RESUMEN
Antibodies against N-methyl-D-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. Elucidating the structural basis of monoclonal antibody (mAb) binding to NMDARs would facilitate the development of targeted therapy for AE. Here, we reconstructed nanodiscs containing green fluorescent protein-fused NMDARs to label and sort individual immune B cells from persons with AE and further cloned and identified mAbs against NMDARs. This allowed cryo-electron microscopy analysis of NMDAR-Fab complexes, revealing that autoantibodies bind to the R1 lobe of the N-terminal domain of the GluN1 subunit. Small-angle X-ray scattering studies demonstrated NMDAR-mAb stoichiometry of 2:1 or 1:2, structurally suitable for mAb-induced clustering and endocytosis of NMDARs. Importantly, these mAbs reduced the surface NMDARs and NMDAR-mediated currents, without tonically affecting NMDAR channel gating. These structural and functional findings imply that the design of neutralizing antibody binding to the R1 lobe of NMDARs represents a potential therapy for AE treatment.
RESUMEN
OBJECTIVE: This study aimed to explore the potential causal relationship between intraocular pressure (IOP) and myopia. METHODS: The study included 3,459 patients who underwent corneal refractive surgery at our institution between 2021 and 2023. Preoperative data on IOP, spherical equivalent (SE), axial length (AL), and corneal thickness (CCT) were collected. The association between IOP and myopia was investigated through rank correlation analysis, and causal inference was examined using Mendelian randomization (MR) methods, including MR-Egger, weighted median, mode-based estimation, simple mode, and inverse variance weighted (IVW) approaches. Utilizing summary statistics from genome-wide association studies (GWAS), IOP was considered as the exposure, with myopia as the outcome variable. IVW method was employed for the primary analysis, supplemented by sensitivity analyses. RESULTS: Cross-sectional analysis revealed a non-significant association between corrected IOP (cIOP) and myopia (râ¯=â¯-0.019, Pâ¯=â¯0.12). MR analysis indicated a non-significant genetic causal relationship between cIOP and myopia under the IVW method (ORâ¯=â¯1.001; 95% CI [0.999-1.003], Pâ¯=â¯0.22), a finding corroborated in replication samples (ORâ¯=â¯0.98; 95% CI [0.96-1.00], Pâ¯=â¯0.099). CONCLUSION: This study did not find a direct causal link between IOP and the development of myopia. These findings challenge the traditional role attributed to IOP in the progression of myopia and highlight the complex, multifactorial process of myopia development. This provides a new perspective on understanding the intricate mechanisms behind myopia progression.
RESUMEN
Low-temperature and low-salt fermented Chinese kohlrabi (LSCK) represents a novel approach to producing low-salt kohlrabi without the need for desalination during processing, as compared to traditional techniques. However, the profile of its non-volatile metabolites remains unclear. In order to investigate the non-volatile metabolites and their changes in LSCK during fermentation, the LSCKs fermented for 0 day (0D), 45 days (45D) and 90 days (90D) were analyzed using LC-MS/MS non-targeted metabolomics coupled with multivariate statistical analysis. The results showed that 60, 74, and 68 differential metabolites were identified in the three groups A1 (0D and 45D), A2 (0D and 90D), and A3 (45D and 90D) (VIP >1, p < 0.05, Log2FC >1), respectively. The differential metabolites were mainly amino acids, peptides, and analogues, fatty acyls, organic acids and derivatives, and carbohydrates and carbohydrate conjugates. Seventeen common differential metabolites were identified in A1, A2, and A3 groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the alanine, aspartate and glutamate metabolism, butanoate metabolism, α-linolenic acid metabolism, arginine biosynthesis, and phenylalanine metabolism were significantly correlated with the differential metabolites. The present study elucidates for the first time the changes in non-volatile differential metabolites and their associated metabolic pathways in the novel Chinese low-salt kohlrabi, providing a theoretical basis for improving the industrial fermentation process of this innovative product.
RESUMEN
Simultaneous detection of the dynamic distribution of long-chain fatty acid ethyl esters (LCFAEEs) during Baijiu distillation is crucial for optimizing its flavor and health attributes. In this study, we synthesized a simple, cost-effective Fe3O4@NH2 adsorbent to simultaneously extract eight LCFAEEs from Baijiu. Through density functional theory and adsorption experiments, we elucidated 1,6-hexanediamine as a surface modifier, with the -NH2 groups providing adsorption sites for the LCFAEEs via hydrogen-bonding interactions and van der Waals forces. Additionally, we established the magnetic solid-phase extraction-GC-MS extraction technique combined with stable isotope dilution analysis to analyze LCFAEEs. This method revealed the dynamic distribution patterns of LCFAEEs during strong aroma-type Baijiu (SAB) distillation. We observed that the concentrations of the eight LCFAEEs gradually decreased with prolonged distillation and were significantly correlated with ethanol concentration. To ensure optimal flavor and clarity in SAB, it is recommended to select the heart-stage base Baijiu with an alcohol content of 58%-63%.
RESUMEN
BACKGROUND: Hepatic fibrosis is becoming an increasingly serious public health issue worldwide. Although liver transplantation is the only and definitive treatment for end-stage liver fibrosis, traditional Chinese medicine offers certain benefits in the treatment of advanced hepatic fibrosis. PURPOSE: This study aims to explore the protective effect of lithospermic acid (LA), an extraction from Salvia miltiorrhiza (the roots of S. miltiorrhiza Bunge, known as Danshen in Chinese), on liver fibrosis and investigate its potential mechanisms. METHODS AND RESULTS: Mice were treated with carbon tetrachloride (CCl4) via intraperitoneal injection for 4 weeks. LA was orally administered or colchicine (COL) was injected intraperitoneally for 3 weeks starting one week after the initial CCl4 injection. After the LA treatment, we observed a decrease in the fibrosis index and an improvement in liver function. Molecular docking results revealed that Piezo1 may be a potential pharmacological target of LA. The further experimental results showed that LA inhibited Piezo1 activation and expression in macrophages. Mechanistically, both Piezo1/Notch-mediated inflammation and oxidative stress regulated by the Piezo1/Ca2+ pathway were alleviated in fibrotic livers following LA treatment. Moreover, less oxidative stress and Notch activation were observed in the deficiency of macrophage Piezo1 (Piezo1ΔLysM) mice. In addition, Piezo1ΔLysM partially counteracted the pharmacological effects of LA on liver fibrosis. CONCLUSION: In conclusion, our present study corroborated LA limits the progression of liver fibrosis by regulating Piezo1-mediated oxidative stress and inflammation. These results indicate that LA could be a potential medication for hepatic fibrosis treatment.
RESUMEN
The ubiquitin-proteasome system (UPS), which involves E3 ligases and deubiquitinates (DUBs), is critical for protein homeostasis. The epigenetic reader ZMYND8 (zinc finger MYND-type containing 8) has emerged as an oncoprotein, and its protein levels are elevated in various types of cancer, including breast cancer. However, the mechanism by which ZMYND8 protein levels are increased in cancer remains elusive. Although ZMYND8 has been reported to be regulated by the E3 ligase FBXW7, it is still unknown whether ZMYND8 could be modulated by DUBs. Here, we identified USP7 (ubiquitin carboxyl-terminal hydrolase 7) as a bona fide DUB for ZMYND8. Mechanically, USP7 directly binds to the PBP (PHD-BRD-PWWP) domain of ZMYND8 via its TRAF (tumor necrosis factor receptor-associated factor) domain and UBL (ubiquitin-like) domain and removes F-box and WD repeat domain containing 7 (FBXW7)-catalyzed poly-ubiquitin chains on lysine residue 1034 (K1034) within ZMYND8, thereby stabilizing ZMYND8 and stimulating the transcription of ZMYND8 target genes ZEB1 (zinc finger E-box binding homeobox 1) and VEGFA (Vascular Endothelial Growth Factor A). Consequently, USP7 enhances the capacity of breast cancer cells for migration and invasion through antagonizing FBXW7-mediated ZMYND8 degradation. Importantly, the protein levels of USP7 positively correlates with those of ZMYND8 in breast cancer tissues. These findings delineate an important layer of migration and invasion regulation by the USP7-ZMYND8 axis in breast cancer cells.
RESUMEN
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is currently the only viable method of curing patients with acute myeloid leukaemia. In 30% to 50% of patients, donors and recipients have some level of ABO blood group incompatibility. ABO blood group incompatibility can cause antibodies against the donor's red blood cells to persist in the recipient's body, resulting in a delay of several months in the recovery of red blood cells. A number of different treatments have been reported for post-transplant pure red cell aplastic anaemia (PRCA), such as plasmapheresis, donor lymphocyte infusions, anti-thymocyte globulin, rituximab and steroids. CASE SUMMARY: A 41-year-old female diagnosed with acute myeloid leukaemia underwent peripheral blood allogeneic haematopoietic stem cell transplantation in November 2013 from an HLA matched unrelated donor. The donor was AB-positive and the recipient was O-positive. The patient was diagnosed with PRCA three months after receiving the donor stem cell transplant. After failing multiple lines of therapy, the patient applied for daratumumab. After receiving three doses of daratumumab, the patient developed a reticulocyte response and no longer required blood transfusions. CONCLUSION: The use of daratumumab anti-CD38 for the remove of plasma cells is safe and effective and may be tried for refractory patients with PRCA after undergoing allo-HSCT for ABO incompatibility.
RESUMEN
Despite advancements in chemotherapy and the availability of novel therapies, the outcome of adult patients with B-cell acute lymphoblastic leukemia (B-ALL) remains unsatisfactory. Therefore, it is necessary to understand the molecular mechanisms underlying the progression of B-ALL. Brahma-related gene 1 (BRG1) is a poor prognostic factor for multiple cancers. Here, the expression of BRG1 was found to be higher in patients with B-ALL, irrespective of the molecular subtype, than in healthy individuals, and its overexpression was associated with a poor prognosis. Upregulation of BRG1 accelerated cell cycle progression into the S phase, resulting in increased cell proliferation, whereas its downregulation facilitated the apoptosis of B-ALL cells. Mechanistically, BRG1 occupies the transcriptional activation site of PPP2R1A, thereby inhibiting its expression and activating the PI3K/AKT signaling pathway to regulate the proto-oncogenes c-Myc and BCL-2. Consistently, silencing of BRG1 and administration of PFI-3 (a specific inhibitor targeting BRG1) significantly inhibited the progression of leukemia and effectively prolonged survival in cell-derived xenograft mouse models of B-ALL. Altogether, this study demonstrates that BRG1-induced overactivation of the PPP2R1A/PI3K/AKT signaling pathway plays an important role in promoting the progression of B-ALL. Therefore, targeting BRG1 represents a promising strategy for the treatment of B-ALL in adults.
Asunto(s)
ADN Helicasas , Progresión de la Enfermedad , Proteínas Nucleares , Proteína Fosfatasa 2 , Factores de Transcripción , Animales , Femenino , Humanos , Masculino , Ratones , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN Helicasas/metabolismo , ADN Helicasas/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Transcripción Genética/efectos de los fármacosRESUMEN
BACKGROUND: Endothelial dysfunction (ED), characterized by markedly reduced nitric oxide (NO) bioavailability, vasoconstriction, and a shift toward a proinflammatory and prothrombotic state, is an important contributor to hypertension, atherosclerosis, and other cardiovascular diseases. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is widely involved in cardiovascular development. Przewaquinone A (PA), a lipophilic diterpene quinone extracted from Salvia przewalskii Maxim, inhibits vascular contraction. PURPOSE: Herein, the goal was to explore the protective effect of PA on ED in vivo and in vitro, as well as the underlying mechanisms. METHODS: A human umbilical vein endothelial cell (HUVEC) model of ED induced by angiotensin II (AngII) was used for in vitro observations. Levels of AMPK, endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO), and endothelin-1 (ET-1) were detected by western blotting and ELISA. A mouse model of hypertension was established by continuous infusion of AngII (1000 ng/kg/min) for 4 weeks using osmotic pumps. Following PA and/or valsartan administration, NO and ET-1 levels were measured. The levels of AMPK signaling-related proteins in the thoracic aorta were evaluated by immunohistochemistry. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured using the tail cuff method. Isolated aortic vascular tone measurements were used to evaluate the vasodilatory function in mice. Molecular docking, molecular dynamics, and surface plasmon resonance imaging (SPRi) were used to confirm AMPK and PA interactions. RESULTS: PA inhibited AngII-induced vasoconstriction and vascular adhesion as well as activated AMPK signaling in a dose-dependent manner. Moreover, PA markedly suppressed blood pressure, activated vasodilation in mice following AngII stimulation, and promoted the activation of AMPK signaling. Furthermore, molecular simulations and SPRi revealed that PA directly targeted AMPK. AMPK inhibition partly abolished the protective effects of PA against endothelial dysfunction. CONCLUSION: PA activates AMPK and ameliorates endothelial dysfunction during hypertension.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Angiotensina II , Endotelio Vascular , Células Endoteliales de la Vena Umbilical Humana , Hipertensión , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III , Óxido Nítrico , Angiotensina II/farmacología , Animales , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Hipertensión/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Óxido Nítrico/metabolismo , Ratones , Salvia/química , Endotelina-1/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Quinonas/farmacología , Simulación del Acoplamiento Molecular , Presión Sanguínea/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: The administration of tranexamic acid (TXA) during spinal surgery has been shown to reduce blood loss. However, the efficacy and safety of intravenous TXA (ivTXA) and topical TXA (tTXA) are poorly documented. The present meta-analysis aimed to compare the efficacy and safety of ivTXA and tTXA administration in spinal surgery. METHODS: Potentially relevant academic articles were identified from PubMed, Ovid, Cochrane Library, CNKI database, and Wanfang Data from the date of inception until March 1, 2024. Randomized controlled trials (RCTs) and nonrandomized controlled trials (non-RCTs) were included in our meta-analysis if they compared the efficacy and safety of ivTXA versus tTXA administration during spinal surgery. Secondary sources were identified from the references of the included literature. The meta-analysis was performed in accordance with the guidelines of the Cochrane Reviewer's Handbook and the PRISMA statement. Data were summarized using RevMan 5.3 software from Denmark. RESULTS: Four RCTs and one non-RCT met our inclusion criteria. The pooled outcomes demonstrated that ivTXA groups compared with tTXA groups had significantly less amount of total blood loss [weighted mean difference (WMD)=-159.55, 95% CI (-181.91,-137.19), P < 0.00001], hidden blood loss [WMD=-132.27, 95% CI (-159.81, -104.72), P < 0.00001], intraoperative blood loss [WMD=-86.22, 95% CI (-99.13, -73.31), P < 0.00001, I2 = 96%], and more high postoperative hemoglobin level [WMD = 8.96, 95% CI (5.18, 12.75), P < 0.00001, I2 = 29%], and less transfusion rate [risk ratio (RR) = 1.11, 95% CI (0.81,1.52), P = 0.50, I2 = 94%]. The pooled results showed no significant difference in thromboembolic events (deep venous thrombosis and pulmonary embolism) between the two groups. CONCLUSION: Our meta-analysis demonstrated that ivTXA was more effective than tTXA in inducing hemostatic effect during spinal surgery. However, the risk of a thrombotic event was not different between the two administration methods of TXA. More high quality RCTs are needed to further confirm our conclusions.
Asunto(s)
Administración Intravenosa , Administración Tópica , Antifibrinolíticos , Pérdida de Sangre Quirúrgica , Ácido Tranexámico , Humanos , Administración Intravenosa/efectos adversos , Antifibrinolíticos/administración & dosificación , Antifibrinolíticos/efectos adversos , Pérdida de Sangre Quirúrgica/prevención & control , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto , Columna Vertebral/cirugía , Ácido Tranexámico/administración & dosificación , Ácido Tranexámico/efectos adversos , Resultado del TratamientoRESUMEN
Therapeutic options for addressing inflammatory bowel disease (IBD) include the administration of an enema to reduce intestinal inflammation and alleviate associated symptoms. However, uncontrollable retention of enemas in the intestinal tract has posed a long-term challenge for improving their therapeutic efficacy and safety. Herein we have developed a protease-labile hydrogel system as an on-demand enema vehicle with tunable degradation and drug release rates in response to varying matrix metalloproteinase-9 (MMP-9) expression. The system, composed of three tailored hydrogel networks, is crosslinked by poly (ethylene glycol) (PEG) with 2-, 4- and 8-arms through dynamic hydrazone bonds to confer injectability and generate varying network connectivity. The retention time of the hydrogels can be tuned from 12 to 36 h in the intestine due to their different degradation behaviors induced by MMP-9. The drug-releasing rate of the hydrogels can be controlled from 0.0003 mg/h to 0.278 mg/h. In addition, injection of such hydrogels in vivo resulted in significant differences in therapeutic effects including MMP-9 consumption, colon tissue repair, reduced collagen deposition, and decreased macrophage cells, for treating a mouse model of acute colitis. Among them, GP-8/5-ASA exhibits the best performance. This study validates the effectiveness of the tailored design of hydrogel architecture in response to pathological microenvironment cues, representing a promising strategy for on-demand therapy of IBD. STATEMENT OF SIGNIFICANCE: The uncontrollable retention of enemas at the delivery site poses a long-term challenge for improving therapeutic efficacy in IBD patients. MMP-9 is highly expressed in IBD and correlates with disease severity. Therefore, an MMP-9-responsive GP hydrogel system was developed as an enema by linking multi-armed PEG and gelatin through hydrazone bonds. This forms a dynamic hydrogel characterized by in situ gelation, injectability, enhanced bio-adhesion, biocompatibility, controlled retention time, and regulated drug release. GP hydrogels encapsulating 5-ASA significantly improved the intestinal phenotype of acute IBD and demonstrated notable therapeutic differences with increasing PEG arms. This method represents a promising on-demand IBD therapy strategy and provides insights into treating diseases of varying severities using endogenous stimulus-responsive drug delivery systems.
Asunto(s)
Hidrogeles , Enfermedades Inflamatorias del Intestino , Metaloproteinasa 9 de la Matriz , Hidrogeles/química , Hidrogeles/farmacología , Animales , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/patología , Polietilenglicoles/química , Ratones Endogámicos C57BL , Colitis/tratamiento farmacológico , Colitis/patologíaRESUMEN
OBJECTIVE: To analyze the relational factors influencing the formation of cauda equina redundant nerve roots (RNRs) of the lumbar spinal stenosis. METHODS: Clinical data of 116 patients with lumbar spinal stenosis treated from January 2016 to June 2019 were retrospectively analyzed. The patients were divided into redundant nerve roots(RNRs) group and non-RNRs group based on the presence or absence of RNRs on sagittal T2-weighted MRI. In the non-RNRs group, there were 74 patients, including 38 males and 36 females with an average age of (62.00±10.41) years old, the body mass index (BMI) was (23.09±2.22) kg·m-2;the maximum stenosis segment was L2-L3 in 12 cases, L3-L4 in 38, L4-L5 in 20, and L5S1 in 4, respectively. In the RNRs group, there were 42 patients, including 18 males and 24 females with an average age of (63.36±8.73) years old, the BMI was (22.63±2.60) kg·m-2;the maximum stenosis segment was L2-L3 in 3 cases, L3-L4 in 9, L4-L5 in 27 and L5S1 in 3, respectively. MRI was performed in the supine position to observe the conshape and morphology of the redundant nerve in the sagittal position. The preoperative low back and leg pain visual analogue scale(VAS), and preoperative Oswestry disability index(ODI) were analyzed, and the rate of spondylolisthesis and ligamentum flavum hypertrophy were compared. Simultaneously, the inter-vertebral height, intervertebral foramen height, inter-vertebral height+vertebral height, median sagittal diameter at the inter-vertebral space level(DIW-MSD), median sagittal diameter at the pedicel level(DV-MSD), range of motion(ROM) of the stenotic segment were measured and analyzed. RESULTS: Among the 116 patients with lumbar spinal stenosis, 42 patients developed RNRs, with an incidence of 36.2%. There were no significant differences in gender, age, BMI, preoperative VAS for lumbar and leg pain and ODI between two groups(P>0.05). There were statistically significant differences regard to the duration of symptoms and the rate of spondylolisthesis and ligamentum flavum hypertrophy (P<0.05);the inter-vertebral height, intervertebral foramen height, inter-vertebral height+vertebral height, DIW-MSD, ROM of the stenotic segment were also significantly different between two groups(P<0.05). However, there was no significant difference in DV-MSD between two groups(P>0.05). CONCLUSION: The inter-vertebral height, inter-vertebral foramen height, inter-vertebral height+vertebral height, DIW-MSD and ROM of the stenotic segment were the crucial factors related to RNRs in lumbar spinal stenosis.
Asunto(s)
Cauda Equina , Vértebras Lumbares , Estenosis Espinal , Humanos , Estenosis Espinal/diagnóstico por imagen , Femenino , Masculino , Persona de Mediana Edad , Vértebras Lumbares/diagnóstico por imagen , Cauda Equina/diagnóstico por imagen , Anciano , Estudios Retrospectivos , Imagen por Resonancia MagnéticaRESUMEN
Adipose tissue, an indispensable organ, fulfils the pivotal role of energy storage and metabolism and is instrumental in maintaining the dynamic equilibrium of energy and health of the organism. Adipocyte hypertrophy and adipocyte hyperplasia (adipogenesis) are the two primary mechanisms of fat deposition. Mature adipocytes are obtained by differentiating mesenchymal stem cells into preadipocytes and redifferentiation. However, the mechanisms orchestrating adipogenesis remain unclear. Autophagy, an alternative cell death pathway that sustains intracellular energy homeostasis through the degradation of cellular components, is implicated in regulating adipogenesis. Furthermore, adipose tissue functions as an endocrine organ, producing various cytokines, and certain inflammatory factors, in turn, modulate autophagy and adipogenesis. Additionally, autophagy influences intracellular redox homeostasis by regulating reactive oxygen species, which play pivotal roles in adipogenesis. There is a growing interest in exploring the involvement of autophagy, inflammation, and oxidative stress in adipogenesis. The present manuscript reviews the impact of autophagy, oxidative stress, and inflammation on the regulation of adipogenesis and, for the first time, discusses their interactions during adipogenesis. An integrated analysis of the role of autophagy, inflammation and oxidative stress will contribute to elucidating the mechanisms of adipogenesis and expediting the exploration of molecular targets for treating obesity-related metabolic disorders.
Asunto(s)
Adipogénesis , Autofagia , Inflamación , Estrés Oxidativo , Adipogénesis/fisiología , Humanos , Autofagia/fisiología , Estrés Oxidativo/fisiología , Inflamación/metabolismo , Inflamación/patología , Animales , Adipocitos/metabolismo , Adipocitos/patología , Obesidad/metabolismo , Obesidad/patología , Tejido Adiposo/metabolismo , Tejido Adiposo/patologíaRESUMEN
The study determined the impacts of dietary fermented residues' (FBR) inclusion on growth, nutrient utilization, carcass characteristics, and meat properties in fattening pigs. Seventy-two robust pigs were randomly assigned to two experimental groups (Duroc × Landrace × Yorkshire, thirty-six pigs each). Each group was subjected to a 52-day trial, during which they received either a corn-soybean meal-based diet or diet enhanced with a 10% addition of FBR. Consequently, adding 10% FBR caused a significant decrease in the digestive utilization of crude dietary components in fattening pigs (p < 0.05) but showed no significant impact on the growth performance. Additionally, FBR inclusion increased the marbling scores (p < 0.05) and total antioxidant functions (p < 0.05) of muscle tissues, indicating improved meat quality. Gender affected backfat depth, with barrows showing thicker backfat depth. In conclusion, dietary supplementation with 10% FBR in finishing pigs influenced the meat quality by improving the marbling score and antioxidant performance while reducing digestibility without compromising growth performance.
RESUMEN
Introduction: Granulocytic myeloid-derived suppressor cells (G-MDSCs) show fast recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) constituting the major part of peripheral blood in the early phase. Although G-MDSCs mediate immune suppression through multiple mechanisms, they may also promote inflammation under specific conditions. Methods: G-MDSCs were isolated from 82 patients following allo-HSCT within 90 days after allo-HSCT, and their interactions with autologous CD3+ T-cells were examined. T-cell proliferation was assessed by flow cytometry following CFSE staining, while differentiation and interferon-γ secretion were characterized using chemokine receptor profiling and ELISpot assays, respectively. NK cell cytotoxicity was evaluated through co-culture with K562 cells. An aGVHD xenogeneic model in humanized mice was employed to study the in vivo effects of human leukocytes. Furthermore, transcriptional alterations in G-MDSCs were analyzed via RNA sequencing to investigate functional transitions. Results: G-MDSCs promoted inflammation in the early-stage, by facilitating cytokine secretion and proliferation of T cells, as well as their differentiation into pro-inflammatory T helper subsets. At day 28, patients with a higher number of G-MDSCs exhibited an increased risk of developing grades II-IV aGvHD. Besides, adoptive transfer of G-MDSCs from patients at day 28 into humanized mice exacerbated aGvHD. However, at day 90, G-MDSCs led to immunosuppression, characterized by upregulated expression of indoleamine 2,3-dioxygenase gene and interleukin-10 secretion, coupled with the inhibition of T cell proliferation. Furthermore, transcriptional analysis of G-MDSCs at day 28 and day 90 revealed that 1445 genes were differentially expressed. These genes were associated with various pathways, revealing the molecular signatures of early post-transplant differentiation in G-MDSCs. In addition, genes linked to the endoplasmic reticulum stress were upregulated in patients without aGvHD. The acquisition of immunosuppressive function by G-MDSCs may depend on the activation of CXCL2 and DERL1 genes. Conclusion: Our findings revealed the alteration in the immune characteristics of G-MDSCs within the first 90 days post-allo-HSCT. Moreover, the quantity of G-MDSCs at day 28 may serve as a predictive indicator for the development of aGvHD.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Células Supresoras de Origen Mieloide , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Animales , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Ratones , Femenino , Masculino , Adulto , Persona de Mediana Edad , Antígenos HLA-DR/metabolismo , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/genética , Enfermedad Injerto contra Huésped/inmunología , Inflamación/inmunología , Adulto Joven , Granulocitos/inmunología , Granulocitos/metabolismo , Adolescente , Antígeno CD11b/metabolismo , Antígeno CD11b/inmunologíaRESUMEN
The lone pair electrons in the electronic structure of molecules have been a prominent research focus in chemistry for more than a century. Stable s2lone pair electrons significantly influence material properties, including thermoelectric properties, nonlinear optical properties, ferroelectricity, and electro(photo)catalysis.While major advances have been achieved in understanding the influence of lone pair electrons on material characteristics, research on this effect in organic-inorganic hybrid materials is in its initial stage. In this work, we successfully obtained a novel organic-inorganic hybrid material incorporating Ge with 4s2 lone pair electrons, (MeHDabco)2[GeBr3]4-H2O (MeHDabco = N-methyl-1,4-diazabicyclo[2.2.2]octane) (1). Driven by the stereochemically active lone pair electrons on the Ge2+, 1 crystallizes in the noncentrosymmetric space group P21 at room temperature and exhibits good second harmonic generation (SHG) responses. Interestingly, 1 also shows electrocatalytic activity for the hydrogen evolution reaction due to the existence of lone pair electrons on Ge2+ cations. The electrochemical experiment combined with the DFT calculations revealed the lone pair electrons act as both an active site for proton adsorption and facilitate the ionization of water. This work not only emphasizes the important role of lone pair electrons in material properties and functions but also provides new insight for designing novel Ge-based hybrid materials.
RESUMEN
To investigate the role of miR-223-3p in the modulatory effect of paeonol (Pae) on high glucose (HG)-induced endothelial cell apoptosis. HG (25 mmol/L) was used to induce cellular damage and apoptosis in the mouse cardiac microvascular endothelial cells (MCMECs). Various concentration of Pae was tested and 60 µmol/L Pae was selected for the subsequent studies. MCMECs were transfected with exogenous miR-223-3p mimics or anti-miR-223-3p inhibitors. Cell viability was assessed by MTT assay and apoptosis was quantified by flow cytometry. The expression of miR-223-3p and NLRP3 mRNA was measured using real-time quantitative RT-PCR, and protein level of NLRP3 and apoptosis-related proteins was detected by immunoblotting. Pae significantly attenuated HG-induced apoptosis of MCMECs in a concentration-dependent manner. In addition, Pae (60 µmol/L) significantly reversed HG-induced down-regulation of miR-223-3p and up-regulation of NLRP3. Pae (60 µmol/L) also significantly blocked HG-induced up-regulation of Bax and Caspase-3 as well as down-regulation of Bcl-2. Moreover, exogenous miR-223-3p mimics not only significantly attenuated HG-induced apoptosis, but also significantly suppressed NRLP-3 and pro-apoptotic proteins in the MCMECs. In contrast, transfection of exogenous miR-223-3p inhibitors into the MCMECs resulted in not only significantly increased apoptosis of the cells, but also significant suppression of NLRP3 and pro-apoptotic proteins in the cells. Pae attenuated HG-induced apoptosis of MCMECs in a concentration-dependent manner. MiR-223-3p may mediate the modulatory effects of Pae on MCMEC survival or apoptosis through targeting NLRP3 and regulating apoptosis-associated proteins.
Asunto(s)
Acetofenonas , Apoptosis , Células Endoteliales , Glucosa , MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Apoptosis/efectos de los fármacos , Ratones , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Glucosa/farmacología , Acetofenonas/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Regulación hacia Arriba/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Microvasos/citología , Microvasos/metabolismo , Microvasos/efectos de los fármacosRESUMEN
OBJECTIVE: Bladder outlet obstruction (BOO) results in significant fibrosis in the chronic stage and elevated bladder pressure. Piezo1 is a type of mechanosensitive (MS) channel that directly responds to mechanical stimuli. To identify new targets for intervention in the treatment of BOO-induced fibrosis, this study investigated the impact of high hydrostatic pressure (HHP) on Piezo1 activity and the progression of bladder fibrosis. METHODS: Immunofluorescence staining was conducted to assess the protein abundance of Piezo1 in fibroblasts from obstructed rat bladders. Bladder fibroblasts were cultured under normal atmospheric conditions (0 cmH2O) or exposed to HHP (50 cmH2O or 100 cmH2O). Agonists or inhibitors of Piezo1, YAP1, and ROCK1 were used to determine the underlying mechanism. RESULTS: The Piezo1 protein levels in fibroblasts from the obstructed bladder exhibited an elevation compared to the control group. HHP significantly promoted the expression of various pro-fibrotic factors and induced proliferation of fibroblasts. Additionally, the protein expression levels of Piezo1, YAP1, ROCK1 were elevated, and calcium influx was increased as the pressure increased. These effects were attenuated by the Piezo1 inhibitor Dooku1. The Piezo1 activator Yoda1 induced the expression of pro-fibrotic factors and the proliferation of fibroblasts, and elevated the protein levels of YAP1 and ROCK1 under normal atmospheric conditions in vitro. However, these effects could be partially inhibited by YAP1 or ROCK inhibitors. CONCLUSION: The study suggests that HHP may exacerbate bladder fibrosis through activating Piezo1.
Asunto(s)
Fibroblastos , Fibrosis , Presión Hidrostática , Vejiga Urinaria , Proteínas Señalizadoras YAP , Quinasas Asociadas a rho , Animales , Vejiga Urinaria/patología , Vejiga Urinaria/metabolismo , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/genética , Ratas , Fibroblastos/metabolismo , Fibroblastos/patología , Proteínas Señalizadoras YAP/metabolismo , Canales Iónicos/metabolismo , Canales Iónicos/genética , Obstrucción del Cuello de la Vejiga Urinaria/metabolismo , Obstrucción del Cuello de la Vejiga Urinaria/patología , Obstrucción del Cuello de la Vejiga Urinaria/genética , Proliferación Celular , Ratas Sprague-Dawley , Mecanotransducción Celular , Células Cultivadas , Femenino , Pirazinas , TiadiazolesRESUMEN
B-cell acute lymphoblastic leukemia (B-ALL) is a malignant blood disorder, particularly detrimental to children and adolescents, with recurrent or unresponsive cases contributing significantly to cancer-associated fatalities. IKBKE, associated with innate immunity, tumor promotion, and drug resistance, remains poorly understood in the context of B-ALL. Thus, this research aimed to explore the impact of the IKBKE inhibitor MCCK1 on B-ALL cells. The study encompassed diverse experiments, including clinical samples, in vitro and in vivo investigations. Quantitative real-time fluorescence PCR and protein blotting revealed heightened IKBKE mRNA and protein expression in B-ALL patients. Subsequent in vitro experiments with B-ALL cell lines demonstrated that MCCK1 treatment resulted in reduced cell viability and survival rates, with flow cytometry indicating cell cycle arrest. In vivo experiments using B-ALL mouse tumor models substantiated MCCK1's efficacy in impeding tumor proliferation. These findings collectively suggest that IKBKE, found to be elevated in B-ALL patients, may serve as a promising drug target, with MCCK1 demonstrating potential for inducing apoptosis in B-ALL cells both in vitro and in vivo.
Asunto(s)
Apoptosis , Proliferación Celular , Quinasa I-kappa B , Animales , Humanos , Ratones , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Supervivencia Celular/efectos de los fármacos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Niño , Adolescente , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Renal fibrosis is the common pathway in the progression of chronic kidney disease (CKD). Acyloxyacyl hydrolase (AOAH) is expressed in various phagocytes and is highly expressed in proximal tubular epithelial cells (PTECs). Research shows that AOAH plays a critical role in infections and chronic inflammatory diseases, although its role in kidney injury is unknown. Here, we found that AOAH deletion led to exacerbated kidney injury and fibrosis after folic acid (FA) administration, which was reversed by overexpression of Aoah in kidneys. ScRNA-seq revealed that Aoah-/- mice exhibited increased subpopulation of CD74+ PTECs, though the percentage of total PTECs were decreased compared to WT mice after FA treatment. Additionally, exacerbated kidney injury and fibrosis seen in Aoah-/- mice was attenuated via administration of methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage inhibition factor (MIF) and CD74 binding. Finally, AOAH expression was found positively correlated with estimated glomerular filtration rate while negatively correlated with the degree of renal fibrosis in kidneys of CKD patients. Thus, our work indicates that AOAH protects against kidney injury and fibrosis by inhibiting renal tubular epithelial cells CD74 signaling pathways. Targeting kidney AOAH represents a promising strategy to prevent renal fibrosis progression.