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AIM: We aimed to explore the impact of DNA methylation alterations on the DNA damage response (DDR) in melanoma prognosis and immunity. MATERIAL & METHODS: Different melanoma cohorts with molecular and clinical data were included. RESULTS: Hierarchical clustering utilizing different combinations of DDR-relevant CpGs yielded distinct melanoma subtypes, which were characteristic of different prognoses, transcriptional function profiles of DDR, and immunity and immunotherapy responses but were associated with similar tumor mutation burdens. We then constructed and validated a clinically applicable 4-CpG risk-score signature for predicting survival and immunotherapy response. CONCLUSION: Our study describes the close interrelationship among DNA methylation, DDR machinery, local tumor immune status, melanoma prognosis, and immunotherapy response.
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Daño del ADN , Metilación de ADN , Melanoma , Melanoma/genética , Melanoma/inmunología , Melanoma/mortalidad , Humanos , Pronóstico , Inmunoterapia/métodos , Islas de CpG , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Regulación Neoplásica de la Expresión Génica/inmunología , MutaciónRESUMEN
The study aimed to investigating the mechanisms of relieved intestinal barrier damage by dynamic high-pressure microfluidization assisted with galactooligosaccharide- glycated whey protein isolate. The modifications changed the multi-structure, and the modified whey protein isolate could promote the proliferation of IEC-6 cells and contributed to the restoration of LPS-induced occludin damage in IEC-6 cells. Also, it could repair cyclophosphamide-induced ileal villus rupture and crypt destruction in BALB/c mice, significantly altered the abundance of dominant bacteria, which were associated with propionic acid, butyric acid, isovaleric acid, and valeric acid. Ileum transcriptomics revealed that the modified whey protein isolate significantly regulate of the levels of Cstad, Cyp11a1, and Hs6st2 genes, relating to the increase of propionic acid, isovaleric acid, and valeric acid. In conclusion, galactooligosaccharide- modified whey protein isolate could regulate the level of Cstad, Cyp11a1 and Hs6st2 genes by altering the gut microbial structure and the level of SCFAs, thereby repairing the intestinal barrier.
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Phototherapy has emerged as a potential treatment strategy for bacteria-infected wounds, but the inadequate bacteria-capturing ability and excessive damage to normal tissues from single phototherapy are huge limitations. To solve the issues, herein we report the design of chitosan-based hydrogel with bacteria capturing and combined photothermal/photodynamic sterilization functions. Such hydrogel is prepared by mixing chitosan (CS) as matrix, protoporphyrin (PpIX) as photosensitizer and polydopamine (PDA) as photothermal agent and then chemically cross-linking CS with glutaraldehyde. The resulting CS-PpIX-PDA hydrogel possesses a porous architecture (average pore porosity = 60.9 %), excellent swelling capabilities (swelling ratio = 1855 %) and rheological property (G' > Gâ³). The hydrogel can effectively produce reactive oxygen species (ROS) under 660 nm light irradiation due to the photodynamic effect of PpIX. Owing to the presence of PDA, the hydrogel displays a photoabsorption range between 600 and 1500 nm and can generate maximal temperature of 60 °C within 10 min under 808 nm laser illumination (0.6 W/cm2) through photothermal effect. Besides, under synergetic illumination of 808/660 nm laser, CS-PpIX-PDA hydrogel can induce the death of 99.9999 % of E. coli and 99.99999 % of S. aureus. Importantly, when coated on the wound site, the hydrogel exhibits a remarkable bacteria-trapping ability due to its porous structure and the presence of amino groups on chitosan. Under the excitation of 660/808 nm, the combined photothermal and photodynamic effects can effectively eradicate bacteria. Simultaneously, the hydrogel also demonstrates anti-inflammatory properties and upregulates Heat Shock Protein 90 (HSP90) expression, thereby promoting collagen deposition and facilitating wound healing. Therefore, the study may provide some new insights into the development of multifunctional hydrogel for photothermal-oxidation sterilization of bacteria-infected wound therapy.
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Background: Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain. Methods: This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques. Results: The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements. Conclusion: Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.
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Background: Emergency medicine (EM) is a growing specialty both clinically and academically. Academic EM development can be measured by number of scientific publications. This study aimed to evaluate the academic international cooperation trend of Taiwan emergency departments (EDs) in the past two decades using social network analysis (SNA). Methods: The study population were publications with first author affiliated with Taiwan EDs and the study duration was publication year before 2021. The enrolled publications were categorized into two groups: Group one, all authors were affiliated with Taiwan (domestic publications) and Group two, authors were affiliated with Taiwan and other countries (international publications). The primary outcome measurement was the degree centrality of Taiwan before 2021. The secondary outcome measurements included the trend in annual publication number of Group one and Group two, the trend in country number of each year in Group two, the top five countries that collaborate with Taiwan, the difference between the median of citation numbers in Group one and Group two, and the difference between the median of author numbers in Group one and Group two. Results: A total 4,363 publications were enrolled, of which 4,046 publications were classified in Group one and 317 publications were in Group two. The annual publication number of both groups increased significantly. The annual country number of collaboration with Taiwan ED publications had also significantly increased. The median of citation number and author number in Group two were both significantly higher than Group one. The top five countries collaborating with Taiwan were the United States, China, Malaysia, Japan, and Australia. Conclusions: Taiwan EDs' growing international collaboration in the past two decades indicated a capacity to conduct multi-country research. International collaboration publications obtained higher citations compared to domestic publications. Researchers should enhance international collaborations for academic advancement.
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The effect of whey protein isolate (WPI)- galacto-oligosaccharides (GOS)/fructo-oligosaccharides (FOS) conjugates on RAW264.7 cells, and further the effect of WPI-GOS conjugates on CTX-induced immunosuppressed mice were investigated. Compared to WPI-FOS conjugates, WPI-GOS conjugates exhibited deeper glycation extent, more pronounced structural unfolding and helix-destabilizing, and obviously improved functional indicators of RAW264.7 macrophages. In addition, WPI-GOS conjugates also repaired immune organ and intestinal barrier and increased IL-1ß and IFN-γ levels in immunosuppressed mice. The alteration of gut microbiota induced by WPI-GOS conjugates changed the serum metabolites, causing the activation of NFκB pathway, which strengthens the immune system. The activation of NFκB pathway maybe associated with the mTOR signal pathway and ABC transporters. However, the precise mechanisms by which NFκB pathway interacts with mTOR signal pathway and ABC transporters to modulate the immune response need for further research.
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Ciclofosfamida , FN-kappa B , Oligosacáridos , Proteína de Suero de Leche , Animales , Ratones , Ciclofosfamida/farmacología , Oligosacáridos/farmacología , Oligosacáridos/química , Proteína de Suero de Leche/química , Proteína de Suero de Leche/farmacología , Células RAW 264.7 , FN-kappa B/metabolismo , Terapia de Inmunosupresión , Microbioma Gastrointestinal/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Masculino , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
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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Juvenile myelomonocytic leukemia (JMML), a clonal hematologic malignancy, originates from mutated hematopoietic stem cells (HSCs). The mechanism sustaining the persistence of mutant stem cells, leading to leukemia development, remains elusive. In this study, we conducted comprehensive examination of gene expression profiles, transcriptional factor regulons, and cell compositions/interactions throughout various stages of tumor cell development in Ptpn11 mutation-associated JMML. Our analyses revealed that leukemia-initiating Ptpn11 E76K/+ mutant stem cells exhibited de novo activation of the myeloid transcriptional program and aberrant developmental trajectories. These mutant stem cells displayed significantly elevated expression of innate immunity-associated anti-microbial peptides and pro-inflammatory proteins, particularly S100a9 and S100a8. Biological experiments confirmed that S100a9/S100a8 conferred a selective advantage to the leukemia-initiating cells through autocrine effects and facilitated immune evasion by recruiting and promoting immune suppressive myeloid-derived suppressor cells (MDSCs) in the microenvironment. Importantly, pharmacological inhibition of S100a9/S100a8 signaling effectively impeded leukemia development from Ptpn11 E76K/+ mutant stem cells. These findings collectively suggest that JMML tumor-initiating cells exploit evolutionarily conserved innate immune and inflammatory mechanisms to establish clonal dominance.
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Heavy metal poisoning of soil from oil spills causes serious environmental problems worldwide. Various causes and effects of heavy metal pollution in the soil environment are discussed in this article. In addition, this study explores new approaches to cleaning up soil that has been contaminated with heavy metals as a result of oil spills. Furthermore, it provides a thorough analysis of recent developments in remediation methods, such as novel nano-based approaches, chemical amendments, bioremediation, and phytoremediation. The objective of this review is to provide a comprehensive overview of the removal of heavy metals from oil-contaminated soils. This review emphasizes on the integration of various approaches and the development of hybrid approaches that combine various remediation techniques in a synergistic way to improve sustainability and efficacy. The study places a strong emphasis on each remediation strategy that can be applied in the real-world circumstances while critically evaluating its effectiveness, drawbacks, and environmental repercussions. Additionally, it discusses the processes that reduce heavy metal toxicity and improve soil health, taking into account elements like interactions between plants and microbes, bioavailability, and pollutant uptake pathways. Furthermore, the current study suggests that more research and development is needed in this area, particularly to overcome current barriers, improve our understanding of underlying mechanisms, and investigate cutting-edge ideas that have the potential to completely transform the heavy metal clean up industry.
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Biodegradación Ambiental , Metales Pesados , Contaminación por Petróleo , Contaminantes del Suelo , Restauración y Remediación Ambiental/métodos , Suelo/químicaRESUMEN
mRNA delivery systems, such as lipid nanoparticle (LNP), have made remarkable strides in improving mRNA expression, whereas immune system activation operates on a threshold. Maintaining a delicate balance between antigen expression and dendritic cell (DC) activation is vital for effective immune recognition. Here, a water-in-oil-in-water (w/o/w) Pickering emulsion stabilized with calcium phosphate nanoparticles (CaP-PME) is developed for mRNA delivery in cancer vaccination. CaP-PME efficiently transports mRNA into the cytoplasm, induces pro-inflammatory responses and activates DCs by disrupting intracellular calcium/potassium ions balance. Unlike LNP, CaP-PME demonstrates a preference for DCs, enhancing their activation and migration to lymph nodes. It elicits interferon-γ-mediated CD8+ T cell responses and promotes NK cell proliferation and activation, leading to evident NK cells infiltration and ameliorated tumor microenvironment. The prepared w/o/w Pickering emulsion demonstrates superior anti-tumor effects in E.G7 and B16-OVA tumor models, offering promising prospects as an enhanced mRNA delivery vehicle for cancer vaccinations.
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Fosfatos de Calcio , Vacunas contra el Cáncer , Células Dendríticas , Emulsiones , Células Asesinas Naturales , Ratones Endogámicos C57BL , Nanopartículas , ARN Mensajero , Animales , Células Dendríticas/inmunología , Células Asesinas Naturales/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Fosfatos de Calcio/química , Nanopartículas/química , Nanopartículas/administración & dosificación , ARN Mensajero/administración & dosificación , Femenino , Línea Celular Tumoral , Ratones , Neoplasias/terapia , Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/terapiaRESUMEN
We prepared the ß-lactoglobulin (BLG)-ferulic acid (FA)-glucose (Glu) conjugates by alkaline method and Maillard reaction to assess the allergenicity. FA and Glu can form a ternary covalent conjugate with BLG, as evidenced by the shortening of SEC retention time, upward migration of SDS-PAGE protein bands, considerable decrease in free amino and sulfhydryl content, and changes in multistructure. BLG-Glu-FA conjugates weakly bound to immunoglobulin E in allergic sera was weak, reduced interleukin 4 and tumor necrosis factor α levels in RBL-2H3 cells and histamin and interleukin 6 secretion levels in KU812 cells, and inhibited the nuclear factor-κB signaling pathway. In vivo experiments showed that the conjugates regulated T-cell homeostasis in mouse splenic and mesenteric lymphocytes and attenuated splenic and duodenal immune injury. Therefore, the conjugates of BLG with FA combined with Glu altered the epitope structure and exhibited low allergenicity.
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Alérgenos , Ácidos Cumáricos , Glucosa , Lactoglobulinas , Animales , Lactoglobulinas/química , Lactoglobulinas/inmunología , Ratones , Ácidos Cumáricos/química , Humanos , Alérgenos/inmunología , Alérgenos/química , Glucosa/química , Inmunoglobulina E/inmunología , Ratones Endogámicos BALB C , Femenino , BovinosRESUMEN
We herein report the facile synthesis of two helical carbon nanorings with small ring sizes, cyclo[6]paraphenylene-1,5-naphthylene ([6]CPPNap1,5), and cyclo[6]paraphenylene-1,5-anthrylene ([6]CPPAn1,5). The structures were determined by NMR and HR-MS. X-ray single-crystal data of [6]CPPNap1,5 was also achieved. The strain energy and racemization processes were investigated by DFT calculations. The reduced ring sizes result in increased ring strain and elevated energy barriers. The photophysical properties were studied by UV-Vis absorption, fluorescence emission, and time-resolved fluorescence decay.
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PURPOSE: Nowadays, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for treating metastatic breast cancer and have achieved inspiring curative effects. But some discoveries have indicated that CDK 4/6 are not the requisite factors in some cell types because CDK2 partly compensates for the inhibition of CDK4/6. Thus, it is urgent to design CDK2/4/6 inhibitors for significantly enhancing their potency. This study aims to explore the mechanism of the binding of CDK2/4/6 kinases and their inhibitors to design novel CDK2/4/6 inhibitors for significantly enhancing their potency in different kinds of cancers. MATERIALS AND METHODS: A series of 72 disparately functionalized 4-substituted N-phenylpyrimidin-2-amine derivatives exhibiting potent inhibitor activities against CDK2, CDK4 and CDK6 were collected to apply to this research. The total set of these derivatives was divided into a training set (54 compounds) and a test set (18 compounds). The derivatives were constructed through the sketch molecule module in SYBYL 6.9 software. A Powell gradient algorithm and Tripos force field were used to calculate the minimal structural energy and the minimized structure was used as the initial conformation for molecular docking. By the means of 3D-QSAR models, partial least squares (PLS) analysis, molecular dynamics (MD) simulations and binding free energy calculations, we can find the relationship between structure and biological activity. RESULTS: In this study, we used molecular docking, 3D-QSAR and molecular dynamics simulation methods to comprehensively analyze the interaction and structure-activity relationships of 72 new CDK2/4/6 inhibitors. We used detailed statistical data to reasonably verify the constructed 3D-QSAR models for three receptors (q2 of CDK2 = 0.714, R2pred = 0.764, q2 = 0.815; R2pred of CDK4 = 0.681, q2 = 0.757; R2pred of CDK6 = 0.674). MD simulations and decomposition energy analysis validated the reasonability of the docking results and identified polar interactions as crucial factors that influence the different bioactivities of the studied inhibitors of CDK2/4/6 receptors, especially the electrostatic interactions of Lys33/35/43 and Asp145/158/163. The nonpolar interaction with Ile10/12/19 was also critical for the differing potencies of the CDK2/4/6 inhibitors. We concluded that the following probably enhanced the bioactivity against CDK2/4/6 kinases: (1) electronegative groups at the N1-position and electropositive and moderate-sized groups at ring E; (2) electrogroups featured at R2; (3) carbon atoms at the X-position or ring C replaced by a benzene ring; and (4) an electrogroup as R4. CONCLUSION: Previous studies, to our knowledge, only utilized a single approach of 3D-QSAR and did not integrate this method with other sophisticated techniques such as molecular dynamics simulations to discover new potential inhibitors of CDK2, CDK4, or CDK6. So we applied the intergenerational technology, such as 3D-QSAR technology, molecular docking simulation techniques, molecular dynamics simulations and MMPBSA19/MMGBSA20-binding free energy calculations to statistically explore the correlations between the structure with biological activities. The constructed 3D-QSAR models of the three receptors were reasonable and confirmed by the excellent statistical data. We hope the results obtained from this work will provide some useful references for the development of novel CDK2/4/6 inhibitors.
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Quinasa 2 Dependiente de la Ciclina , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/química , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/química , Humanos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/química , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad CuantitativaRESUMEN
To explore the molecular pathogenesis of pulmonary arterial hypertension (PAH) and identify potential therapeutic targets, we performed transcriptome sequencing of lung tissue from mice with hypoxia-induced pulmonary hypertension. Our Gene Ontology analysis revealed that "extracellular matrix organization" ranked high in the biological process category, and matrix metallopeptidases (MMPs) and other proteases also played important roles in it. Moreover, compared with those in the normoxia group, we confirmed that MMPs expression was upregulated in the hypoxia group, while the hub gene Timp1 was downregulated. Crocin, a natural MMP inhibitor, was found to reduce inflammation, decrease MMPs levels, increase Timp1 expression levels, and attenuate hypoxia-induced pulmonary hypertension in mice. In addition, analysis of the cell distribution of MMPs and Timp1 in the human lung cell atlas using single-cell RNAseq datasets revealed that MMPs and Timp1 are mainly expressed in a population of fibroblasts. Moreover, in vitro experiments revealed that crocin significantly inhibited myofibroblast proliferation, migration, and extracellular matrix deposition. Furthermore, we demonstrated that crocin inhibited TGF-ß1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-ß1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-ß1-induced myofibroblast activation.
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Carotenoides , Hipertensión Pulmonar , Hipoxia , Metaloproteinasa 2 de la Matriz , Inhibidor Tisular de Metaloproteinasa-1 , Animales , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Ratones , Hipoxia/metabolismo , Hipoxia/complicaciones , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Carotenoides/farmacología , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Masculino , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Modelos Animales de Enfermedad , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos C57BL , Proteína smad3/metabolismo , Movimiento Celular/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Pulmón/efectos de los fármacosRESUMEN
Limited knowledge is available about the association between autistic spectrum disorder (ASD) and precocious puberty. Our study examined the association between the two medical conditions and effect modification by sex and neuropsychiatric comorbidities in a nationwide population. To compare the risk of precocious puberty between ASD and non-ASD cases, we conducted a Cox regression analysis using ASD as the exposure and time to precocious puberty as the outcome. We adjusted for sex, attention-deficit/hyperactivity disorder (ADHD), tic disorder, obsessive-compulsive disorder (OCD), anxiety disorder, intellectual disability, and epilepsy. We performed a moderation analysis to examine the potential moderating effects of sex and comorbidities. Patients with ASD were prone to have precocious puberty, with an adjusted hazard ratio (aHR) of 1.80 (95% CI: 1.61-2.01). For effect modification, sex, specifically females, moderated the association between ASD and precocious puberty, with a relative excess risk due to interaction (RERI) of 7.35 (95% CI 4.90-9.80). No significant effect modification was found for any of the comorbidities within the scope of additive effect modification. We found that patients with ASD were prone to precocious puberty, regardless of sex or comorbid neuropsychiatric disorders. Girls with ASD are at a particularly higher risk of developing precocious puberty.
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Venous/arterial thrombosis poses significant threats to human health. However, drug-enabled thrombolysis treatment often encounters challenges such as short half-life and low bioavailability. To address these issues, the design of erythrocyte-membrane (EM) camouflaged nanocapsules (USIO/UK@EM) incorporating ultra-small iron oxide (USIO) and urokinase (UK) drug, which exhibits remarkable photothermal/magnetothermal effects and drug delivery ability for venous/arterial thrombolysis, is reported. USIO, UK, and EM are coextruded to fabricate USIO/UK@EM with average sizes of 103.7 nm. As USIO/UK@EM possesses wide photoabsorption and good magnetic properties, its solution demonstrates a temperature increase to 41.8-42.9 °C within 5 min when exposed to an 808 nm laser (0.33 mW cm-2) or alternating magnetic field (AMF). Such photothermal/magnetothermal effect along with UK confers impressive thrombolytic rates of 82.4% and 74.2%, higher than that (≈15%) achieved by UK alone. Further, the EM coating extends the circulating half-life (t1/2 = 3.28 h). When USIO/UK@EM is administered to mice and rabbits, tail vein thrombus in mice and femoral artery thrombus in rabbits can be dissolved by the synergetic effect of thermothrombolysis and UK. Therefore, this study not only offers insights into the rational design of multifunctional biomimetic nanocapsules but also showcases a promising thrombolysis strategy utilizing nanomedicine.
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Membrana Eritrocítica , Nanocápsulas , Terapia Trombolítica , Activador de Plasminógeno de Tipo Uroquinasa , Animales , Nanocápsulas/química , Membrana Eritrocítica/química , Ratones , Terapia Trombolítica/métodos , Activador de Plasminógeno de Tipo Uroquinasa/química , Conejos , Trombosis , Compuestos Férricos/química , HumanosRESUMEN
BACKGROUND: Antibody-mediated rejection (AMR) often leads to chronic kidney allograft damage and is a critical cause of allograft failure. The Banff classification, used to diagnose AMR, has become complex and challenging for clinicians. A Banff-based histologic chronicity index (CI) was recently proposed as a simplified prognostic indicator. Its reliability and reproducibility have not been externally validated. METHODS: This study investigated 71 kidney allograft biopsies diagnosed with AMR. Interobserver reproducibility of the recently proposed CI and its components (cg, cv, ct, and ci) were assessed. The association between CI and allograft failure was analyzed, and CI cut-off values were evaluated by Cox proportional hazards regression and Kaplan-Meier estimator with log-rank test. RESULTS: The study confirmed the association of CI with allograft failure, but also revealed that the assessment of CI varied between pathologists, impacting its reproducibility as a prognostic tool. Only 49 (69.0%) of the biopsies showed complete agreement on the proposed cut-off value of CI < 4 or CI ≥ 4. Furthermore, this cut-off did not reliably stratify allograft failure. Notably, the cg score, which carries significant weight in the CI calculation, had the lowest agreement between observers (kappa = .281). CONCLUSIONS: While a simplified prognostic indicator for AMR is needed, this study highlights the limitations of CI, particularly its poor interobserver reproducibility. Our findings suggest that clinicians should interpret CI cautiously and consider establishing their own cut-off values. This study underscores the need to address interobserver reproducibility before CI can be widely adopted for AMR management.
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Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Riñón , Variaciones Dependientes del Observador , Humanos , Rechazo de Injerto/patología , Rechazo de Injerto/etiología , Rechazo de Injerto/diagnóstico , Femenino , Masculino , Pronóstico , Persona de Mediana Edad , Estudios de Seguimiento , Reproducibilidad de los Resultados , Adulto , Factores de Riesgo , Estudios Retrospectivos , Tasa de Filtración Glomerular , Complicaciones Posoperatorias , Pruebas de Función RenalRESUMEN
A novel strategy combining ferulic acid and glucose was proposed to reduce ß-lactoglobulin (BLG) allergenicity and investigate whether the reduction in allergenicity was associated with gut microbiome and serum metabolism. As a result, the multistructure of BLG changed, and the modified BLG decreased significantly the contents of IgE, IgG, IgG1, and mMCP-1 in serum, improved the diversity and structural composition of gut microbiota, and increased the content of short-chain fatty acids (SCFAs) in allergic mice. Meanwhile, allergic mice induced by BLG affected arachidonic acid, tryptophan, and other metabolic pathways in serum, the modified BLG inhibited the production of metabolites in arachidonic acid metabolism pathway and significantly increased tryptophan metabolites, and this contribution helps in reducing BLG allergenicity. Overall, reduced allergenicity of BLG after ferulic acid was combined with glucose modification by regulating gut microbiota, the metabolic pathways of arachidonic acid and tryptophan. The results may offer new thoughts alleviating the allergy risk of allergenic proteins.
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Alérgenos , Ácidos Cumáricos , Microbioma Gastrointestinal , Glucosa , Lactoglobulinas , Ácidos Cumáricos/metabolismo , Ácidos Cumáricos/química , Animales , Lactoglobulinas/inmunología , Lactoglobulinas/química , Lactoglobulinas/metabolismo , Ratones , Humanos , Alérgenos/inmunología , Alérgenos/química , Alérgenos/metabolismo , Glucosa/metabolismo , Femenino , Bacterias/inmunología , Bacterias/metabolismo , Bacterias/clasificación , Bacterias/genética , Ratones Endogámicos BALB C , Inmunoglobulina E/inmunología , Inmunoglobulina E/sangre , Ácidos Grasos Volátiles/metabolismo , Bovinos , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Hipersensibilidad a la Leche/inmunologíaRESUMEN
Free phosphaborenes have a labile boron-phosphorus double bond and therefore require extensive steric shielding by bulky substituents to prevent isomerisation and oligomerisation. In the present work, the small free phosphaborene F2B-P[double bond, length as m-dash]BF was isolated by matrix-isolation techniques and was characterised by infrared spectroscopy in conjunction with quantum-chemical methods. In contrast to its sterically hindered relatives, this small phosphaborene exhibits an acute BPB angle of 83° at the CCSD(T) level. An alternative orbital structure for the B[double bond, length as m-dash]P double bond is found in the triradical B[double bond, length as m-dash]PF3, the direct adduct of laser-ablated atomic B and PF3. The single-bonded isomer F2B-PF and the dimer F3P-B[triple bond, length as m-dash]B-PF3 are also tentatively assigned.
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PURPOSE: This study analyzes the relationship between human papillomavirus (HPV) infection, vaginal microecology, and cervical lesions to provide a basis for the prevention and treatment of cervical cancer (CC) in the Xinjiang region. METHODS: Real-time quantitative PCR was used for HPV genotyping and viral load. The Gram staining and dry biochemical enzyme kit were utilized to diagnose vaginal secretions. The χ2 test and Logistic regression analysis were used for statistical analysis. RESULTS: The HPV infection rate among women in the Xinjiang region was 30.29%, of which the single HPV infection accounts for 77%. HPV16 and HPV52 were the main infection types. There was significant differences in the HPV infection rate and infection types among the Han, Uighur, Hui, and Kazakh ethnic groups. The viral load of HPV16 and HPV52 increases with the upgrade of cervical lesions. There were significant differences in vaginal microecology evaluation indicators H2O2, SNA, LE, GUS, trichomonas, clue cells, and lactobacilli among different ethnic groups. HPV negative patients with varying grades of cervical lesions exhibit a notable variance in H2O2 and LE, which is statistically significant. Single HPV infection and high viral load HPV significantly increase the risk of CC. CONCLUSIONS: This study indicates that HPV infection and vaginal microecology differ among ethnic groups, which have a strong correlation with the progression of CC, offering guidance on CC screening and interventions in the Xinjiang area.