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ETHNOPHARMACOLOGICAL RELEVANCE: Hypercholesterolemia (HLC) was a key risk factor for cardiovascular disease (CVD) characterized by elevated cholesterol levels, particularly LDL. While traditional Chinese medicine preparations Compound Danshen Pills(CDP) has been clinically used for hypercholesterolemia and coronary heart disease, its specific therapeutic effect on HLC remains understudied, necessitating further investigation into its mechanisms. AIM OF THE STUDY: The aim of this study was to explore the potential of CDP in treating HLC and elucidate its underlying mechanisms and active components. MATERIALS AND METHODS: A hypercholesterolemic lipemia rat model induced by a high-fat diet was employed. Network pharmacology combined with UHPLC-Q exactive orbitrap HRMS technique was used to predict the active components, targets and mechanisms of CDP for HLC. Histological analysis and serum biochemical assays were used to assess the therapeutic effect of CDP and its main active ingredient Sa B on hypercholesterolemic lipemia rat model. Immunofluorescence assays and western blotting were used to verify the mechanism of CDP and Sa B in the treatment of HLC. Metabolomics approach was used to demonstrate that CDP and Sa B affected the metabolic profile of HLC. RESULTS: Our findings demonstrated that both CDP and its main active ingredient Sa B significantly ameliorated hypercholesterolemic lipemic lesions, reducing levels of TC, LDL, AST, ALT, and ALP. Histological analysis revealed a decrease in lipid droplet accumulation and collagen fiber deposition in the liver, as well as reduced collagen fiber deposition in the aorta. Network pharmacology predicted potential targets such as PPARα and CYP27A1. Immunofluorescence assays and western blotting confirmed that CDP and Sa B upregulated the expression of Adipor1, PPARα and CYP27A1. Metabolomics analyses further indicated improvements in ABC transporters metabolic pathways, with differential metabolites such as riboflavin, taurine, and choline showed regression in levels after CDP treatment and riboflavin, L-Threonine, Thiamine, L-Leucine, and Adenosine showed improved expression after Sa B treatment. CONCLUSION: CDP and Sa B have been shown to alleviate high-fat diet-induced hypercholesterolemia by activating the PPAR pathway and improving hepatic lipid metabolism. Our study demonstrated, for the first time, the complex mechanism of CDP, Sa B in the treatment of hypercholesterolemia at the protein and metabolic levels and provided a new reference that could elucidate the pharmacological effects of traditional Chinese medicine on hypercholesterolemia from multiple perspectives.

Asunto(s)

Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Hipercolesterolemia , Metabolómica , Farmacología en Red , Ratas Sprague-Dawley , Salvia miltiorrhiza , Animales , Hipercolesterolemia/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Cromatografía Líquida de Alta Presión , Salvia miltiorrhiza/química , Ratas , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Canfanos , Panax notoginseng

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Carbopalladation-initiated cascade reaction involving 1,4-Pd migration is a straightforward and powerful approach to activate remote C─H bond, forging versatile fused polycyclic compounds containing fluorene fragment which are highly valuable synthetic targets. However, its asymmetric variants pose considerable challenges and have not been explored. Here the first asymmetric palladium-catalyzed tandem carbopalladation is reported, 1,4-Pd migration reaction of ortho-iodophenol-derived allyl ether under mild conditions, allowing the transformation of a wide range of substrates in good to excellent enantioselectivities, and providing a facile and straight forward access to tetracyclic dihydroindeno[1,2,3-de]chromene bearing a chiral fluorene skeleton. A good functional group tolerance, high stereoselectivity, as well as the good chiroptical properties (high fluorescence quantum yields, circular dichroism) of the products make this approach highly attractive. Moreover, density functional theory (DFT) calculations indicate that the protonation of five-membered palladacycle intermediate is more favorable rather than its direct reductive elimination process.

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Background: We aimed to use lactate dehydrogenase (LDH) as a marker of inflammation burden and quantify post-stroke inflammation's direct and indirect effect on functional disability. Methods: We analyzed 5,129 patients with acute ischemic stroke (AIS) admitted to Shenyang First People's Hospital. Stroke recurrence and functional outcome measured by the modified Rankin Scale (mRS) were assessed at 90 days. Functional disability was defined as mRS score > 2. Receiver operating characteristic curve and restricted cubic spline (RCS) analysis were conducted to illustrate the associations between LDH levels and 90-day functional outcomes in patients with AIS. Mediation analyses were performed to examine the potential causal chain in which stroke recurrence may mediate the relationship between LDH and functional outcome. Positive correlation between LDH and hs-CRP was found and mediation effects of stroke recurrence in the association between LDH or hs-CRP and functional disability were both less than 20%. Sensitivity analyses in different subgroups showed comparable results. Results: Among 5,129 included AIS patients, the median (IQR) level of LDH was 186 (161-204.4) U/L. Functional disability was seen in 1200 (23.4%) patients and recurrence was observed in 371(7.2%) patients at 90-day follow-up. Each standard deviation increase in the concentration of LDH was linked to an increased risk of functional disability (adjusted odds ratio[aOR], 1.07; 95%CI,1.04-1.09) and stroke recurrence (aOR,1.02; 95%CI, 1.01-1.04) within 90 days. The highest quartile of LDH (>204.2 U/L) had an elevated risk of suffering functional disability (aOR, 1.21; 95%CI, 1.00-1.47) and recurrence (aOR, 1.21; 95%CI,1.00-1.47) compared with the lowest quartile of LDH (<161 U/L). Stroke recurrence during follow-up explained 12.90% (95%CI, 6.22-21.16%) of the relationship between LDH and functional disability. Positive correlation between LDH and hs-CRP was found and mediation effects of recurrence in the association between LDH or hs-CRP and functional disability were both less than 20%. Sensitivity analyses in different subgroups showed comparable results. Conclusion: The relationship between LDH and functional disability at 90 days among AIS patients is partially mediated by stroke recurrence, accounting for less than 20%. LDH deserves equal attention as hs-CRP in predicting recurrence and functional outcome. In addition to traditional secondary prevention measures, innovative anti-inflammatory strategies warrant further investigation.

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The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.

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East Asian herbivorous waterfowl intensively use farmland in spring, next to their natural habitat. Accordingly, they might have expanded their migration strategy from merely tracking the green wave of newly emerging vegetation to also incorporating the availability of post-harvest agricultural seeds (here dubbed the seed wave). However, if and how waterfowl use multiple food resources to time their seasonal migration is still unknown. We test this migration strategy using 167 spring migration tracks of five East Asian herbivorous waterfowl species and mixed-effect resource selection function models. We found that all study species arrived at their core stopover sites in the Northeast China Plain after agricultural seeds became available, extended their stay after spring vegetation emerged and arrived at their breeding sites around the emergence of vegetation. At the core stopover sites, all study species used snowmelt as a cue to track seed availability, although smaller-bodied species tended to arrive later. At the breeding sites, swans tracked the onset of vegetation emergence and geese tracked the mid- or end phases of snowmelt. Our findings suggest that waterfowl track multiple resource waves to fine-tune their migration, highlighting new opportunities for conservation.

Asunto(s)

Migración Animal , Anseriformes , Herbivoria , Estaciones del Año , Animales , Anseriformes/fisiología , China , Gansos/fisiología , Ecosistema

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Ionizing radiation (IR)-induced intestinal injury remains a major limiting factor in abdominal radiation therapy, and its pathogenesis remains unclear. In this study, mouse models of IR-induced intestinal injury were established, and the effect of IR on nuclear factor erythroid 2-related factor 2 (Nrf2) was determined. More severe IR-induced intestinal damage was observed in Nrf2 knockout (KO) mice than in wild-type mice. Then, the negative regulation of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling by Nrf2 was examined both in vivo and in vitro after IR. This was accompanied by alterations in the intestinal neutrophil and macrophage populations in mice. Subsequently, the effect of the cGAS/STING pathway on the intestinal toxicity of IR was also investigated. Moreover, the downregulation of cGAS/STING by Nrf2 via its target gene, Pirin, was confirmed using transfection assays. A rescue experiment with Pirin was also conducted using adeno-associated virus in Nrf2 KO mice. Finally, the protective effect of calcitriol against IR-induced intestinal injury, along with increased Nrf2 and Pirin levels and decreased cGAS, pSTING, and interferon-beta levels, were observed. Taken together, our results suggest that Nrf2 alleviates IR-induced intestinal injury through Pirin-mediated inhibition of the innate immunity-related cGAS/STING pathway.

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Multivariate machine learning techniques are a promising set of tools for identifying complex brain-behavior associations. However, failure to replicate results from these methods across samples has hampered their clinical relevance. Here we aimed to delineate dimensions of brain functional connectivity that are associated with child psychiatric symptoms in two large and independent cohorts: the Adolescent Brain Cognitive Development (ABCD) Study and the Generation R Study (total n = 6935). Using sparse canonical correlations analysis, we identified two brain-behavior dimensions in ABCD: attention problems and aggression/rule-breaking behaviors. Importantly, out-of-sample generalizability of these dimensions was consistently observed in ABCD, suggesting robust multivariate brain-behavior associations. Despite this, out-of-study generalizability in Generation R was limited. These results highlight that the degrees of generalizability can vary depending on the external validation methods employed as well as the datasets used, emphasizing that biomarkers will remain elusive until models generalize better in true external settings.

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Cells contain intricate protein nanostructures, but replicating them outside of cells presents challenges. One such example is the vertical fibronectin pillars observed in embryos. Here, we demonstrate the creation of cell-free vertical fibronectin pillar mimics using nonequilibrium self-assembly. Our approach utilizes enzyme-responsive phosphopeptides that assemble into nanotubes. Enzyme action triggers shape changes in peptide assemblies, driving the vertical growth of protein nanopillars into bundles. These bundles, with peptide nanotubes serving as a template to remodel fibronectin, can then recruit collagen, which forms aggregates or bundles depending on their types. Nanopillar formation relies on enzyme-catalyzed nonequilibrium self-assembly and is governed by the concentrations of enzyme, protein, peptide, the structure of the peptide, and peptide assembly morphologies. Cryo-EM reveals unexpected nanotube thinning and packing after dephosphorylation, indicating a complex sculpting process during assembly. Our study demonstrates a cell-free method for constructing intricate, multiprotein nanostructures with directionality and composition.

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Merging traditional Chinese medicine's (TCM) principles of medicine-food homology with modern flavor chemistry, this research unveils PungentDB (http://www.pungentdb.org.cn/home), a database documenting 205 unique pungent flavor compounds from 231 TCMs. It provides detailed insights into their chemical attributes, biological targets (including IC50/EC50 values), and molecular structures (2D/3D), enriched with visualizations of target organ distribution and protein structures, exploring the pungent flavor space with the help of a feature-rich visual interface. This collection, derived from over 3249 sources and highlighting 9129 targets, delves into the compounds' unique pungent flavors-taste, aroma, and thermal sensations-and their interaction with taste and olfactory receptors. PungentDB bridges ancient wisdom and culinary innovation, offering a nuanced exploration of pungent flavors' role in enhancing food quality, safety, and sensory experiences. This initiative propels flavor chemistry forward, serving as a pivotal resource for food science advancement and the innovative application of pungent flavors.

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As a critical part of the circulatory system, blood vessels transport oxygen and nutrients to every corner of the body, nourishing each cell, and also remove waste and toxins. Defects in vascular development and function are closely associated with many diseases, such as heart disease, stroke, and atherosclerosis. In the nervous system, the nervous and vascular systems are intricately connected in both development and function. First, peripheral blood vessels and nerves exhibit parallel distribution patterns. In the central nervous system (CNS), nerves and blood vessels form a complex interface known as the neurovascular unit. Second, the vascular system employs similar cellular and molecular mechanisms as the nervous system for its development. Third, the development and function of CNS vasculature are tightly regulated by CNS-specific signaling pathways and neural activity. Additionally, vascular endothelial cells within the CNS are tightly connected and interact with pericytes, astrocytes, neurons, and microglia to form the blood-brain barrier (BBB). The BBB strictly controls material exchanges between the blood and brain, maintaining the brain's microenvironmental homeostasis, which is crucial for the normal development and function of the CNS. Here, we comprehensively summarize research on neural regulation of vascular and BBB development and propose directions for future research.

Asunto(s)

Barrera Hematoencefálica , Humanos , Animales , Barrera Hematoencefálica/metabolismo , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/crecimiento & desarrollo , Neuronas/metabolismo , Células Endoteliales/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/crecimiento & desarrollo , Vasos Sanguíneos/fisiología , Transducción de Señal

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ETHNOPHARMACOLOGICAL RELEVANCE: Hepatic ischemia/reperfusion injury (HIRI) is a common occurrence during or after liver surgery, representing a major cause for postoperative complications or increased morbidity and mortality in liver diseases. Rehmanniae Radix Praeparata (RRP) is a traditional Chinese medicine frequently used and has garnered extensive attention for its therapeutic potential treating cardiovascular and hepatic ailments. Recent studies have indicated the possibility of RRP in regulating lipid accumulation and apoptosis in hepatocytes. AIM OF THE STUDY: This study aimed to investigate the specific mechanisms by which RRP may impede the progression of HIRI through the regulation of lipid metabolism. MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) was used to identify the major components of RRP water extract. C57BL/6J mice were orally given RRP at doses of 2.5 g/kg, 5 g/kg, and 10 g/kg for a duration of 7 days before undergoing HIRI surgery. Furthermore, we established a lipid-loaded in vitro model by exposing hepatocytes to oleic acid and palmitic acid (OAPA). The anti-HIRI effect of RRP was determined through transcriptomics and various molecular biology experiments. RESULTS: After identifying active ingredients in RRP, we observed that RRP exerted lipid-lowering and hepatoprotective effects on HIRI mice and OAPA-treated hepatocytes. RRP activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR), which further on the one hand, inhibited the cleavage and activation of sterol regulatory element binding protein 2 (SREBP2) by limiting the movement of SREBPs cleavage-activating protein (SCAP)-SREBP2 complex with the help of endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) and insulin-induced gene 1 (INSIG1), and on the other hand, promoted liver X receptor α (LXRα) nuclear transportation and subsequent cholesterol efflux. Meanwhile, the anti-lipotoxic effect of RRP can be partly reversed by an LXRα inhibitor but largely blocked by the application of compound C, an AMPK inhibitor. CONCLUSION: Our study elucidated that RRP served as a potential AMPK activator to alleviate HIRI by blocking SREBP2 activation and cholesterol synthesis, while also activating LXRα to facilitate cholesterol efflux. These findings shed new light on the potential therapeutic use of RRP for improving HIRI.

Asunto(s)

Hepatocitos , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Extractos Vegetales , Rehmannia , Daño por Reperfusión , Animales , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Masculino , Rehmannia/química , Extractos Vegetales/farmacología , Ratones , Receptores X del Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Proteínas Quinasas Activadas por AMP/metabolismo , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismo

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Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.

Asunto(s)

Reparación de la Incompatibilidad de ADN , Linfoma de Células B Grandes Difuso , Microambiente Tumoral , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Reparación de la Incompatibilidad de ADN/genética , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Masculino , Femenino , Mutación , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Adulto , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo

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Purpose: To describe the anatomical and histological characteristics of the human MTL (meniscotibial ligament) that keeps the meniscus stable and are rarely discussed. Study design: Descriptive laboratory study. Methods: In total, six fresh-frozen adult cadaver knees were dissected, and the dissection protocol were designed by two experienced anatomy professors. The anatomical morphology of MTL was observed. The main anatomical specimens included meniscus, tibial plateau, MTL. The osteotome was used to excise the portion of the tibial plateau, which could obtain the complex including partial meniscus, MTL, and a tibial fragment. A histopathologic study was performed by two experienced pathologists. Results: Macroscopically, the MTL could be divided into two parts: medial meniscotibial ligament (MMTL)and lateral meniscotibial ligament (LMTL). The MMTL is distributed continuously, whereas the LMTL is discontinuous on the tibial plateau. The average length from the tibial attachment of the LMTL to the articular surface was 19 ± 1.0mm (mean ± SD). The average length from the tibial attachment of the MMTL to the articular surface was 10 ± 1.2 mm (mean ± SD). Microscopy of the MTL showed that the MTL is a ligamentous tissue, composed of a network of oriented collagenous fibers. Conclusions: In all knees, the MTL was inserted on the outer edge of the meniscus, attaching to the tibia below the level of articular cartilage, which was key to maintaining the rotational stability of knee and the meniscus in the physiological position on the tibial plateau. Histological analysis of this ligament demonstrated that the MTL is a veritable ligamentous structure, which is made up of collagen type I-expressing fibroblasts. Clinical relevance: This article contributes to the understanding of the anatomical and histological characteristics of the MTL. It is beneficial to promote the development of relevant surgical techniques for the MTL lesion.

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INTRODUCTION: The aim of the study was to examine alterations in visual acuity in patients with diabetic macular edema (DME), classified according to the TCED-HFV optical coherence tomography (OCT) system, following anti-vascular epithelial growth factor (VEGF) therapy. METHODS: The medical records of patients with DME receiving anti-VEGF therapy were retrospectively reviewed. Patients were divided into four groups according to the TCED-HFV OCT classification. Patient demographic and clinical characteristics and best-corrected visual acuity (BCVA) before and after treatment were compared among the groups. RESULTS: The BCVA before treatment was 0.49 ± 0.18, 0.81 ± 0.41, 0.83 ± 0.41, and 0.82 ± 0.49 in the early DME, advanced DME, severe DME, and atrophic maculopathy groups, respectively. The BCVA in the early DME group was therefore significantly lower than that in the other three groups (p = 0.042). After treatment, the BCVA improved to 0.15 ± 0.17, 0.52 ± 0.31, 0.62 ± 0.32, and 0.69 ± 0.47 in the early DME, advanced DME, severe DME, and atrophic maculopathy groups, respectively (p < 0.005). There were some differences among patients in the four groups in terms of the duration of diabetes, percentage of hemoglobin A1c, and duration of hypertension. CONCLUSION: The TCED-HFV OCT classification of patients with DME is exact and functional and can allow the severity of DME, and its response to anti-VEGF therapy, to be estimated.

Asunto(s)

Inhibidores de la Angiogénesis , Retinopatía Diabética , Inyecciones Intravítreas , Edema Macular , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Humanos , Tomografía de Coherencia Óptica/métodos , Edema Macular/tratamiento farmacológico , Edema Macular/clasificación , Edema Macular/diagnóstico , Edema Macular/etiología , Masculino , Estudios Retrospectivos , Femenino , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/clasificación , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/fisiopatología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Persona de Mediana Edad , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anciano , Ranibizumab/uso terapéutico , Ranibizumab/administración & dosificación , Mácula Lútea/patología , Mácula Lútea/diagnóstico por imagen , Bevacizumab/uso terapéutico , Estudios de Seguimiento , Angiografía con Fluoresceína/métodos , Resultado del Tratamiento

RESUMEN

Plastic waste pollution is the serious environmental problem, and catalytic pyrolysis of waste plastics is an effective way to solve this problem. Carbon nanotubes (CNTs) are prepared by catalytic pyrolysis of low-density polyethylene (LDPE) waste plastics by one-stage method using iron nitrate and nickel nitrate as catalyst. The growth mechanism of CNTs is analyzed in detail. TPO, XRD, SEM and Raman analyses show that increasing Ni content contributes to the production of CNTs with good morphology and high graphitization degree. While the increasing Fe content contributes to improving the yield of CNTs. The outer and inner diameters of the FeNi12-CNTs-800 are about 21 nm and 8 nm with the length of 18.9 µm, respectively. LDPE pyrolysis gases are analyzed to determine that the primary carbon source required for CNTs growth is C2H4. The C2H4 adsorption and decomposition processes on FeNi alloys are performed to reveal the growth mechanism of CNTs, based on density functional theory calculation. Three kinds of the growth models are proposed to explain the difference of the CNTs tubular shape. FeNi12-CNTs-800 are used to remove microplastics from wastewater due to existence of magnetic. PVC can be quickly removed from wastewater with removal of 100 % at 20 min. This study provides an effective way for recycling and treatment of waste plastic.

Asunto(s)

Nanotubos de Carbono , Plásticos , Pirólisis , Nanotubos de Carbono/química , Catálisis , Plásticos/química , Níquel/química , Polietileno/química , Reciclaje/métodos

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BACKGROUND: Apelin is an endogenous prepropeptide that regulates cardiac homeostasis and various physiological processes. Intravenous injection has been shown to improve cardiac contractility in patients with heart failure. However, its short half-life prevents studying its impact on left ventricular remodeling in the long term. Here, we aim to study whether microparticle-mediated slow release of apelin improves heart function and left ventricular remodeling in mice with myocardial infarction (MI). METHODS: A cardiac patch was fabricated by embedding apelin-containing microparticles in a fibrin gel scaffold. MI was induced via permanent ligation of the left anterior descending coronary artery in adult C57BL/6J mice followed by epicardial patch placement immediately after (acute MI) or 28 days (chronic MI) post-MI. Four groups were included in this study, namely sham, MI, MI plus empty microparticle-embedded patch treatment, and MI plus apelin-containing microparticle-embedded patch treatment. Cardiac function was assessed by transthoracic echocardiography. Cardiomyocyte morphology, apoptosis, and cardiac fibrosis were evaluated by histology. Cardioprotective pathways were determined by RNA sequencing, quantitative polymerase chain reaction, and Western blot. RESULTS: The level of endogenous apelin was largely reduced in the first 7 days after MI induction and it was normalized by day 28. Apelin-13 encapsulated in poly(lactic-co-glycolic acid) microparticles displayed a sustained release pattern for up to 28 days. Treatment with apelin-containing microparticle-embedded patch inhibited cardiac hypertrophy and reduced scar size in both acute and chronic MI models, which is associated with improved cardiac function. Data from cellular and molecular analyses showed that apelin inhibits the activation and proliferation of cardiac fibroblasts by preventing transforming growth factor-ß-mediated activation of Smad2/3 (supporessor of mothers against decapentaplegic 2/3) and downstream profibrotic gene expression. CONCLUSIONS: Poly(lactic-co-glycolic acid) microparticles prolonged the apelin release time in the mouse hearts. Epicardial delivery of the apelin-containing microparticle-embedded patch protects mice from both acute and chronic MI-induced cardiac dysfunction, inhibits cardiac fibrosis, and improves left ventricular remodeling.

Asunto(s)

Apelina , Ratones Endogámicos C57BL , Infarto del Miocardio , Animales , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Apelina/administración & dosificación , Apelina/metabolismo , Apelina/farmacología , Ratones , Masculino , Remodelación Ventricular/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Fibrosis , Modelos Animales de Enfermedad , Apoptosis/efectos de los fármacos

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The first step in blood testing necessitates blood separation to obtain an adequate volume of plasma. Traditional centrifugation is bulky, expensive and electricity-powered, which is not suitable for micro-scale blood plasma separation in point-of-care testing (POCT) cases. Microfluidic paper-based plasma separation devices present a promising alternative for plasma separation in such occasions. However, they are limited in terms of plasma yield, which hinders analyte detection. Herein, we proposed a humidity-enhanced paper-based microfluidic plasma separation method to address this issue. Specifically, paper was first treated by blood-typing antibodies, then samples of whole blood were introduced into the prepared paper. After waiting for 5 min for RBC agglutination and plasma wicking under high humidity, micro-scale plasma separation from whole blood was achieved. As a result, an extremely high plasma yield of up to 60.1% could be separated from whole blood through using Xuan-paper. Meanwhile, the purity of plasma could reach 99.99%. Finally, this innovative approach was effortlessly integrated into distance-based glucose concentration detection, enabling rapid determination of blood glucose levels through naked-eye observation. Considering the simplicity and inexpensiveness of this method, we believe that this technology could be integrated to more paper-based microfluidic analytical devices for rapid and accurate detection of plasma analytes in POCT.

Asunto(s)

Humedad , Técnicas Analíticas Microfluídicas , Papel , Humanos , Técnicas Analíticas Microfluídicas/instrumentación , Plasma/química , Dispositivos Laboratorio en un Chip , Glucemia/análisis , Diseño de Equipo , Pueblos del Este de Asia

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The evolution of hypervirulent and carbapenem-resistant Klebsiella pneumoniae can be categorized into three main patterns: the evolution of KL1/KL2-hvKp strains into CR-hvKp, the evolution of carbapenem-resistant K. pneumoniae (CRKp) strains into hv-CRKp, and the acquisition of hybrid plasmids carrying carbapenem resistance and virulence genes by classical K. pneumoniae (cKp). These strains are characterized by multi-drug resistance, high virulence, and high infectivity. Currently, there are no effective methods for treating and surveillance this pathogen. In addition, the continuous horizontal transfer and clonal spread of these bacteria under the pressure of hospital antibiotics have led to the emergence of more drug-resistant strains. This review discusses the evolution and distribution characteristics of hypervirulent and carbapenem-resistant K. pneumoniae, the mechanisms of carbapenem resistance and hypervirulence, risk factors for susceptibility, infection syndromes, treatment regimens, real-time surveillance and preventive control measures. It also outlines the resistance mechanisms of antimicrobial drugs used to treat this pathogen, providing insights for developing new drugs, combination therapies, and a "One Health" approach. Narrowing the scope of surveillance but intensifying implementation efforts is a viable solution. Monitoring of strains can be focused primarily on hospitals and urban wastewater treatment plants.

Asunto(s)

Antibacterianos , Carbapenémicos , Infecciones por Klebsiella , Klebsiella pneumoniae , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/patogenicidad , Humanos , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/tratamiento farmacológico , Virulencia , Carbapenémicos/farmacología , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Enterobacteriaceae Resistentes a los Carbapenémicos/patogenicidad , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Plásmidos/genética , Salud Pública , Salud Global , Factores de Virulencia/genética , Factores de Riesgo

RESUMEN

Although the molecular composition and architecture of synapses have been widely explored, much less is known about what genetic programs directly activate synaptic gene expression and how they are modulated. Here, using Caenorhabditis elegans dopaminergic neurons, we reveal that EGL-43/MECOM and FOS-1/FOS control an activity-dependent synaptogenesis program. Loss of either factor severely reduces presynaptic protein expression. Both factors bind directly to promoters of synaptic genes and act together with CUT homeobox transcription factors to activate transcription. egl-43 and fos-1 mutually promote each other's expression, and increasing the binding affinity of FOS-1 to the egl-43 locus results in increased presynaptic protein expression and synaptic function. EGL-43 regulates the expression of multiple transcription factors, including activity-regulated factors and developmental factors that define multiple aspects of dopaminergic identity. Together, we describe a robust genetic program underlying activity-regulated synapse formation during development.

Asunto(s)

Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Neuronas Dopaminérgicas , Neurogénesis , Sinapsis , Animales , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Sinapsis/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neurogénesis/fisiología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regulación del Desarrollo de la Expresión Génica