative proteomics analysis of CAF/NF-derived exosomes demonstrated differential expression of CTHRC1, a protein overexpressed in multiple tumors, promoting cancer progression through enhanced cell migration and invasion. Exosomal overload of CTHRC1 significantly contributes to EC cell migration. Mechanically, we determined that ITGB3 was immunoprecipitated by CTHRC1 and phosphorylated FAK on Tyr397, which was important for exosomal CTHRC1 mediated migratory ability of EC cells. Overexpression of CTHRC1 in secreted exosomes promotes the metastatic ability of EC cells in mouse models and may be eliminated by Defactinib, an inhibitor of FAK Tyr397 phosphorylation. Moreover, overexpression of CTHRC1 was increased in EC patients, elevating with cancer progression, and correlated with negative tumor prognosis. Our results revealed that CAF mediated endometrial cancer progression is related to high levels of CTHRC1 and exosomal CTHRC1 derived from CAF may be a promising therapeutic strategy for metastatic endometrial cancer.
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BACKGROUND: The efficacy of mesenchymal stem cells (MSCs) in treating liver fibrosis has been demonstrated in several clinical studies. However, their low survival and liver implantation rates remain problematic. In recent years, a large number of studies in animal models of liver fibrosis have shown that MSCs combined with drugs can improve the efficacy of MSCs in the treatment of liver fibrosis alone and inhibit its progression to end-stage liver disease. This has inspired new ways of thinking about treating liver fibrosis. AIM: To investigate the effectiveness and mechanisms of MSCs combined with drugs in treating liver fibrosis. METHODS: Data sources included four electronic databases and were constructed until January 2024. The subjects, interventions, comparators, outcomes, and study design principle were used to screen the literature, and the quality of the literature was evaluated to assess the risk of bias. Relevant randomised controlled trials were selected, and the final 13 studies were included in the final study. RESULTS: A total of 13 studies were included after screening. Pooled analysis showed that MSCs combined with drug therapy significantly improved liver function, promoted the repair of damaged liver tissues, reduced the level of liver fibrosis-related indexes, and effectively ameliorated hepatic fibrosis by modulating the hepatic inflammatory microenvironment, promoting the homing of MSCs, and regulating the relevant signaling pathways, and the treatment efficacy was superior to MSCs alone. However, the combined treatment statistics showed no ame-lioration in serum albumin levels (standardized mean difference = 0.77, 95% confidence interval: -0.13 to 1.68, P = 0.09). CONCLUSION: In conclusion, MSCs combined with drugs for treating liver fibrosis effectively make up for the shortcomings of MSCs in their therapeutic effects. However, due to the different drugs, the treatment mechanism and effect also differ. Therefore, more randomized controlled trials are needed to compare the therapeutic efficacy of different drugs in combination with MSCs, aiming to select the "best companion" of MSCs in treating hepatic fibrosis.
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Cirrosis Hepática , Trasplante de Células Madre Mesenquimatosas , Animales , Humanos , Terapia Combinada/métodos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hígado/patología , Hígado/efectos de los fármacos , Cirrosis Hepática/patología , Cirrosis Hepática/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Thyroid cancer (TC) is a significant global healthcare burden. However, the lack of comprehensive data has impeded our understanding of its global impact. We aimed to examine the burden of TC and its trends at the global, regional, and national levels using data stratified by sociodemographic index (SDI), sex, and age. Data on TC, including incidence, mortality, and disability-adjusted life-years (DALYs) from 1990 to 2021, were obtained from the Global Burden of Disease Study 2021. Estimated annual percentage changes (EAPCs) were calculated to assess the incidence rate, mortality, and DALYs trends. The incidence, mortality, and DALYs of TC in 2021 were 249,538 (95% uncertainty interval: 223,290-274,638), 44,799 (39,925-48,541), and 646,741 (599,119-717,357), respectively. The age-standardized incidence rate (ASIR) in 2021 was 2.914 (2.607-3.213), with an EAPC of 1.25 (1.14-1.37) compared to 1990. In 2021, the age-standardized death rate (ASDR) was 0.53 (0.47-0.575) and age-standardized DALYs rate was 14.571 (12.783-16.115). Compared with 1990, the EAPCs of ASDR and age-standardized DALYs rate showed decreasing trends, at - 0.24 (- 0.27 to - 0.21) and - 0.14 (- 0.17 to - 0.11), respectively. Low SDI regions showed the highest ASDR and age-standardized DALYs rate, at 0.642 (0.516-0.799) and 17.976 (14.18-23.06), respectively. Low-middle SDI regions had the highest EAPCs for ASDR and age-standardized DALYs rate, at 0.74 (0.71-0.78) and 0.67 (0.63-0.7), respectively. Females exhibited decreasing trend in ASDR and age-standardized DALYs rate, with EAPCs of - 0.58 (- 0.61 to - 0.55) and - 0.45 (- 0.47 to - 0.42), respectively. In contrast, males showed an increasing trend in ASDR and age-standardized DALYs rate, with EAPCs of 0.41 (0.35-0.46) for both. In high-income regions, most countries with decreased annual changes in deaths experience increasing age-related deaths. Over the past few decades, a notable increase in TC incidence and decreased mortality has been observed globally. Regions characterized by lower SDI, male sex, and an aging population exhibited no improvement in TC mortality. Effective resource allocation, meticulous control of risk factors, and tailored interventions are crucial for addressing these issues.
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Carga Global de Enfermedades , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/mortalidad , Carga Global de Enfermedades/tendencias , Masculino , Femenino , Incidencia , Persona de Mediana Edad , Salud Global/estadística & datos numéricos , Adulto , Años de Vida Ajustados por Discapacidad , Anciano , Adolescente , Adulto JovenRESUMEN
PURPOSE: To explore the microstate characteristics and underlying brain network activity of Ménière's disease (MD) patients based on high-density electroencephalography (EEG), elucidate the association between microstate dynamics and clinical manifestation, and explore the potential of EEG microstate features as future neurobiomarkers for MD. METHODS: Thirty-two patients diagnosed with MD and 29 healthy controls (HC) matched for demographic characteristics were included in the study. Dysfunction and subjective symptom severity were assessed by neuropsychological questionnaires, pure tone audiometry, and vestibular function tests. Resting-state EEG recordings were obtained using a 256-channel EEG system, and the electric field topographies were clustered into four dominant microstate classes (A, B, C, and D). The dynamic parameters of each microstate were analyzed and utilized as input for a support vector machine (SVM) classifier to identify significant microstate signatures associated with MD. The clinical significance was further explored through Spearman correlation analysis. RESULTS: MD patients exhibited an increased presence of microstate class C and a decreased frequency of transitions between microstate class A and B, as well as between class A and D. The transitions from microstate class A to C were also elevated. Further analysis revealed a positive correlation between equilibrium scores and the transitions from microstate class A to C under somatosensory challenging conditions. Conversely, transitions between class A and B were negatively correlated with vertigo symptoms. No significant correlations were detected between these characteristics and auditory test results or emotional scores. Utilizing the microstate features identified via sequential backward selection, the linear SVM classifier achieved a sensitivity of 86.21% and a specificity of 90.61% in distinguishing MD patients from HC. CONCLUSIONS: We identified several EEG microstate characteristics in MD patients that facilitate postural control yet exacerbate subjective symptoms, and effectively discriminate MD from HC. The microstate features may offer a new approach for optimizing cognitive compensation strategies and exploring potential neurobiological markers in MD.
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Electroencefalografía , Enfermedad de Meniere , Humanos , Masculino , Femenino , Electroencefalografía/métodos , Enfermedad de Meniere/fisiopatología , Enfermedad de Meniere/diagnóstico , Enfermedad de Meniere/psicología , Persona de Mediana Edad , Adulto , Cognición/fisiología , Adaptación Fisiológica/fisiología , Máquina de Vectores de Soporte , Pruebas Neuropsicológicas , AncianoRESUMEN
The separation and purification of chemical raw materials, particularly neutral compounds with similar physical and chemical properties, represents an ongoing challenge. In this study, we introduce a class of water-soluble macrocycle compound, calix[2]azolium[2]benzimidazolone (H), comprising two azolium and two benzimidazolone subunits. The heterocycle subunits form a hydrophobic binding pocket that enables H1 to encapsulate a series of neutral guests in water with 1:1 or 2:1 stoichiometry, including aldehydes, ketones, and nitrile compounds. The host-guest complexation in the solid state was further confirmed through X-ray crystallography. Remarkably, H1 was shown to be a nonporous adaptive crystal material to separate valeraldehyde from the mixture of valeraldehyde/2-methylbutanal/pentanol with high selectivity and recyclability in the solid states. This work not only demonstrates that azolium-based macrocycles are promising candidates for the encapsulation of organic molecules but also shows the potential application in separation science.
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Two extremely devastating super dust storms (SDS) hit Mongolia and Northern China in March 2021, causing many deaths and substantial economic damage. Accurate forecasting of dust storms is of great importance for avoiding or mitigating their effects. One of the most critical factors affecting dust emissions is soil moisture, but its value in desert exhibits significant uncertainty. In this study, model experiments were conducted to simulate dust emissions using four soil moisture datasets. The results were compared with observations to assess the effects of soil moisture on the dust emission strength. The Integrated Source Apportionment Method (ISAM) was used to track the dust sources and quantify the contribution from each source region to the dust load over the North China Plain (NCP), Korea peninsula, and western Japan. The results show large differences in the dust load depending on the soil moisture datasets used. The high soil moisture in the NCEP dataset results in substantial underestimation of the dust emission flux and PM10 concentration. Despite a minor overestimation of PM10 concentrations in many Northern China cities, the ERA5 dataset yields the best simulation performance. During the two SDS events, about 7.5 Mt dust was released from the deserts in Mongolia and 2.8 Mt from the deserts in China. Source apportionment indicates that the Mongolian Gobi Desert is the dominant source of PM10 in the NCP, Korea peninsula, and western Japan, accounting for 60 %-80 %, while Inner Mongolia contributed 10 %-20 %.
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Organics and divalent cations are the primary barriers constraining the performance of membrane technology, while the interactions between them and the detailed mechanisms of their impacts are still lacking in-depth analysis. In this study, sodium alginate and xanthan gum were selected as polysaccharides models, and the formation of transparent extracellular polymer particles (TEP) was assessed to examine the effect of Ca2+ and polysaccharides type on membrane fouling from both qualitative and quantitative perspectives. The results revealed that higher Ca2+ concentrations led to a greater abundance of TEP, and the transformation of TEP microstructure is a key factor for the membrane fouling change indicated by specific filtration resistance (SFR). TEP formed by sodium alginate underwent a transformation from amorphous-TEP (a-TEP) form to particle-TEP (p-TEP), corresponding to a unimodal pattern of SFR variation. With increasing Ca2+ concentration, the molecular interactions of xanthan gum became stronger, resulting in larger fibrous a-TEP and a continuous SFR increase. According to the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory, TEP formed by xanthan gum exhibited higher adhesion energy, thus causing more severe membrane fouling. The SFR variation of the TEP system can be satisfactorily explained by the conception of chemical potential change in the filtration process depicted in Flory-Huggins theory. This study is the first work to introduce models regarding chemical potential and TEP microstructure, linking the system chemical potential and TEP microstructure with membrane fouling indicated by SFR. As all, this study provided a new perspective for analyzing the polysaccharide fouling behavior via TEP determination and further enhanced the understanding through thermodynamic analysis.
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BACKGROUND AND AIM: Cardiometabolic diseases (CMDs) are leading causes of death and disability, but little is known about the additive mortality effects of multiple CMDs. This study aimed to examine the association between single and multiple CMDs and all-cause mortality among older Chinese population. METHODS AND RESULTS: Using the Chinese Longitudinal Healthy Longevity Survey (CLHLS) database, we analyzed data from 2008 to 2018 to assess the relationship between CMDs and mortality. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for single and multiple CMDs. At baseline, 11,351 participants (56.9% female) aged 60 years or older were included. 11.91% of participants had a single CMD, 1.51% had two CMDs, and 0.22% had three CMDs. Over a decade follow-up, 8992 deaths (79.2%) were recorded. A dose-response relationship was observed, with the mortality risk increasing by 17% for each additional disease. The fully-adjusted HRs for all-cause mortality were 1.16, 1.36, and 2.03 for one, two, and three CMDs, respectively. Larger effects of single and multiple CMDs were observed in the male group (P = 0.015) and the younger senior group (P < 0.001). CONCLUSIONS: This large-scale study found that CMDs multiply mortality risks, especially in younger seniors and males. The risk is highest when heart disease and stroke coexist, and diabetes further increases it. Public health efforts should prioritize evidence-based management and prevention of CMDs.
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Factores de Riesgo Cardiometabólico , Causas de Muerte , Bases de Datos Factuales , Humanos , Masculino , Femenino , Anciano , China/epidemiología , Estudios Prospectivos , Persona de Mediana Edad , Medición de Riesgo , Factores de Edad , Anciano de 80 o más Años , Factores de Tiempo , Enfermedades Cardiovasculares/mortalidad , Multimorbilidad , Pronóstico , Factores Sexuales , Factores de Riesgo , Pueblos del Este de AsiaRESUMEN
The most prevalent form of colon cancer also ranks high among cancer-related deaths globally. Traditional chemotherapy drugs do not provide sufficient therapeutic efficacy, and advanced colon cancer demonstrates considerable resistance to chemotherapy. As an oral kinase inhibitor, sorafenib (SOR) suppresses the growth of tumour cells, the formation of new blood vessels, and the death of cancer cells. Unfortunately, sorafenib's limited bioavailability, rapid metabolism, and poor solubility have severely limited its clinical use. We developed nanoparticles targeting P-selectin and SOR, with fucoidan (FU) as a ligand. The SOR-CS-FU-NPs were developed by coating polylactide-co-glycolide nanoparticles with chitosan and FU through electrostatic interaction. The SOR-CS-FU-NPs exhibited an average particle diameter of 209.98 ± 1.25 nm and a polydisperse index (PDI) of 0.229 ± 0.022. The SOR-CS-FU nanoparticles exhibited a continuous release pattern for up to 120 h. The SOR-CS-FU nanoparticles exhibited cytotoxicity 8 times greater than free SOR in HCT116 colorectal cancer cells. The cellular absorption of Rhodamine-CS-FU-NPs was three times more than that of free Rhodamine and 19 times greater than that of Rhodamine-CS-NPs. Enhanced reactive oxygen species (ROS) generation and mitochondrial membrane potential damage were also shown in SOR-CS-FU-NPs. An investigation of cell death found that SOR-CS-FU-NPs had an apoptosis index that was 7.5 times greater than free SOR. After that, the SOR-CS-FU-NPs demonstrated a more significant inhibition of cell migration, leading to a wound closure of about 5 %. No toxicity was shown in the non-cancer VERO cell line when exposed to the developed NPs. Taken together, these results provide strong evidence that biocompatible SOR-CS-FU-NPs fabricated effective carriers for the targeted delivery of dasatinib to colorectal cancer.
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This paper uses panel data of 260 prefecture-level cities from 2000 to 2019 to explore spatial characteristics such as spatiotemporal divergence and dynamic convergence based on measuring the level of human capital misallocation in Chinese cities and empirically tests the green development effect of human capital misallocation. The study finds that: â the human capital misallocation levels of the country and the eight major urban agglomerations show a fluctuating downward trend. â¡ Divergences in human capital misallocation continue to narrow across the country and urban agglomerations, and the difference between inter-urban agglomerations is the primary source of regional difference. ⢠The YRD, PRD, MYR, HC, and CP have significant σ-convergence characteristics of human capital misallocation. Meanwhile, the country and each urban agglomeration show significant spatial absolute ß-convergence and conditional ß-convergence trends. ⣠Human capital misallocation significantly negatively affects green economic efficiency, inhibiting green economy efficiency. Therefore, in the future, it is necessary to improve the match between regional industrial structure and human capital allocation through a combination of targeted policy guidance and market mechanisms tailored to local conditions to enhance the efficiency of the green economy. The significance of the study lies in accelerating the accumulation of human capital while realizing the appropriate matching of human capital, releasing the human capital dividend to the maximum extent, and boosting the structural reform of the labor market to realize the transformation of the green economy.
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Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 µm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.
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Recently, microplastics (MPs) have attracted extensive attention to their wide distribution and potential toxicity in ecosystems. However, there was a lack of research focused on MPs in seaweed bed ecosystems. This study investigated the distribution and toxicity of MPs in macrobenthos in Sargassum ecosystem. According to the in-situ investigation results, the abundance of MPs in the sediment was 0.9-2.3 items/g, the indoor microcosmic experiment was constructed. After exposure to MPs (0, 2, and 20 items/g) for 30 days, the abundance of MPs in macrobenthos exhibits a concentration-dependent increase. However, there was no significant bioaccumulation of MPs at the trophic level. The indoor toxicity test revealed that MPs induced oxidative stress and altered intestinal microflora composition in macrobenthos, even at actual environmental concentrations (2 items/g). It may result in a perturbation of the organism's homeostatic equilibrium. High-concentration (20 items/g) MPs had a greater impact on alkaline phosphatase (AKP) in Mollusks. The increase in AKP activity could be indicative of an adaptive mechanism in some macrobenthos while the decline in AKP activity might signal a decrease in their survival. These results elucidated the fate of MPs in ecosystem and the ecological risks of MPs to large benthic animals on model environmental conditions.
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Ecosistema , Microplásticos , Sargassum , Contaminantes Químicos del Agua , Sargassum/química , Microplásticos/toxicidad , Animales , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisis , Sedimentos Geológicos/química , Monitoreo del Ambiente , Moluscos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
Major depression is a severe neuropsychiatric disorder that poses a significant challenge to health. However, development of an effective therapy for the disease has long been difficult. Here, we investigate the efficacy of a novel combinatorial treatment employing sub-effective doses of Ro25-6981, an antagonist targeting GluN2B-containing NMDA receptors, in conjunction with ZL006, an inhibitor of the PSD95/nNOS, on mouse models of depression. We employed social isolation, chronic restraint stress, or a combination of both to establish a depressed mouse model. Treatment with the drug combination reduced depressive-like behaviors without affecting locomotor activity in mice subjected to social isolation or chronic restraint stress. Furthermore, the combination therapy ameliorated depressive-like behaviors induced by combined stress of chronic restraint followed by social isolation. Mechanistic studies revealed that the combined treatment downregulated the hippocampal nitric oxide level. However, the therapeutic benefits of this combination were negated by the activation of NMDA receptors with a low dose of NMDA or by increasing nitric oxide levels with l-arginine. Moreover, the combinatorial treatment had negligible effects on object memory and contextual fear memory. Our data establish a combined therapy paradigm, providing a potential strategy targeting major depression.
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Depresión , Ratones Endogámicos C57BL , Piperidinas , Receptores de N-Metil-D-Aspartato , Estrés Psicológico , Animales , Masculino , Ratones , Depresión/tratamiento farmacológico , Depresión/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Estrés Psicológico/tratamiento farmacológico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Fenoles/farmacología , Fenoles/uso terapéutico , Conducta Animal/efectos de los fármacos , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Quimioterapia Combinada , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Óxido Nítrico/metabolismoRESUMEN
Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer. Evidence suggests that the ionotropic glutamate receptor N-methyl-D-aspartate (NMDA) receptor, a critical molecule in the central nervous system, is expressed in NSCLC. However, the specific expression patterns, subcellular localization, functional modulation, and pathological implications of NMDA receptor subtypes in NSCLC have not been fully elucidated. In this study, we employed a multi-disciplinary approach, combining biochemical and molecular biology with electrophysiological recordings and behavioral assays, to investigate these aspects. We reveal the expression of GluN2B-containing NMDA receptors in A549 and H460 NSCLC cell lines and the induction of NMDA receptor-mediated currents by glutamate in A549 cells. Furthermore, the GluN2B-specific inhibitors ifenprodil and Ro 25-6981 significantly reduced cell viability and migration, while promoting apoptosis. Importantly, intraperitoneal administration of ifenprodil in nude mice inhibited the growth of subcutaneous tumors derived from A549 and H460 cells and ameliorated depression-like behaviors. These findings underscore the potential antiproliferative effects of ifenprodil and Ro 25-6981 and suggest that GluN2B-containing NMDA receptors may represent novel therapeutic targets for NSCLC, with the added benefit of potential antidepressant action.
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Antidepresivos , Antineoplásicos , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Piperidinas , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ratones , Piperidinas/farmacología , Piperidinas/uso terapéutico , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Ratones Desnudos , Proliferación Celular/efectos de los fármacos , Fenoles/farmacología , Fenoles/uso terapéutico , Línea Celular Tumoral , Masculino , Depresión/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Células A549RESUMEN
Lanthanide-based upconversion molecular complexes have potential application in diverse fields and attracted considerable research interest in recent years. However, the similar coordination reactivity of lanthanide ions has constrained the designability of target molecule with well-defined structure, and many attempts obtained statistical mixtures. Herein, an ion-paired Yb-Eu heteronuclear complex [Eu(TpPy)2][Yb(ND)4] (TpPy = tris[3-(2-pyridyl)pyrazolyl]hydroborate, ND = 3-cyano-2-methyl-1,5-naphthyridin-4-olate) was designed and synthesized. Thanks to the radius difference between Eu3+ (1.07 Å) and Yb3+ (0.98 Å) ions, the hexadentate TpPy ligand was selected to coordinate with Eu3+ and the Yb3+ with a smaller radius was chelated by bidentate ND ligand. As a result, the sites of Eu3+ and Yb3+ in the complex can be clarified by high-resolution mass spectrometry and single-crystal structure analysis. Upon the excitation of Yb3+ at 980 nm, the upconversion emission of Eu3+ was realized through a cooperative sensitization process. Furthermore, [Eu(TpPy)2][Yb(ND)4] demonstrated excellent photostability during continuous high-power density 980 nm laser irradiation, with a LT95 (the time to 95% of the initial emission intensity) of 420 minutes. This work provides the first example of a pure ion-paired Yb-Eu heteronuclear complex upconversion system and may bring insights into rational design of lanthanide-based upconversion molecular complexes.
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BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.
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Modelos Animales de Enfermedad , Células Madre Mesenquimatosas , Mucosa Olfatoria , Enfermedad de Parkinson , Factor de Crecimiento Transformador beta1 , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Trasplante de Células Madre Mesenquimatosas/métodos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/terapia , Recuperación de la Función , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Sclerotinia sclerotiorum (Ss) is one of the most devastating fungal pathogens, causing huge yield loss in multiple economically important crops including oilseed rape. Plant resistance to Ss pertains to quantitative disease resistance (QDR) controlled by multiple minor genes. Genome-wide identification of genes involved in QDR to Ss is yet to be conducted. In this study, we integrated several assays including genome-wide association study (GWAS), multi-omics co-localization, and machine learning prediction to identify, on a genome-wide scale, genes involved in the oilseed rape QDR to Ss. Employing GWAS and multi-omics co-localization, we identified seven resistance-associated loci (RALs) associated with oilseed rape resistance to Ss. Furthermore, we developed a machine learning algorithm and named it Integrative Multi-Omics Analysis and Machine Learning for Target Gene Prediction (iMAP), which integrates multi-omics data to rapidly predict disease resistance-related genes within a broad chromosomal region. Through iMAP based on the identified RALs, we revealed multiple calcium signaling genes related to the QDR to Ss. Population-level analysis of selective sweeps and haplotypes of variants confirmed the positive selection of the predicted calcium signaling genes during evolution. Overall, this study has developed an algorithm that integrates multi-omics data and machine learning methods, providing a powerful tool for predicting target genes associated with specific traits. Furthermore, it makes a basis for further understanding the role and mechanisms of calcium signaling genes in the QDR to Ss.