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Nutrients and energy have emerged as central modulators of developmental programmes in plants and animals1-3. The evolutionarily conserved target of rapamycin (TOR) kinase is a master integrator of nutrient and energy signalling that controls growth. Despite its key regulatory roles in translation, proliferation, metabolism and autophagy2-5, little is known about how TOR shapes developmental transitions and differentiation. Here we show that glucose-activated TOR kinase controls genome-wide histone H3 trimethylation at K27 (H3K27me3) in Arabidopsis thaliana, which regulates cell fate and development6-10. We identify FERTILIZATION-INDEPENDENT ENDOSPERM (FIE), an indispensable component of Polycomb repressive complex 2 (PRC2), which catalyses H3K27me3 (refs. 6-8,10-12), as a TOR target. Direct phosphorylation by TOR promotes the dynamic translocation of FIE from the cytoplasm to the nucleus. Mutation of the phosphorylation site on FIE abrogates the global H3K27me3 landscape, reprogrammes the transcriptome and disrupts organogenesis in plants. Moreover, glucose-TOR-FIE-PRC2 signalling modulates vernalization-induced floral transition. We propose that this signalling axis serves as a nutritional checkpoint leading to epigenetic silencing of key transcription factor genes that specify stem cell destiny in shoot and root meristems and control leaf, flower and silique patterning, branching and vegetative-to-reproduction transition. Our findings reveal a fundamental mechanism of nutrient signalling in direct epigenome reprogramming, with broad relevance for the developmental control of multicellular organisms.
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Arabidopsis , Glucose , Alvo Mecanístico do Complexo 2 de Rapamicina , Fosfatidilinositol 3-Quinases , Desenvolvimento Vegetal , Complexo Repressor Polycomb 2 , Proteínas Repressoras , Transdução de Sinais , Arabidopsis/embriologia , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Glucose/metabolismo , Histonas/química , Histonas/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Desenvolvimento Vegetal/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genéticaRESUMO
Balanced control of stem cell proliferation and differentiation underlines tissue homeostasis. Disruption of tissue homeostasis often results in many diseases. However, how endogenous factors influence the proliferation and differentiation of intestinal stem cells (ISCs) under physiological and pathological conditions remains poorly understood. Here, we find that the evolutionarily conserved endoplasmic reticulum membrane protein complex (EMC) negatively regulates ISC proliferation and intestinal homeostasis. Compromising EMC function in progenitors leads to excessive ISC proliferation and intestinal homeostasis disruption. Mechanistically, the EMC associates with and stabilizes Hippo (Hpo) protein, the key component of the Hpo signaling pathway. In the absence of EMC, Yorkie (Yki) is activated to promote ISC proliferation due to Hpo destruction. The EMC-Hpo-Yki axis also functions in enterocytes to maintain intestinal homeostasis. Importantly, the levels of the EMC are dramatically diminished in tunicamycin-treated animals, leading to Hpo destruction, thereby resulting in intestinal homeostasis disruption due to Yki activation. Thus, our study uncovers the molecular mechanism underlying the action of the EMC in intestinal homeostasis maintenance under physiological and pathological conditions and provides new insight into the pathogenesis of tunicamycin-induced tumorigenesis.
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Proteínas de Drosophila , Proteínas Serina-Treonina Quinases , Animais , Proteínas Serina-Treonina Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais/fisiologia , Proteínas de Drosophila/metabolismo , Tunicamicina/metabolismo , Transativadores/metabolismo , Proliferação de Células , Proteínas Nucleares/metabolismo , Homeostase , Drosophila melanogaster/metabolismoRESUMO
Epithelial polarity is critical for proper functions of epithelial tissues, tumorigenesis, and metastasis. The evolutionarily conserved transmembrane protein Crumbs (Crb) is a key regulator of epithelial polarity. Both Crb protein and its transcripts are apically localized in epithelial cells. However, it remains not fully understood how they are targeted to the apical domain. Here, using Drosophila ovarian follicular epithelia as a model, we show that epithelial polarity is lost and Crb protein is absent in the apical domain in follicular cells (FCs) in the absence of Diamond (Dind). Interestingly, Dind is found to associate with different components of the dynactin-dynein complex through co-IP-MS analysis. Dind stabilizes dynactin and depletion of dynactin results in almost identical defects as those observed in dind-defective FCs. Finally, both Dind and dynactin are also required for the apical localization of crb transcripts in FCs. Thus our data illustrate that Dind functions through dynactin/dynein-mediated transport of both Crb protein and its transcripts to the apical domain to control epithelial apico-basal (A/B) polarity.
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Proteínas de Drosophila , Animais , Polaridade Celular , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Complexo Dinactina/metabolismo , Dineínas/metabolismo , Células Epiteliais/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter-based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T-cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4+ and CD8+ T cells in LNs, as well as a decrease of CD8+ T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αßT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αßT-cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer-based Foxo1-Klf2 transcriptional program and the migration of αßT cells into LNs, providing valuable insights into the molecular mechanisms underlying T-cell migration.
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Stem cells constantly divide and differentiate to maintain adult tissue homeostasis, and uncontrolled stem cell proliferation leads to severe diseases such as cancer. How stem cell proliferation is precisely controlled remains poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Yun, required for proliferation of normal and transformed ISCs. Yun is mainly expressed in progenitors; our genetic and biochemical evidence suggest that it acts as a scaffold to stabilize the Prohibitin (PHB) complex previously implicated in various cellular and developmental processes and diseases. We demonstrate that the Yun/PHB complex is regulated by and acts downstream of EGFR/MAPK signaling. Importantly, the Yun/PHB complex interacts with and positively affects the levels of the transcription factor E2F1 to regulate ISC proliferation. In addition, we find that the role of the PHB complex in cell proliferation is evolutionarily conserved. Thus, our study uncovers a Yun/PHB-E2F1 regulatory axis in stem cell proliferation.
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Células-Tronco Adultas/metabolismo , Proliferação de Células/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Fator de Transcrição E2F1/metabolismo , Intestinos/metabolismo , Proibitinas/metabolismo , Animais , Animais Geneticamente Modificados , Diferenciação Celular/fisiologia , Homeostase/fisiologia , Interferência de RNA/fisiologia , Transdução de Sinais/fisiologiaRESUMO
We aimed to explore the aberrant expression status of hsa-miR-141-3p and dual-specificity protein phosphatase 1 (DUSP1) and their relative mechanisms in uterine cervical carcinoma (UCC).Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was conducted to detect the expression of hsa-miR-141-3p. Immunohistochemical (IHC) staining was performed to examine the expression of DUSP1 in UCC. Gene chips and RNA-seq datasets were also obtained to assess the expression level. Integrated standardized mean difference (SMD) was calculated to evaluate the expression status of hsa-miR-141-3p in UCC tissues comprehensively. DUSP1-overexpression and hsa-miR-141-3p-inhibition HeLa cells were established, and CCK-8, transwell, wound healing, cell cycle, and apoptosis assays were implemented. The targets of hsa-miR-141-3p were obtained with online tools, and the combination of hsa-miR-141-3p and DUSP1 was validated via dual-luciferase reporter assay. Single-cell RNA-seq data were analyzed to explore hsa-miR-141-3p and DUSP1 in different cells. An integrated SMD of 1.41 (95% CI[0.45, 2.38], p = 0.0041) with 558 samples revealed the overexpression of hsa-miR-141-3p in UCC tissues. And the pooled SMD of -1.06 (95% CI[-1.45, -0.66], p < 0.0001) with 1,268 samples indicated the downregulation of DUSP1. Inhibition of hsa-miR-141-3p could upregulate DUSP1 expression and suppress invasiveness and metastasis of HeLa cells. Overexpression of DUSP1 could hamper proliferation, invasion, and migration and boost apoptosis and distribution of G1 phase. The dual-luciferase reporter assay validated the combination of hsa-miR-141-3p and DUSP1. Moreover, the targets of hsa-miR-141-3p were mainly enriched in the MAPK signaling pathway and activated in fibroblasts and endothelial cells. The current study illustrated the upregulation of hsa-miR-141-3p and the downregulation of DUSP1 in UCC tissues. Hsa-miR-141-3p could promote UCC progression by targeting DUSP1.
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Fosfatase 1 de Especificidade Dupla , MicroRNAs , Regulação para Cima , Neoplasias do Colo do Útero , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfatase 1 de Especificidade Dupla/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Feminino , Células HeLa , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Apoptose , Movimento Celular , Progressão da DoençaRESUMO
BACKGROUND: Deep brain stimulation (DBS) is a promising therapy for refractory Gilles de la Tourette syndrome (GTS). However, its long-term efficacy, safety, and recommended surgical age remain controversial, requiring evidence to compare different age categories. METHODS: This retrospective cohort study recruited 102 GTS patients who underwent DBS between October 2006 and April 2022 at two national centers. Patients were divided into two age categories: children (aged < 18 years; n = 34) and adults (aged ≥ 18 years; n = 68). The longitudinal outcomes as tic symptoms were assessed by the YGTSS, and the YBOCS, BDI, and GTS-QOL were evaluated for symptoms of obsessive-compulsive disorder (OCD), depression, and quality of life, respectively. RESULTS: Overall, these included patients who finished a median 60-month follow-up, with no significant difference between children and adults (p = 0.44). Overall, the YGTSS total score showed significant postoperative improvements and further improved with time (improved 45.2%, 51.6%, 55.5%, 55.6%, 57.8%, 61.4% after 6, 12, 24, 36, 48, and ≥ 60 months of follow-up compared to baseline, respectively) in all included patients (all p < 0.05). A significantly higher improvement was revealed in children than adults at ≥ 60 months of follow-up in the YGTSS scores (70.1% vs 55.9%, p = 0.043), and the time to achieve 60% improvement was significantly shorter in the children group (median 6 months vs 12 months, p = 0.013). At the last follow-up, the mean improvements were 45.4%, 48.9%, and 55.9% and 40.3%, 45.4%, and 47.9% in YBOCS, BDI, and GTS-QOL scores for children and adults, respectively, which all significantly improved compared to baseline (all p < 0.05) but without significant differences between these two groups (all p > 0.05), and the children group received significantly higher improvement in GTS-QOL scores than adults (55.9% vs. 47.9%, p = 0.049). CONCLUSIONS: DBS showed acceptable long-term efficacy and safety for both children and adults with GTS. Surgeries performed for patients younger than 18 years seemed to show acceptable long-term efficacy and safety and were not associated with increased risks of loss of benefit compared to patients older than 18 at the time of surgery. However, surgeries for children should also be performed cautiously to ensure their refractoriness and safety.
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Estimulação Encefálica Profunda , Síndrome de Tourette , Humanos , Síndrome de Tourette/terapia , Estimulação Encefálica Profunda/métodos , Masculino , Feminino , Criança , Adulto , Adolescente , Estudos Retrospectivos , Seguimentos , Adulto Jovem , Resultado do Tratamento , Qualidade de Vida , Pessoa de Meia-Idade , Fatores EtáriosRESUMO
Chronic diabetic wounds remain a worldwide challenge for both the clinic and research. Given the vicious circle of oxidative stress and inflammatory response as well as the impaired angiogenesis of the diabetic wound tissues, the wound healing process is disturbed and poorly responds to the current treatments. In this work, a nickel-based metal-organic framework (MOF, Ni-HHTP) with excellent antioxidant activity and proangiogenic function is developed to accelerate the healing process of chronic diabetic wounds. The Ni-HHTP can mimic the enzymatic catalytic activities of antioxidant enzymes to eliminate multi-types of reactive species through electron transfer reactions, which protects cells from oxidative stress-related damage. Moreover, this Ni-based MOF can promote cell migration and angiogenesis by activating transforming growth factor-ß1 (TGF-ß1) in vitro and reprogram macrophages to the anti-inflammatory phenotype. Importantly, Ni-HHTP effectively promotes the healing process of diabetic wounds by suppressing the inflammatory response and enhancing angiogenesis in vivo. This study reports a versatile and promising MOF-based nanozyme for diabetic wound healing, which may be extended in combination with other wound dressings to enhance the management of diabetic or non-healing wounds.
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Diabetes Mellitus Experimental , Estruturas Metalorgânicas , Animais , Espécies Reativas de Oxigênio , Estruturas Metalorgânicas/farmacologia , Níquel , Angiogênese , Cicatrização/fisiologia , Antioxidantes , HidrogéisRESUMO
OBJECTIVE: Emerging pathological evidence suggests that there is an association between glymphatic dysfunction and the progression of Parkinson's disease (PD). However, the clinical evidence of this association remains lacking. METHODS: In this study, the index for diffusion tensor image analysis along the perivascular space (ALPS index) was calculated to evaluate glymphatic function. RESULTS: Overall, 289 patients with PD were enrolled in the cross-sectional study. The ALPS index was found to be negatively correlated with age, disease severity, and dyskinesia. In the longitudinal study, the information on a total of 95 PD patients with 5-year follow-up examinations was collected from the Parkinson's Progression Marker Initiative, 33 of which were classified into the low ALPS index group, and all others were classified into the mid-high ALPS index group based on the first tertile of the baseline ALPS index. The results of longitudinal regression indicated that there was a significant main group effect on autonomic dysfunction, as well as on activities of daily living. In addition, the low ALPS index group had faster deterioration in MDS-UPDRS part III and part II, Symbol Digit Modalities Test and Hopkins Verbal Learning Test. Path analysis showed that ALPS index acted as a significant mediator between tTau/ Aß1-42 and cognitive change in the Symbol Digit Modalities Test score at year 4 and year 5. INTERPRETATION: The ALPS index, an neuroimaging marker of glymphatic function, is correlated with PD disease severity, motor symptoms, and autonomic function, and is predictive of faster deterioration in motor symptoms and cognitive function. Additionally, glymphatic function may mediate the pathological role of toxic protein in cognitive decline. ANN NEUROL 2023;94:672-683.
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Atividades Cotidianas , Doença de Parkinson , Humanos , Estudos Transversais , Estudos Longitudinais , Doença de Parkinson/diagnóstico por imagem , NeuroimagemRESUMO
BACKGROUND: Rapid eye movement (REM) sleep behaviour disorder (RBD) is one of the most common sleep problems and represents a key prodromal marker in Parkinson's disease (PD). It remains unclear whether and how basal ganglia nuclei, structures that are directly involved in the pathology of PD, are implicated in the occurrence of RBD. METHOD: Here, in parallel with whole-night video polysomnography, we recorded local field potentials from two major basal ganglia structures, the globus pallidus internus and subthalamic nucleus, in two cohorts of patients with PD who had varied severity of RBD. Basal ganglia oscillatory patterns during RBD and REM sleep without atonia were analysed and compared with another age-matched cohort of patients with dystonia that served as controls. RESULTS: We found that beta power in both basal ganglia nuclei was specifically elevated during REM sleep without atonia in patients with PD, but not in dystonia. Basal ganglia beta power during REM sleep positively correlated with the extent of atonia loss, with beta elevation preceding the activation of chin electromyogram activities by ~200 ms. The connectivity between basal ganglia beta power and chin muscular activities during REM sleep was significantly correlated with the clinical severity of RBD in PD. CONCLUSIONS: These findings support that basal ganglia activities are associated with if not directly contribute to the occurrence of RBD in PD. Our study expands the understanding of the role basal ganglia played in RBD and may foster improved therapies for RBD by interrupting the basal ganglia-muscular communication during REM sleep in PD.
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Chronic inflammation is a common foundation for the development of many non-communicable diseases, particularly diabetes, atherosclerosis, and tumors. The activation of the axis involving Advanced Glycation End products (AGEs) and their receptor RAGE is a key promotive factor in the chronic inflammation process, influencing the pathological progression of these diseases. The accumulation of AGEs in the body results from an increase in glycation reactions and oxidative stress, especially pronounced in individuals with diabetes. By binding to RAGE, AGEs activate signaling pathways such as NF-κB, promoting the release of inflammatory factors, exacerbating cell damage and inflammation, and further advancing the formation of atherosclerotic plaques and tumor development. This review will delve into the molecular mechanisms by which the AGEs-RAGE axis activates chronic inflammation in the aforementioned diseases, as well as strategies to inhibit the AGEs-RAGE axis, aiming to slow or halt the progression of chronic inflammation and related diseases. This includes the development of AGEs inhibitors, RAGE antagonists, and interventions targeting upstream and downstream signaling pathways. Additionally, the early detection of AGEs levels and RAGE expression as biomarkers provides new avenues for the prevention and treatment of diabetes, atherosclerosis, and tumors.
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Produtos Finais de Glicação Avançada , Inflamação , Receptor para Produtos Finais de Glicação Avançada , Transdução de Sinais , Humanos , Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Inflamação/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Aterosclerose/metabolismo , Aterosclerose/patologiaRESUMO
OBJECTIVES: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered. METHODS: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo. RESULTS: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice. CONCLUSION: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis.
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Colite , Saponinas , Ratos , Camundongos , Animais , Piruvato Carboxilase/metabolismo , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/metabolismo , Saponinas/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Macrófagos/metabolismo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Changing the wettability and surface texturing have a significant impact on lubrication. In this study, the researchers used the molecular dynamics (MD) method to investigate how adjusting the interaction between alkanes and the wall affects oil film morphology and frictional properties under boundary lubrication. The findings revealed that the bearing capacity was influenced by both the morphology of the oil film and the strength of solid-liquid adsorption. In cases where the walls had weak wettability, the alkanes formed clusters to effectively separate the walls, while in cases where the walls had strong wettability, the oil film spread and formed a strong adsorption film. The super oleophilic textured surface could enhance the oil film adsorption capacity and replenish the oil film to the friction area in time, and the super oleophobic smooth surface could further reduce the friction coefficient. Therefore, a composite surface consisting of a super oleophilic textured surface and a super oleophobic smooth surface can be designed to enhance the bearing capacity of the oil film and reduce friction.
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BACKGROUND: Quantitative measurement of pupil change has not been assessed against the Richmond Agitation and Sedation Scale (RASS) and spectral edge frequency (SEF) during sedation. The aim of this study was to evaluate pupillometry against these measures in sedated critically ill adult patients. METHODS: In ventilated and sedated patients, pupillary variables were measured by automated pupillometry at each RASS level from -5 to 0 after discontinuation of hypnotics, while processed electroencephalogram variables were displayed continuously and SEF was recorded at each RASS level. Correlations were made between percentage pupillary light reflex (%PLR) and RASS, and between %PLR and SEF. The ability of %PLR to differentiate light sedation (RASS ≥-2), moderate (RASS =-3), and deep sedation (RASS ≤-4) was assessed by areas under receiver operating characteristic (ROC) curves. RESULTS: A total of 163 paired measurements were recorded in 38 patients. With decreasing sedation depth, median %PLR increased progressively from 20% (interquartile range 17-25%) to 36% (interquartile range 33-40%) (P<0.001). Strong correlations were found between %PLR and RASS (Rho=0.635) and between %PLR and SEF (R=0.641). Area under the curve (AUC) of 0.87 with a %PLR threshold of 28% differentiated moderate/light sedation from deep sedation with sensitivity of 83% and specificity of 83%. An AUC of 0.82 with a threshold of 31% distinguished light sedation from moderate/deep sedation with a sensitivity of 81% and a specificity of 75%. CONCLUSIONS: Quantitative assessment of %PLR correlates with other indicators of sedation depth in critically ill patients.
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Estado Terminal , Hipnóticos e Sedativos , Adulto , Humanos , Estudos Prospectivos , Sedação Consciente , EletroencefalografiaRESUMO
While Kawasaki disease (KD) induced coronary artery aneurysms (KD CAAs) in children are well studied, the features and prognosis of non-KD induced CAAs (non-KD CAAs) in the pediatric population are poorly documented. This case series study is to analyze the etiology and prognosis of non-KD CAAs in children and compare the characteristics of non-KD CAAs and KD CAAs. Non-KD CAA and KD CAA cases at our department from January 2022 to December 2023 were retrospectively collected. Etiologies and prognosis of non-KD CAAs were analyzed. Furthermore, demographic data, biochemical parameters and outcomes between children with Non-KD CAAs and children with KD CAAs were comparatively studied. Fifteen children with non-KD CAAs with a median age of 6 years and 117 children with KD CAAs with a median age of 2.0 years (p = 0.022) were included in this study. The causes of non-KD CAAs include: unknown etiologies (2 cases), coronary artery structural abnormalities (4), Takayasu arteritis (2), virus infection (2), cardiomyopathy (2), aplastic anemia with agranulocytosis (1), ANCA-associated vasculitis (1), and mucopolysaccharidosis (1). In the non-KD CAA group, there were a total of 19 CAAs with 3 being giant, 5 medium, and 11 small; 4 patients had complete CAA regression; an infant with a fistula between the right coronary artery and the coronary sinus complicated with cardiac enlargement died of heart failure. The KD group had significantly higher levels of CRP, white cells counts and ESR with zero mortality. Non-KD CAA cases had a significantly lower regression rate than KD-CAA cases (26.7% vs 66.7%, p = 0.004), and the probability of CAA regression in non-KD patients was 0.341 of that in KD patients (p = 0.006, OR = 0.341, 95% CI: 0.179-0.647). CONCLUSIONS: Various etiologies for Non-KD CAAs are identified. Patients with Non-KD CAAs were observed to have lower inflammatory indexes but poorer recovery than patients with KD CAAs. Therapeutic strategies different than those for KD may be needed for non-KD CAAs. WHAT IS KNOWN: ⢠Coronary artery aneurysm (CAA) in children is most commonly induced by Kawasaki disease (KD CAA), with a 50 ~ 70% regression rate in 1 to 2 years. ⢠CAA induced by diseases other than KD (non-KD CAA) in children is rare and its prognosis remains largely unknown. WHAT IS NEW: ⢠Most non-KD CAA cases are caused by coronary artery structural malformations. ⢠Non-KD CAA in children has poorer prognosis and lower regression rate compared with KD CAA. ⢠In addition to guideline directed anti-platelet and anti-coagulant therapies, treatments targeting the causal factor are necessary for non-KD CAA.
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BACKGROUND: Despite recent advances the prognosis of pulmonary hypertension remains poor and warrants novel therapeutic options. Extensive studies, including ours, have revealed that hypoxia-induced pulmonary hypertension is associated with high oxidative stress. Cerium oxide nanozyme or nanoparticles (CeNPs) have displayed catalytic activity mimicking both catalase and superoxide dismutase functions and have been widely used as an anti-oxidative stress approach. However, whether CeNPs can attenuate hypoxia-induced pulmonary vascular oxidative stress and pulmonary hypertension is unknown. RESULTS: In this study, we designed a new ceria nanozyme or nanoparticle (AuCeNPs) exhibiting enhanced enzyme activity. The AuCeNPs significantly blunted the increase of reactive oxygen species and intracellular calcium concentration while limiting proliferation of pulmonary artery smooth muscle cells and pulmonary vasoconstriction in a model of hypoxia-induced pulmonary hypertension. In addition, the inhalation of nebulized AuCeNPs, but not CeNPs, not only prevented but also blunted hypoxia-induced pulmonary hypertension in rats. The benefits of AuCeNPs were associated with limited increase of intracellular calcium concentration as well as enhancement of extracellular calcium-sensing receptor (CaSR) activity and expression in rat pulmonary artery smooth muscle cells. Nebulised AuCeNPs showed a favorable safety profile, systemic arterial pressure, liver and kidney function, plasma Ca2+ level, and blood biochemical parameters were not affected. CONCLUSION: We conclude that AuCeNPs is an improved reactive oxygen species scavenger that effectively prevents and treats hypoxia-induced pulmonary hypertension.
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Cério , Hipertensão Pulmonar , Hipóxia , Miócitos de Músculo Liso , Artéria Pulmonar , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Animais , Cério/farmacologia , Cério/química , Cério/uso terapêutico , Ratos , Hipertensão Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Nanopartículas/química , Cálcio/metabolismoRESUMO
BACKGROUND: Rotator cuff tears (RCT) is a common musculoskeletal disorder in the shoulder which cause pain and functional disability. Diabetes mellitus (DM) is characterized by impaired ability of producing or responding to insulin and has been reported to act as a risk factor of the progression of rotator cuff tendinopathy and tear. Long non-coding RNAs (lncRNAs) are involved in the development of various diseases, but little is known about their potential roles involved in RCT of diabetic patients. METHODS: RNA-Sequencing (RNA-Seq) was used in this study to profile differentially expressed lncRNAs and mRNAs in RCT samples between 3 diabetic and 3 nondiabetic patients. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed to annotate the function of the differentially expressed genes (DEGs). LncRNA-mRNA co-expression network and competing endogenous RNA (ceRNA) network were constructed to elucidate the potential molecular mechanisms of DM affecting RCT. RESULTS: In total, 505 lncRNAs and 388 mRNAs were detected to be differentially expressed in RCT samples between diabetic and nondiabetic patients. GO functional analysis indicated that related lncRNAs and mRNAs were involved in metabolic process, immune system process and others. KEGG pathway analysis indicated that related mRNAs were involved in ferroptosis, PI3K-Akt signaling pathway, Wnt signaling pathway, JAK-STAT signaling pathway and IL-17 signaling pathway and others. LncRNA-mRNA co-expression network was constructed, and ceRNA network showed the interaction of differentially expressed RNAs, comprising 5 lncRNAs, 2 mRNAs, and 142 miRNAs. TF regulation analysis revealed that STAT affected the progression of RCT by regulating the apoptosis pathway in diabetic patients. CONCLUSIONS: We preliminarily dissected the differential expression profile of lncRNAs and mRNAs in torn rotator cuff tendon between diabetic and nondiabetic patients. And the bioinformatic analysis suggested some important RNAs and signaling pathways regarding inflammation and apoptosis were involved in diabetic RCT. Our findings offer a new perspective on the association between DM and progression of RCT.
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Diabetes Mellitus , MicroRNAs , RNA Longo não Codificante , Lesões do Manguito Rotador , Humanos , RNA Longo não Codificante/genética , Manguito Rotador/metabolismo , Lesões do Manguito Rotador/genética , Redes Reguladoras de Genes , MicroRNAs/genética , RNA Mensageiro/genéticaRESUMO
Eight new caffeoyl derivatives, elephantomentosides A-H (1 - 8), together with ten known ones (9 - 18), were isolated from the whole plant of Elephantopos tomentosus L. Their structures were elucidated using detailed spectroscopic analysis. Structurally, compounds 1 - 8 are composed of ß-D-glucopyranose, and almost all of the substituent positions are at the C-1' and C-4' of glucopyranose. The anti-inflammatory and antioxidant activities of all isolated compounds were evaluated in vitro. Compounds 9-10, 13-15, and 17-18 exhibited significant DPPH scavenging capacity with IC50 values in the range of 10.01-25.07 µM, in comparison with Vc (IC50, 17.98 µM).
Assuntos
Antioxidantes , Asteraceae , Estrutura Molecular , Antioxidantes/farmacologia , Antioxidantes/química , Asteraceae/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/químicaRESUMO
BACKGROUND: Polygonatum kingianum Coll. & Hemsl (PK), a prominent medicine and food homology plant, has been consumed as a decoction from boiling water for thousands of years. 'Nine Steaming Nine Sun-drying' processing has been considered an effective method for enriching tonic properties, but studies investigating such impacts on PK and underlying mechanisms are extremely rare. RESULTS: We first demonstrated substantial improvements in the anti-oxidative, anti-inflammatory and anti-hyperglycemia effects of the Nine Steaming Nine Sun-drying processed PK water extracts compared with crude PK in cell models (i.e., HepG2 and Raw 264.7 cells). We then integrated foodomics and network pharmacology analysis to uncover the key compounds responsible for the improved benefits. A total of 551 metabolites of PK extracts were identified, including polyphenols, flavonoids, alkaloids, and organic acids. During processing, 204 metabolites were enhanced, and 32 metabolites were recognized as key constituents of processed PK responsible for the improved health-promoting activities, which may affect PI3K-Akt-, MAPK-, and HIF-1 pathways. We further confirmed the high affinity between identified key constituents of processed PK and their predicted acting targets using molecular docking. CONCLUSION: Our results provide novel insights into bioactive compounds of processed PK, elaborating the rationality of processing from the perspective of tonic effects. Consuming processed PK could be an efficacious strategy to combat the high prevalence of metabolic diseases that currently affect millions of people worldwide. © 2023 Society of Chemical Industry.
Assuntos
Hiperglicemia , Polygonatum , Humanos , Polygonatum/química , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Hiperglicemia/prevenção & controle , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Estresse Oxidativo , Água/metabolismoRESUMO
Ischemic ulcers pose a multifaceted clinical dilemma for patients with atherosclerosis, frequently compounded by suboptimal wound healing mechanisms. The dual function of Transforming Growth Factor Beta 3 (TGF-ß3) in ischemic ulcer healing is not fully comprehended, despite its involvement in modulating inflammatory responses and tissue regeneration. The main aim of this investigation was to clarify the functions and mechanisms by which TGF-ß3 regulates inflammatory responses and promotes wound healing in patients with ischemic ulcers who have atherosclerosis. Between August 2022 and November 2023, this cross-sectional investigation was conducted on 428 patients diagnosed with atherosclerotic ischemic ulcers in Haikou, China. The expression and function of TGF-ß3 were examined throughout the different stages of wound healing, including inflammation, proliferation and remodelling. In addition to documenting patient demographics and ulcer characteristics, an analysis was conducted on biopsy samples to determine the expression of TGF-ß3, pro-inflammatory and anti-inflammatory markers. A subset of patients were administered topical TGF-ß3 in order to evaluate its therapeutic effects. The expression pattern of TGF-ß3 was found to be stage-dependent and significant, exhibiting increased levels during the phase of inflammation and reduced activity in subsequent phases. TGF-ß3 levels were found to be greater in ulcers that were larger and deeper, especially in inflammatory phase. TGF-ß3 applied topically induced discernible enhancement in ulcer healing parameters, such as reduction in ulcer depth and size. The therapeutic significance of TGF-ß3 was emphasised due to its twofold function of regulating the inflammatory environment and facilitating the regeneration of damaged tissues. Ischemic ulcer lesion healing is significantly influenced by TGF-ß3, which functions as an anti-inflammatory and pro-inflammatory mediator. Its correlation with ulcer characteristics and stages of healing suggests that it may have utility as a targeted therapeutic agent.