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ADORA3 is mainly expressed in intestinal tract, and has the potential to promote the expression of mucin 2 (MUC2), the function-related factor of goblet cells, under asthma conditions. This study aims to confirm the induction and mechanisms of ADORA3 activation on goblet cells in ulcerative colitis (UC). A significant decrease in ADORA3 expression was found in mucosal biopsies from UC patients and in the colons of colitis mice. This reduction correlated negatively with disease severity and positively with goblet cell number. ADORA3 activation mitigated dextran sulfate sodium (DSS)-induced colitis and facilitated ATOH1-mediated goblet cell differentiation in both in vivo and in vitro. Metabolomics analysis unveiled that ADORA3 activation bolstered ketogenesis, leading to elevated levels of the metabolite BHB. Subsequently, BHB heightened the activity of HDAC1/2, augmenting histone acetylation at the H3K9ac site within the promoter region of the ATOH1 gene. Furthermore, the reason for ADORA3 activation to enhance ketogenesis was attributed to controlling the competitive binding among ß-arrestin2, SHP1 and PPARγ. This results in the non-ligand-dependent activation of PPARγ, thereby promoting the transcription of HMGCS2. The exact mechanisms by which ADORA3 promoted goblet cell differentiation and alleviated UC were elucidated using MRS1191 and shHMGCS2 plasmid. Collectively, ADORA3 activation promoted goblet cell differentiation and alleviated UC by enhancing ketogenesis via the "BHB-HDAC1/2-H3K9ac" pathway.
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As an increasingly well-known derivative of coumarin, daphnetin (7,8-dithydroxycoumarin) has demonstrated various pharmacological activities, including anti-inflammation, anti-cancer, anti-autoimmune diseases, antibacterial, organ protection, and neuroprotection properties. Various studies have been conducted to explore the action mechanisms and synthetic methods of daphnetin, given its therapeutic potential in clinical. Despite these initial insights, the precise mechanisms underlying the pharmacological activities of daphnetin remain largely unknown. In order to address this knowledge gap, we explore the molecular effects from the perspectives of signaling pathways, NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory factors; and try to find out how these mechanisms can be utilized to inform new combined therapeutic strategies.
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OBJECTIVES: Adverse cardiovascular events are the leading cause of death in peritoneal dialysis patients. Identifying indicators that can predict adverse cardiovascular events in these patients is crucial for prognosis. This study aims to assess the value of dual-specificity phosphatase 6 (DUSP6) in peripheral blood mononuclear cells as a predictor of adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy patients. METHODS: A total of 124 diabetic nephropathy patients underwent peritoneal dialysis treatment at the Department of Nephrology of the First Affiliated Hospital of Hebei North University from June to September 2022 were selected as study subjects. The levels of DUSP6 in peripheral blood mononuclear cells were determined using Western blotting. Patients were categorized into high-level and low-level DUSP6 groups based on the median DUSP6 level. Differences in body mass index, serum albumin, high-sensitivity C-reactive protein, and dialysis duration were compared between the 2 groups. Pearson, Spearman, and multiple linear regression analyses were performed to examine factors related to DUSP6. Patients were followed up to monitor the occurrence of adverse cardiovascular events, and risk factors for adverse cardiovascular events after peritoneal dialysis were analyzed using Kaplan-Meier and Cox regression. RESULTS: By the end of the follow-up, 33 (26.61%) patients had experienced at least one adverse cardiovascular event. The high-level DUSP6 group had higher body mass index, longer dialysis duration, and higher high-sensitivity C-reactive protein, but lower serum albumin levels compared to the low-level DUSP6 group (all P<0.05). DUSP6 was negatively correlated with serum albumin levels (r=-0.271, P=0.002) and positively correlated with dialysis duration (rs=0.406, P<0.001) and high-sensitivity C-reactive protein (rs=0.367, P<0.001). Multiple linear regression analysis revealed that dialysis duration and high-sensitivity C-reactive protein were independently correlated with DUSP6 levels (both P<0.05). The cumulative incidence of adverse cardiovascular events was higher in the high-level DUSP6 group than in the low-level DUSP6 group (46.67% vs 7.81%, P<0.001). Cox regression analysis indicated that low serum albumin levels (HR=0.836, 95% CI 0.778 to 0.899), high high-sensitivity C-reactive protein (HR=1.409, 95% CI 1.208 to 1.644), and high DUSP6 (HR=6.631, 95% CI 2.352 to 18.693) were independent risk factors for adverse cardiovascular events in peritoneal dialysis patients. CONCLUSIONS: Dialysis duration and high-sensitivity C-reactive protein are independently associated with DUSP6 levels in peripheral blood mononuclear cells of diabetic nephropathy patients undergoing peritoneal dialysis. High DUSP6 levels indicate a higher risk of adverse cardiovascular events.
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Enfermedades Cardiovasculares , Nefropatías Diabéticas , Fosfatasa 6 de Especificidad Dual , Leucocitos Mononucleares , Diálisis Peritoneal , Humanos , Diálisis Peritoneal/efectos adversos , Enfermedades Cardiovasculares/etiología , Nefropatías Diabéticas/sangre , Fosfatasa 6 de Especificidad Dual/genética , Femenino , Masculino , Leucocitos Mononucleares/metabolismo , Factores de Riesgo , Proteína C-Reactiva/metabolismo , Persona de Mediana Edad , Pronóstico , Albúmina Sérica/metabolismo , Albúmina Sérica/análisisRESUMEN
BACKGROUND: Acute graft-versus-host disease (aGVHD), which is mainly mediated by allogeneic T cells, is a decisive factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). Prophylaxis for aGVHD in clinical patients is unsatisfactory, and there is still a huge unmet need for novel approaches. Icariin (ICA) shows potent anti-inflammatory activity and suppresses T cell-mediated immune responses. Thus, ICA is a potential drug for the prevention of aGVHD. However, there is no data assessing the impact of ICA on aGVHD after allo-HCT. PURPOSE: This study aimed to investigate the protective effect of ICA against aGVHD and its mechanisms. Moreover, the impact of ICA on the graft-versus-leukemia (GVL) effect and engraftment of donor hematopoietic and immune cells were assessed. METHODS: Different murine models of allo-HCT were developed to study the influence of the ICA on GVHD and GVL effect. Flow cytometry was used to analyze the growth of leukemia cells, alterations in different immune cells, and apoptosis. Cell proliferation was determined using a CCK-8 assay. RNA sequencing and quantitative proteomic analysis were performed to elucidate the underlying mechanisms, which were further verified by polymerase chain reaction or functional experiments. RESULTS: Different concentrations of ICA exhibited opposite effects: low-concentration ICA promoted, while high concentrations suppressed the proliferation and function of T cells. A high dose of ICA administration during days +3 to +5 post-allo-HCT can alleviate murine aGVHD but does not affect the course of chronic GVHD (cGVHD), the GVL effect against both acute myeloid and lymphoblastic leukemia, or the recovery of donor hematological and immune cells. ICA extensively represses the expansion, function, and infiltration of donor alloreactive T cells, while preserving regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Quantitative proteomic analysis showed that downregulation of integrin-linked kinase (ILK) and lymphocyte cytosolic protein 2 (LCP2) expression was possibly associated with ICA-mediated aGVHD protective effects. Furthermore, an inhibitor of ILK, which can alleviate murine aGVHD administered early after allo-HCT. CONCLUSION: These findings suggest that the bioactivities of ICA are associated with its concentration and that ICA can effectively mitigate aGVHD without losing GVL activity or engraftment of donor hematopoietic and immune cells. Thus, ICA may be a promising drug for preventing aGVHD in clinical settings.
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Flavonoides , Enfermedad Injerto contra Huésped , Efecto Injerto vs Leucemia , Trasplante de Células Madre Hematopoyéticas , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Enfermedad Injerto contra Huésped/prevención & control , Animales , Flavonoides/farmacología , Efecto Injerto vs Leucemia/efectos de los fármacos , Ratones , Trasplante Homólogo , Modelos Animales de Enfermedad , Masculino , Femenino , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacosRESUMEN
INTRODUCTION: Although several estrogen receptor ß (ERß) agonists have been reported to alleviate IBD, the pivotal mechanism remains obscure. OBJECTIVES: To examine the effects and mechanisms of ERß activation on cytokine/chemokine networks in colitis mice. METHODS: Dextran sulfate sodium salt (DSS) and trinitro-benzene-sulfonic acid (TNBS) were used to induce mouse colitis model. Multiple molecular biological methods were employed to evaluate the severity of mouse colitis and the level of cytokine and/or chemokine. RESULTS: Bioinformatics analysis, ELISA and immunofluorescence results showed that the targeted cytokines and/or chemokines associated with ERß expression and activation is IL-1ß, and the anti-colitis effect of ERß activation was significantly attenuated by the overexpression of AAV9-IL-1ß. Immunofluorescence analysis indicated that ERß activation led to most evident downregulation of IL-1ß expression in colonic macrophages as compared to monocytes and neutrophils. Given the pivotal roles of NLRP3, NLRC4, and AIM2 inflammasome activation in the production of IL-1ß, we examined the influence of ERß activation on inflammasome activity. ELISA and WB results showed that ERß activation selectively blocked the NLRP3 inflammasome assembly-mediated IL-1ß secretion. The calcium-sensing receptor (CaSR) and calcium signaling play crucial roles in the assembly of the NLRP3 inflammasome. WB and immunofluorescence results showed that ERß activation reduced intracellular CaSR expression and calcium signaling in colonic macrophages. Combination with CaSR overexpression plasmid reversed the suppressive effect of ERß activation on NLRP3 inflammasome assembly, and counteracting the downregulation of IL-1ß secretion. CONCLUSION: Our research uncovers that the anti-colitis effect of ERß activation is accomplished through the reduction of IL-1ß levels in colonic tissue, achieved by specifically decreasing CaSR expression in macrophages to lower intracellular calcium levels and inhibit NLRP3 inflammasome assembly-mediated IL-1ß production.
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BACKGROUND AND PURPOSE: Silibinin is used to treat non-alcohol fatty liver disease (NAFLD) despite having rapid liver metabolism. Therefore, we investigated the role of the intestine in silibinin mechanism of action. EXPERIMENTAL APPROACH: NAFLD mice model was established by feeding them with a high-fat diet (HFD). Liver pathological were examined using H&E and oil red O staining. Tissue distribution of silibinin was detected by LC-MS/MS. SiRNA was employed for gene silencing and plasmid was used for gene overexpression. ChIP-qPCR assay was performed to detect the levels of histone acetylation. Recombinant adeno-associated virus 9-short hairpin-fibroblast growth factor (FGF)-15 and -farnesoid X receptor (FXR; NR1H4) were used to knockdown expression of FGF-15 and FXR. KEY RESULTS: Oral silibinin significantly reversed NAFLD in mice, although liver concentration was insufficient for reduction of lipid accumulation in hepatocytes. Among endogenous factors capable of reversing NAFLD, the expression of Fgf-15 was selectively up-regulated by silibinin in ileum and colon of mice. When intestinal expression of Fgf-15 was knocked down, protection of silibinin against lipid accumulation and injury of livers nearly disappeared. Silibinin could reduce activity of histone deacetylase 2 (HDAC2), enhance histone acetylation in the promoter region of FXR and consequently increase intestinal expression of FGF-15/19. CONCLUSION AND IMPLICATIONS: Oral silibinin selectively promotes expression of FGF-15/19 in ileum by enhancing transcription of FXR via reduction of HDAC2 activity, and FGF-15/19 enters into circulation to exert anti-NAFLD action. As the site of action is the intestine this would explain the discrepancy between pharmacodynamics and pharmacokinetics of silibinin.
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BACKGROUND AND PURPOSE: Ulcerative colitis (UC) is a refractory inflammatory disease associated with immune dysregulation. Elevated levels of heat shock protein (HSP) 90 in the ß but not α subtype were positively associated with disease status in UC patients. This study validated the possibility that pharmacological inhibition or reduction of HSP90ß would alleviate colitis, induced by dextran sulfate sodium, in mice and elucidated its mechanisms. EXPERIMENTAL APPROACH: Histopathological and biochemical analysis assessed disease severity, and bioinformatics and correlation analysis explained the association between the many immune cells and HSP90ß. Flow cytometry was used to analyse the homeostasis and transdifferentiation of Th17 and Treg cells. In vitro inhibition and adoptive transfer assays were used to investigate functions of the phenotypically transformed Th17 cells. Metabolomic analysis, DNA methylation detection and chromatin immunoprecipitation were used to explore these mechanisms. KEY RESULTS: The selective pharmacological inhibitor (HSP90ßi) and shHSP90ß significantly mitigated UC in mice and promoted transformation of Th17 to Treg cell phenotype, via Foxp3 transcription. The phenotypically-transformed Th17 cells by HSP90ßi or shHSP90ß were able to inhibit lymphocyte proliferation and colitis in mice. HSP90ßi and shHSP90ß selectively weakened glycolysis by stopping the direct association of HSP90ß and GLUT1, the key glucose transporter, to accelerate ubiquitination degradation of GLUT1, and enhance the methylation of Foxp3 CNS2 region. Then, the mediator path was identified as the "lactate-STAT5-TET2" cascade. CONCLUSION AND IMPLICATIONS: HSP90ß shapes the fate of Th17 cells via glycolysis-controlled methylation modification to affect UC progression, which provides a new therapeutic target for UC.
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Tripterygium wilfordii (TW) preparations have been utilized in China for treating rheumatoid arthritis and autoimmune diseases. However, their clinical use is limited due to reproductive toxicity, notably premature ovarian failure (POF). Our study aimed to investigate the effect and mechanism of bergenin in attenuating POF induced by triptolide in mice. POF was induced in female ICR mice via oral triptolide administration (50⯵g/kg) for 60 days. Mice received bergenin (25, 50, 100â¯mg/kg, i.g.) or estradiol valerate (EV) (0.1â¯mg/kg, i.g.) daily, 1â¯h before triptolide treatment. In vitro, ovarian granulosa cells (OGCs) were exposed to triptolide (100â¯nM) and bergenin (1, 3, 10⯵M). Antioxidant enzyme activity, protein expression, apoptosis rate, and reactive oxygen species (ROS) levels were assessed. The results showed that triptolide-treated mice exhibited evident atrophy, along with an increase in atretic follicles. Bergenin (50, 100â¯mg/kg) and EV (0.1â¯mg/kg), orally administered, exerted significant anti-POF effect. Bergenin and EV also decreased apoptosis in mouse ovaries. In vitro, bergenin (1, 3, 10⯵M) attenuated triptolide-induced OGCs apoptosis by reducing levels of apoptosis-related proteins. Additionally, bergenin reduced oxidative stress through downregulation of antioxidant enzymes activity and overall ROS levels. Moreover, the combined use with Sh-Nrf2 resulted in a reduced protection of bergenin against triptolide-induced apoptosis of OGCs. Together, bergenin counteracts triptolide-caused POF in mice by inhibiting Nrf2-mediated oxidative stress and preventing OGC apoptosis. Combining bergenin with TW preparations may effectively reduce the risk of POF.
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Antioxidantes , Apoptosis , Benzopiranos , Diterpenos , Compuestos Epoxi , Células de la Granulosa , Ratones Endogámicos ICR , Fenantrenos , Insuficiencia Ovárica Primaria , Especies Reactivas de Oxígeno , Animales , Femenino , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Insuficiencia Ovárica Primaria/prevención & control , Diterpenos/farmacología , Fenantrenos/toxicidad , Fenantrenos/farmacología , Compuestos Epoxi/toxicidad , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Células CultivadasRESUMEN
Intestinal fibrosis is a common complication of Crohn's disease and characterized by excessive extracellular matrix (ECM) deposition. The aryl hydrocarbon receptor (AhR) detects micronutrients and microbial metabolites in diet and can attenuate intestinal fibrosis with unclear mechanisms. In this study, AhR activation was demonstrated to downregulate the transcription of collagen I and fibronectin in a Sp1- but not Sp3- or AP-1-dependent manner. A suppressed fatty acid synthesis was highlighted using untargeted metabolomics analyses, and synthetic products, palmitic acid (PA), were used as the intermediary agent. After a screening study, fatty acid synthase (FASN) was identified as the main targeted protein, and AhR activation regulated "HDAC3-acetylation" signals but not glycosylation to enhance FASN degradation. Furthermore, results of bioinformatics analysis and others showed that after being activated, AhR targeted miR-193a-3p to control HDAC3 transcription. Collectively, AhR activation inhibited ECM deposition and alleviated intestinal fibrosis by limiting fatty acid synthesis subsequent to the inhibition of "miR-193a-3p-HDAC3-FASN" signals.
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Ácidos Grasos , Fibrosis , Histona Desacetilasas , Intestinos , MicroARNs , Receptores de Hidrocarburo de Aril , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , MicroARNs/genética , MicroARNs/metabolismo , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Ácidos Grasos/metabolismo , Fibrosis/metabolismo , Humanos , Animales , Ratones , Ratones Endogámicos C57BL , Masculino , Acido Graso Sintasa Tipo I/metabolismo , Acido Graso Sintasa Tipo I/genética , Mucosa Intestinal/metabolismo , Transducción de SeñalRESUMEN
The gut microbiota constitutes a vast ecological system within the human body, forming a mutually interdependent entity with the host. In recent years, advancements in molecular biology technologies have provided a clearer understanding of the role of the gut microbiota. They not only influence the local immune status and metabolic functions of the host's intestinal tract but also impact the functional transformation of hematopoietic stem cells (HSCs) through the gut-blood axis. In this review, we will discuss the role of the gut microbiota in influencing hematopoiesis. We analyze the interactions between HSCs and other cellular components, with a particular emphasis on the direct functional regulation of HSCs by the gut microbiota and their indirect influence through cellular components in the bone marrow microenvironment. Additionally, we propose potential control targets for signaling pathways triggered by the gut microbiota to regulate hematopoietic function, filling crucial knowledge gaps in the development of this research field.
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Microbioma Gastrointestinal , Hematopoyesis , Células Madre Hematopoyéticas , Hematopoyesis/fisiología , Microbioma Gastrointestinal/fisiología , Humanos , Células Madre Hematopoyéticas/microbiología , Animales , Transducción de Señal , Bacterias/metabolismo , Bacterias/clasificación , Bacterias/genética , Tracto Gastrointestinal/microbiología , Médula Ósea/microbiología , Médula Ósea/fisiologíaRESUMEN
PURPOSE: The performance of swing movement during spikes and serves plays a crucial role in determining the outcomes of volleyball matches. This study aims to explore the effects of the participation of the trunk and lower limbs' involvement on the velocity and power of the swing movement of adolescent male volleyball players, as well as the differences in power and velocity performance of the swing movement among different ages and specific positions. METHODS: The study involved 22 adolescent male volleyball players, with 11 high school students and 11 middle school students. The Kineo Globus equipment was used to assess the swing movement performance involving different segments, including arm swing movement only involving arm limb participation; upper swing movement involving trunk and arm limb participation; and whole body swing movement involving lower limb, trunk, and arm limb participation. The measured parameters included power and velocity performance levels. Before the test, each subject practiced three movement patterns twice. RESULTS: The study found that swing movement involving both the trunk and arm limbs had significantly higher average (F = 17.70, p < 0.001) and peak power performance (F = 31.47, p < 0.001), as well as in average (F = 9.14, p = 0.03) and peak velocity performance (F = 23.17, p < 0.001). There were no significant differences in average (F = 17.70; p = 0.46) and peak power (F = 31.47, p = 0.94), as well as in average (F = 9.14, p = 0.99) and peak velocity performance (F = 23.17, p = 0.90) between movements involving the whole body and those involving the trunk and upper limbs. Among different age groups, the swing movement performance of middle school athletes showed significant enhancements in both average (F = 9.20, p < 0.001) and peak power (F = 19.93, p < 0.001), as well as in average (F = 10.75, p < 0.001) and peak velocity (F = 34.35, p < 0.001) when arm swing with trunk involvement was compared to arm swing movement. High school athletes also showed significant improvements in peak velocity (F = 34.35, p < 0.001), peak power (F = 17.31, p < 0.001), and average power (F = 9.41, p < 0.001) during upper swing movements, except for average velocity performance (F = 1.56, p = 0.21), when compared to arm swing movement. The increase rate in average velocity performance of swing movements involving trunk participation was significantly higher in middle school athletes than in high school athletes (p < 0.001). Among athletes in specific positions, Middle Blocker (MB) players exhibited significantly better average power performance in swing movements involving trunk and arm limb participation compared to Outside Hitter (OH) players (p = 0.04). Furthermore, the rate of average (p = 0.01) and peak (p = 0.03) power change during upper swing movements involving lower limb participation was significantly higher among OH players than MB players. CONCLUSIONS: The involvement of the trunk segment has been observed to significantly improve power and velocity in swing movements during spike and serves among adolescent male volleyball players. This underscores the importance of coordination between the trunk and arm in influencing swing movement performance during spikes and serves. High school athletes demonstrate superior power and velocity in arm swing movements compared to middle school athletes. MB exhibits greater power in upper limb swing movements than OH, although OH players show better coordination between the arm, trunk, and lower limb segments in the swing movement. To enhance swing movement performance in adolescent male volleyball players, particularly focusing on the trunk segment was crucial. Specialized physical training programs should target improving both arm strength and rotational power of the trunk simultaneously. This approach would help in consistently enhancing coordination between the trunk and arms, ultimately leading to optimized force generation during swing movements such as spikes and serves.
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Progress in understanding early human development has been impeded by the scarcity of reference datasets from natural embryos, particularly those with spatial information during crucial stages like gastrulation. We conducted high-resolution spatial transcriptomics profiling on 38,562 spots from 62 transverse sections of an intact Carnegie stage (CS) 8 human embryo. From this spatial transcriptomic dataset, we constructed a 3D model of the CS8 embryo, in which a range of cell subtypes are identified, based on gene expression patterns and positional register, along the anterior-posterior, medial-lateral, and dorsal-ventral axis in the embryo. We further characterized the lineage trajectories of embryonic and extra-embryonic tissues and associated regulons and the regionalization of signaling centers and signaling activities that underpin lineage progression and tissue patterning during gastrulation. Collectively, the findings of this study provide insights into gastrulation and post-gastrulation development of the human embryo.
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Embrión de Mamíferos , Gastrulación , Regulación del Desarrollo de la Expresión Génica , Imagenología Tridimensional , Humanos , Embrión de Mamíferos/metabolismo , Transcriptoma/genética , Gástrula/metabolismo , Gástrula/embriología , Transducción de Señal , Linaje de la Célula , Perfilación de la Expresión Génica , Tipificación del Cuerpo/genéticaRESUMEN
Aging is an extremely intricate and progressive phenomenon that is implicated in many physiological and pathological conditions. Icariin (ICA) is the main active ingredient of Epimedium and has exhibited multiple bioactivities, such as anti-tumor, neuroprotective, antioxidant, anti-inflammatory, and anti-aging properties. ICA could extend healthspan in both invertebrate and vertebrate models. In this review, the roles of ICA in protection from declined reproductive function, neurodegeneration, osteoporosis, aging intestinal microecology, and senescence of cardiovascular system will be summarized. Furthermore, the underlying mechanisms of ICA-mediated anti-aging effects will be introduced. Finally, we will discuss some key aspects that constrain the usage of ICA in clinical practice and the corresponding strategies to solve these issues.
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This study was to investigate the improvement value of Niaoduqing particles in the outcome of non-diabetic patients with stage IV chronic kidney disease (CKD). The non-diabetic patients with stage IV CKD who were to receive Niaoduqing particles were set as the study group (252 cases), and the patients with the same disease who only received Western medicine in the public database were set as the control group (220 cases). The follow-up visits were 3 months/time for 1 year. Deaths due to various causes, doubling of creatinine levels, and end-stage renal disease were used as hard end points to stop follow-up. The clinical indexes of the 2 groups were observed and compared. The results showed that the rate of compound outcome was significantly lower in the study group (28.17%) than in the control group (36.82%), the glomerular filtration rate was significantly higher than that in the control group, and the levels of uric acid and urea were significantly lower than that in the control group (Pâ <â .05). Niaoduqing particles can reduce creatinine and urea nitrogen, stabilize renal function, delay dialysis time, and improve the incidence of compound outcome in patients with non-diabetic stage IV CKD, which is worthy of clinical promotion.
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Diálisis Renal , Insuficiencia Renal Crónica , Humanos , Estudios Retrospectivos , Creatinina , Progresión de la Enfermedad , Insuficiencia Renal Crónica/epidemiología , Tasa de Filtración Glomerular , UreaAsunto(s)
Ejercicio Físico , Receptores Notch , Transducción de Señal , Vía de Señalización Wnt , Humanos , Receptores Notch/metabolismo , Receptores Notch/fisiología , Ejercicio Físico/fisiología , Vía de Señalización Wnt/fisiología , Transducción de Señal/fisiología , Proteínas Wnt/metabolismo , Proteínas Wnt/fisiología , AnimalesRESUMEN
The school students are facing mental health issues, and their performance is not improving in China. Health education policies are not implemented at the school level in China. However, scholars focus on college students' health education, but the school student is neglected. The research's primary objective is to answer the question: What is the impact of health education on the psychological well-being of school students? A sample of 549 10th grade students is collected from China's public and private sector institutes. The partial least square-structural equation modelling (PLS-SEM) is employed to analyze the data. The outcomes highlighted that the impact of health education is significant on the psychological well-being of school students in China. Furthermore, the study introduced that the moderating role of sustainable health exercise and sports participation is critical as it positively influences the relationship between health education and psychological wellbeing. This research improves literature as the novel contribution are highlighted in theory. Furthermore, the government education policies must be reframed under the light of this research' findings to improve students' health.
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Educación y Entrenamiento Físico , Deportes , Humanos , Ejercicio Físico , Instituciones Académicas , Estudiantes/psicologíaRESUMEN
Colonic mucosal defect constitutes the major reason of recurrence and deterioration of ulcerative colitis (UC), and mucosal healing has become the therapeutic endpoint of UC. Unfortunately, specific promoter of mucosal healing is still absent. Our previous researches demonstrated that arctigenin could alleviate colitis symptoms in mice, but whether it has a positive impact on colonic mucosal healing remains unclear. This study explores whether and how arctigenin promotes mucosal healing. Orally administered arctigenin was shown to alleviate colitis in mice primarily by enhancing mucosal healing. In vitro, arctigenin was shown to promote the wound healing by accelerating colonic epithelial cell migration but not proliferation. Acceleration of the focal adhesion turnover, especially assembly, is crucial for arctigenin promoting the cell migration. Arctigenin was able to activate focal adhesion kinase (FAK) in colonic epithelial cells through directly binding with Tyr251 site of FAK, as evidenced by surface plasmon resonance assay and site-directed mutagenesis experiment. In the colonic epithelial cells of UC patients and colitis mice, FAK activation was significantly down-regulated compared with the controls. Arctigenin promoted colonic epithelial cell migration and mucosal healing in dextran sulphate sodium (DSS)-induced colitis mice dependent on activating FAK, as confirmed by combined use with FAK inhibitor. In summary, arctigenin can directly promote mucosal healing in colitis mice through facilitating focal adhesion turnover, especially assembly, and consequent migration of epithelial cells via targeting FAK. Arctigenin may be developed as a mucosal healing promoter, and FAK is a potential therapeutic target for UC and other mucosal defect-related diseases.
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Colitis Ulcerosa , Colitis , Furanos , Lignanos , Humanos , Ratones , Animales , Colitis Ulcerosa/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/uso terapéutico , Adhesiones Focales/metabolismo , Colitis/inducido químicamente , Movimiento Celular , Cicatrización de Heridas , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Sulfato de Dextran , Ratones Endogámicos C57BLRESUMEN
Neurogenesis is known to be closely associated with depression. We aimed to investigate whether a polypeptide monomer derived from pilose antler (polypeptide sequence LSALEGVFYP, PAP) exerts an antidepressant effect by influencing neurogenesis, and to elucidate the mechanism of its antidepressant action. Behavioral tests were performed to observe the antidepressant effect of PAP. Neurogenesis in the dentate gyrus (DG) region of hippocampus was observed by immunofluorescence. The expression of key proteins of Sentrin/SUMO-specific proteases 2 (SENP2)- Phosphoinositide-specific phospholipase C beta 4 (PLCß4) pathway was accessed by co-immunoprecipitation (Co-IP), and the calcium homeostasis associated proteins were observed via Western blot (WB). Subsequently, temozolomide (TMZ) pharmacologically blocked neurogenesis to verify the antidepressant effect of PAP on neurogenesis. The mechanism of PAP antidepressant effect was verified by constructing a sh-SENP2 virus vector to silence SENP2 protein. Finally, corticosterone (CORT)-induced PC12 cell model was used to verify whether PAP was involved in the process of deconjugated PLCß4 SUMOylated. The results showed that PAP improved depression-like behavior and neurogenesis induced by chronic unpredictable mild stimulation (CUMS). In addition, PAP acted on SENP2-PLCß4 pathway to deconjugate the SUMOylation of PLCß4 and affect calcium homeostasis. Pharmacological blockade of neurogenesis by TMZ treatment impaired the antidepressant efficacy of PAP. Knockout of SENP2 in the CUMS model attenuated the antidepressant response of PAP, and the impaired neurogenesis was not ameliorated by PAP treatment. In summary, PAP acted on the SENP2-PLCß4 signaling pathway to inhibit the SUMOylation of PLCß4 and maintain calcium homeostasis, thereby protecting neurogenesis and playing an antidepressant role.
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Depresión , Péptido Hidrolasas , Animales , Depresión/tratamiento farmacológico , Depresión/etiología , Depresión/metabolismo , Fosfolipasa C beta/metabolismo , Péptido Hidrolasas/farmacología , Calcio/metabolismo , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antidepresivos/metabolismo , Transducción de Señal , Péptidos/farmacología , Endopeptidasas/metabolismo , Endopeptidasas/farmacología , Hipocampo , Estrés Psicológico/metabolismo , Modelos Animales de EnfermedadRESUMEN
Different functional regions of brain are fundamental for basic neurophysiological activities. However, the regional specification remains largely unexplored during human brain development. Here, by combining spatial transcriptomics (scStereo-seq) and scRNA-seq, we built a spatiotemporal developmental atlas of multiple human brain regions from 6-23 gestational weeks (GWs). We discovered that, around GW8, radial glia (RG) cells have displayed regional heterogeneity and specific spatial distribution. Interestingly, we found that the regional heterogeneity of RG subtypes contributed to the subsequent neuronal specification. Specifically, two diencephalon-specific subtypes gave rise to glutamatergic and GABAergic neurons, whereas subtypes in ventral midbrain were associated with the dopaminergic neurons. Similar GABAergic neuronal subtypes were shared between neocortex and diencephalon. Additionally, we revealed that cell-cell interactions between oligodendrocyte precursor cells and GABAergic neurons influenced and promoted neuronal development coupled with regional specification. Altogether, this study provides comprehensive insights into the regional specification in the developing human brain.
Asunto(s)
Encéfalo , Transcriptoma , Humanos , Neuronas Dopaminérgicas , Neuronas GABAérgicas , Mesencéfalo , Neocórtex , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismoRESUMEN
INTRODUCTION: Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with FLT3-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with FLT3-ITD mutations. This study aimed to evaluate the anti-leukemic effects of shikonin (SHK) and its mechanisms of action against AML cells with FLT3-ITD mutations in vitro and in vivo. METHODS: The CCK-8 assay was used to analyze cell viability, and flow cytometry was used to detect cell apoptosis and differentiation. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to examine the expression of certain proteins and genes. Leukemia mouse model was created to evaluate the anti-leukemia effect of SHK against FLT3-ITD mutated leukemia in vivo. RESULTS: After screening a series of leukemia cell lines, those with FLT3-ITD mutations were found to be more sensitive to SHK in terms of proliferation inhibition and apoptosis induction than those without FLT3-ITD mutations. SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules. Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells. Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations. Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice. CONCLUSION: The findings of this study indicate that SHK is a promising drug for the treatment of FLT3-ITD mutated AML.