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Exosomes are nanoscale vesicles of cellular origin. One of the main characteristics of exosomes is their ability to carry a wide range of biomolecules from their parental cells, which are important mediators of intercellular communication and play an important role in physiological and pathological processes. Exosomes have the advantages of biocompatibility, low immunogenicity, and wide biodistribution. As researchers' understanding of exosomes has increased, various strategies have been proposed for their use in diagnosing and treating diseases. Here, we provide an overview of the biogenesis and composition of exosomes, describe the relationship between exosomes and disease progression, and focus on the use of exosomes as biomarkers for early screening, disease monitoring, and guiding therapy in refractory diseases such as tumors and neurodegenerative diseases. We also summarize the current applications of exosomes, especially engineered exosomes, for efficient drug delivery, targeted therapies, gene therapies, and immune vaccines. Finally, the current challenges and potential research directions for the clinical application of exosomes are also discussed. In conclusion, exosomes, as an emerging molecule that can be used in the diagnosis and treatment of diseases, combined with multidisciplinary innovative solutions, will play an important role in clinical applications.
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BACKGROUND: Somatic mutations have been observed to induce aldosterone-producing adenomas (APAs). These may be accelerated during pregnancy. Somatic PRKACA mutations are common in cortisol-producing adenomas (CPAs). However, their role in APAs, particularly aldosterone- and cortisol-producing adenomas (A/CPAs), is not well understood. This study aims to investigate the association between PRKACA mutations and the accelerated development of A/CPAs during pregnancy. CASE PRESENTATION: A patient with primary aldosteronism (PA) associated with severe Cushing's syndrome (CS) underwent surgical resection of an adrenal tumor one year after delivery. Pathologic examination revealed an adrenocortical adenoma characterized primarily by zona glomerulosa hyperplasia. Somatic mutation analysis revealed the presence of the somatic PRKACA mutation, which was validated as a deleterious mutation by various computational databases. Immunohistochemical results showed positive staining for cytochrome P450 family 11 subfamily B member 1 (CYP11B1), cytochrome P450 family 11 subfamily B member 2 (CYP11B2), and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Our study included a review of 20 previously documented cases of aldosterone- and cortisol-producing adenomas (A/CPAs), two of which were concurrently positive for both CYP11B1 and CYP11B2, consistent with our findings. CONCLUSION: Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression.
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Neoplasias do Córtex Suprarrenal , Adenoma Adrenocortical , Aldosterona , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico , Hidrocortisona , Mutação , Complicações Neoplásicas na Gravidez , Humanos , Feminino , Gravidez , Adulto , Hidrocortisona/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/cirurgia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Aldosterona/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Complicações Neoplásicas na Gravidez/genética , Complicações Neoplásicas na Gravidez/patologia , Hiperaldosteronismo/genética , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Síndrome de Cushing/genética , Síndrome de Cushing/patologia , Adenoma/genética , Adenoma/patologia , Adenoma/metabolismoRESUMO
Purpose: To investigate the mechanism by which Qingguang'an inhibits scar formation in rabbits administered glaucoma filtering surgery (GFS). Methods: Combined trabeculectomy was performed in 100 rabbits diagnosed with glaucoma, which were assigned to five groups, including the no surgery, surgery only, mitomycin C (MMC; positive control), Qingguang'an (experimental) and PBS (negative control) groups. The animals were followed up at postoperative days 1-28. Ultrastructure was observed under a transmission electron microscope (TEM). Real-Time Polymerase Chain Reaction (RT-PCR), Western blot, Hematoxylin and Eosin (H&E) staining, Masson's trichrome staining and Immuno-histochemistry (IHC) were performed to assess the harvested blocks. Results: In the Qingguang'an group, intraocular pressure (IOP) on postoperative D28 was significantly lower than values in the no surgery, surgery only and PBS groups (P < 0.05). Its blebs kept better filtering function and less complications in follow-up, which be detected to have less fibroblasts and collagen deposition histologically. Compared with the PBS group, ATG5, Beclin1 and LC3-II mRNA levels were significantly increased while P62 was downregulated in the Qingguang'an group (P < 0.05). Correspondingly, ATG5 and Beclin1 protein amounts in the Qingguang'an group were increased while P62 was downregulated. The LC3-II/â ratio tended to rise to the process of autophagy. Abundant autophagosomes were captured under TEM in this condition. Conclusions: Qingguang'an granules can inhibit scar formation in rabbits after GFS and restrain IOP increase by inducing autophagy in TFs.
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In modern times, a notable trend toward delayed childbearing has been observed in most developed countries. As a result, sperm aging and quality loss, as well as premature ovarian failure (POF), have emerged as major causes of infertility. The pathogenesis of sperm aging and POF is complex and has not been clearly elucidated. However, evidence from some studies has linked germ cell aging to epigenetic modifications. Epigenetics refers to the heritable changes in gene expression that occur in the absence of any alterations to the gene's nucleotide sequence. This paper systematically reviewed and analyzed the relevant literature to describe the relationship of DNA methylation, non-coding RNA regulation, histone modifications, chromatin remodeling, and RNA modifications with sperm aging and POF. In addition, we analyzed how sperm aging and POF can be mitigated via epigenetic interventions. This review could provide new therapeutic insights and guide strategies for improving sperm quality and ovarian function.
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Based on bone metastasis potential of mouse breast cancer 4T1 cells, the bone disseminated breast tumor cells 4T1 (B-4T1) were acquired through the screening of 6-mercaptopurine. The characteristics of B-4T1 were studied by morphological observation, proliferation assay, expression of epithelial and mesenchymal cell markers detection, transcriptome sequencing, and tumor formation experiments. The results showed that B-4T1 was round and spindle-shaped than primary 4T1 cells, and its proliferation rate was reduced, as well as epithelial cell adhesion molecule (EpCAM) and E-cadherin expression. The transcript level of N-cadherin was increased in the B-4T1, but not vimentin, indicating that B-4T1 had partial epithelial mesenchymal transition. Besides, B-4T1 had higher fatty acid metabolism and better tumor formation capacity. This study lays the experimental foundation for the basic study of metastasis in breast cancer. All animal experiments in this paper were conducted in accordance with the standards of the Animal Ethics Committee of China Pharmaceutical University.
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Introduction: Chronic thyrotoxic myopathy (CTM) is a common, easily neglected complication of hyperthyroidism. There are currently no standard diagnostic criteria for CTM, and the ultrasonic characteristics of CTM-affected skeletal muscle remain unclear. Herein, we aimed to evaluate hyperthyroid patients for CTM by ultrasound and identify ultrasonic muscle parameter cutoffs for CTM diagnosis. Materials and methods: Each participant underwent ultrasonography. The original (muscle thickness (MT), pennation angle (PA), and cross-sectional area (CSA)) and corrected (MT/height (HT), MT/body mass index (BMI), CSA/HT, and CSA/BMI) parameters of the vastus lateralis and vastus medialis (VM) were evaluated. The diagnostic effectiveness of ultrasound for predicting CTM was determined using receiver operating characteristic (ROC) curve analysis. Our study included 203 participants: 67 CTM patients (18 males, 49 females), 67 non-CTM patients (28 males, 39 females) and 69 healthy controls (20 males, 49 females). Results: The CTM group had lower muscular ultrasonic and anthropometric parameters, higher thyroid hormone and thyroid-stimulating hormone receptor antibody (TRAb) levels, and a longer duration of hyperthyroidism than the non-CTM group (P < 0.05). The VM-PA, VM-CSA, VM-CSA/HT, and VM-CSA/BMI were lower in females than in males (P < 0.05). Free thyroxine (FT4) and TRAb both showed significant negative correlations with VM-MT, VM-MT/HT, VM-CSA, and VM-CSA/HT (P < 0.05). VM-MT/BMI and VM-CSA/HT, respectively, best predicted male and female CTM (AUC = 0.84, 0.85; cutoff ≤ 0.07, < 4.01). Conclusion: Ultrasound measurement of muscular parameters, especially in the VM, is a valid and feasible way of diagnosing and characterizing possible CTM in hyperthyroidism.
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OBJECTIVES: To determine whether dual-energy CT (DECT) can be used to accurately and reliably detect anterior cruciate ligament (ACL) rupture. MATERIALS AND METHODS: Participants with unilateral ACL rupture were prospectively enrolled, and the bilateral knees were scanned by DECT. A tissue-specific mapping algorithm was applied to improve the visualization of the ACLs. The 80-keV CT value, mixed-keV CT value, electron density (Rho), and effective atomic number (Zeff) were measured to quantitatively differentiate torn ACLs from normal ACLs. MRI and arthroscopy served as the reference standards. RESULTS: Fifty-one participants (mean age, 27.0 ± 8.7 years; 31 men) were enrolled. Intact and torn ACLs were explicitly differentiated on color-coded DECT images. The 80-keV CT value, mixed-keV CT value, and Rho were significantly lower for the torn ACLs than for the intact ACLs (p < 0.001). The optimal cutoff values were an 80-keV CT value of 61.8 HU, a mixed-keV CT value of 60.9 HU, and a Rho of 51.8 HU, with AUCs of 98.0% (95% CI: 97.0-98.9%), 99.2% (95% CI: 98.6-99.7%), and 99.8% (95% CI: 99.6-100.0%), respectively. Overall, DECT had almost perfect reliability and validity in detecting ACL integrity (sensitivity = 97.1% [95% CI: 88.1-99.8%]; specificity = 98.0% [95% CI: 89.5-99.9%]; PPV = 98.0% [95% CI: 93.0-99.8%]; NPV = 97.1% [95% CI: 91.7-99.4%]; accuracy = 97.5% [95% CI: 94.3-99.2%]). There was no evidence of a difference between MRI and DECT in the diagnostic performance (p > 0.99). CONCLUSION: DECT has excellent diagnostic accuracy and reliability in qualitatively and quantitatively diagnosing ACL rupture. CLINICAL RELEVANCE STATEMENT: DECT could validly and reliably diagnose ACL rupture using both qualitative and quantitative methods, which may become a promising substitute for MRI to evaluate the integrity of injured ACLs and the maturity of postoperative ACL autografts. KEY POINTS: ⢠On color-coded DECT images, an uncolored ACL was a reliable sign for qualitatively diagnosing ACL rupture. ⢠The 80-keV CT value, mixed-keV CT value, and Rho were significantly lower for the torn ACLs than for the intact ACLs, which contributed to the quantitative diagnosis of ACL rupture. ⢠DECT had an almost perfect diagnostic performance for ACL rupture, and diagnostic capability was comparable between MRI and DECT.
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Lesões do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior , Masculino , Humanos , Adolescente , Adulto Jovem , Adulto , Ligamento Cruzado Anterior/diagnóstico por imagem , Ligamento Cruzado Anterior/cirurgia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Lesões do Ligamento Cruzado Anterior/diagnóstico por imagem , Lesões do Ligamento Cruzado Anterior/cirurgia , Tomografia Computadorizada por Raios X/métodosRESUMO
Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.
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Neoplasias , Macrófagos Associados a Tumor , Humanos , Animais , Camundongos , Macrófagos Associados a Tumor/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Macrófagos/metabolismo , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Hidroliases/genéticaRESUMO
Correlated states have emerged in low-dimensional systems owing to enhanced Coulomb interactions. Elucidating these states requires atomic-scale characterization and delicate control capabilities. Herein, spectroscopic imaging-scanning tunneling microscopy was employed to investigate the correlated states residing in 1D electrons of the monolayer and bilayer MoSe2 mirror twin boundary (MTB). The Coulomb energies, determined by the wire length, drive the MTB into two types of ground states with distinct respective out-of-phase and in-phase charge orders. The two ground states can be reversibly converted through a metastable zero-energy state with in situ voltage pulses, which tune the electron filling of the MTB via a polaronic process, substantiated by first-principles calculations. Our Hubbard model calculation with an exact diagonalization method reveals the ground states as correlated insulators from an on-site U-originated Coulomb interaction, dubbed the Hubbard-type Coulomb blockade effect. Our study lays a foundation for understanding and tailoring correlated physics in complex systems.
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Oral nanoparticles (NPs) are more suitable for obesity control compared to NPs administered intravenously, as their convenience increases patient compliance. Herein, we developed an oral nano-system to improve the anti-obesity efficacy of celastrol (Cel). The observed enhanced efficacy was mediated by zein core NPs decorated with adipose-homing peptides that were coated with N-trimethylated chitosan. The optimized Cel/AHP-NPs@TMC exhibited spherical morphology by TEM, as well as narrow size distribution (221.76 ± 6.73 nm) and adequate stability in a gastrointestinal environment. Based on the combined delivery advantages of AHP-NPs@TMC - i.e., improved cellular internalization within Caco-2 cells and enhanced white adipose tissue (WAT) vascular targeting - Cel/AHP-NPs@TMC significantly reduced the body weight, blood lipid levels, adipose inflammation, and WAT distribution in diet-induced obese mice without side-effects. In short, this study provides clear evidence that TMC-based oral NPs can effectively improve celastrol for obesity treatment.
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Quitosana , Nanopartículas , Humanos , Camundongos , Animais , Quitosana/farmacologia , Células CACO-2 , Obesidade/tratamento farmacológico , Tecido Adiposo BrancoRESUMO
Inhibition of Notch1 signaling has been shown to promote astrocyte-derived neurogenesis after stroke. To investigate the regulatory role of Notch1 signaling in this process, in this study, we used a rat model of stroke based on middle cerebral artery occlusion and assessed the behavior of reactive astrocytes post-stroke. We used the γ-secretase inhibitor N-[N-(3,5-diuorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT) to block Notch1 signaling at 1, 4, and 7 days after injury. Our results showed that only administration of DAPT at 4 days after stroke promoted astrocyte-derived neurogenesis, as manifested by recovery of white matter fiber bundle integrity on magnetic resonance imaging, which is consistent with recovery of neurologic function. These findings suggest that inhibition of Notch1 signaling at the subacute stage post-stroke mediates neural repair by promoting astrocyte-derived neurogenesis.
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Correction for 'Protective mechanisms of Zanthoxylum bungeanum essential oil on DSS-induced ulcerative colitis in mice based on a colonic mucosal transcriptomic approach' by Huan Zhang et al., Food Funct., 2022, 13, 9324-9339, https://doi.org/10.1039/D1FO04323D.
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Endometrial carcinoma is a common gynecological malignant tumor, small nucleolar RNAs (snoRNAs) are involved in cancer development. However, researches on the roles of snoRNAs in endometrial carcinoma are limited. The expression levels of snoRNAs in endometrial cancer tissues were analyzed using The Cancer Genome Atlas (TCGA) database. Antisense oligonucleotides (ASOs) and plasmids were used for transfection. Moreover, CCK-8, EdU, wound-healing assay, transwell, cell apoptosis, western blotting, and xenograft model were employed to examine the biological functions of related molecules. real-time reverse transcription polymerase chain reaction and western blotting were performed to detect messenger RNA (mRNA) and protein levels. Including bioinformatics, fluorescence in situ hybridization, RNA pulldown, actinomycin D and RTL-P assays were also carried out to explore the molecular mechanism. Analysis of data from TCGA showed that the expression level of small nucleolar RNA, C/D box 60 (SNORD60) in endometrial cancer tissues is observably higher than that in normal endometrial tissues. Further research suggested that SNORD60 played a carcinogenic role both in vitro and in vivo, and significantly upregulated the expression of PIK3CA. However, the carcinogenic effects can be reversed by knocking down fibrillarin (FBL) or PIK3CA. SNORD60 forms complexes by binding with 2'-O-methyltransferase fibrillarin, thus catalyzes the 2'-O-methylation (Nm) modification of PIK3CA mRNA and modulates the PI3K/AKT/mTOR signaling pathway, so as to promote the development of endometrial cancer. In short, SNORD60 might become a new biomarker for the therapy of endometrial cancer in the future and provide new strategies for diagnosis and treatment.
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Neoplasias do Endométrio , Proteínas Proto-Oncogênicas c-akt , Feminino , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Hibridização in Situ Fluorescente , Linhagem Celular Tumoral , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Neoplasias do Endométrio/patologia , Carcinogênese/genética , Carcinogênese/patologia , RNA Mensageiro/genética , Transformação Celular Neoplásica , Classe I de Fosfatidilinositol 3-Quinases/genética , Proliferação de Células/genéticaRESUMO
PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.
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Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Frutas , Estudos Prospectivos , Incidência , Glucose , Fatores de RiscoRESUMO
Ajania belonging to the subtribe Artemisiinae of Anthemideae(Asteraceae) is a genus of semi-shrubs closely related to Chrysanthemum. There are 24 species of Ajania in northwestern China, most of which are folk herbal medicines with strong stress tolerance. Modern medical studies have demonstrated that the chemical constituents of Ajania mainly include terpenoids, flavonoids, phenylpropanoids, alkynes, and essential oils. These compounds endow the plants with antimicrobial, anti-inflammatory, antitumor, antimalarial, antioxidant, and insecticide effects. In this study, we reviewed the research progress in the chemical constituents and pharmacological activities of Ajania, aiming to provide reference for the further research and development of Ajania.
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Asteraceae , Chrysanthemum , Alcinos , Antimaláricos , Antioxidantes/farmacologiaRESUMO
Cholestasis is the most destructive pathological manifestation of liver disease and available treatments are very limited. Paeoniae Radix Rubra (PRR) is an important traditional Chinese drug used to treat cholestasis. This study combined targeted metabonomics, PCR array analysis, and 16S rRNA sequencing analysis to further clarify the mechanisms of PRR in the treatment of cholestasis. PRR conspicuously reversed the elevation of fatty acids (FFA 14:0 and other 14 fatty acids) and the decrease of organic acids (pyruvic acid and citric acid) in a cholestatic model induced by α-naphthyl isothiocyanate (ANIT). Eight elevated amino acids (L-proline, etc.) and five elevated secondary bile acids (taurohyodeoxycholic acid, etc.) in model rats were also reduced by PRR. Pathway analysis revealed that PRR significantly alleviated eight pathways (ß-alanine metabolism). Furthermore, we found that PRR significantly reversed the decrease of Cpt1a, Hadha, Ppara, and Slc25a20 (four genes relevant to fatty acid ß-oxidation) mRNAs caused by ANIT, and PRR conspicuously decreased nine acylcarnitines (the forms of fatty acids into mitochondria for ß-oxidation) that increased in model rats. These results indicate that PRR could enhance fatty acid ß-oxidation, which may be the way for PRR to reduce the levels of 15 fatty acids in the serum of model rats. 16S rRNA sequencing analysis revealed that PRR alleviated gut microbiota disorders in model rats, including upregulating four genera (Coprococcus, Lactobacillus, etc.) and downregulating four genera (Bacteroides, Escherichia, etc.). As the relative abundance of these eight genera was significantly correlated with the levels of the five secondary bile acids (deoxycholic acid, taurolithocholic acid, etc.) reduced by PRR, and Bacteroides and Escherichia were reported to promote the production of secondary bile acid, we inferred that the downregulation of PRR on five secondary bile acids in model rats was inseparable from gut microbiota. Thus, the gut microbiota also might be a potential pharmacological target for the anticholestatic activity of PRR. In conclusion, we consider that the mechanisms of PRR in treating cholestasis include enhancing fatty acid ß-oxidation and alleviating gut microbiota disorders.
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Background: GLP-1 receptor agonists (GLP-1RA) are common clinical agents that are clinically protective against diabetic complications, such as diabetic retinopathy (DR). Previous studies have shown that the RhoA/ROCK pathway plays an important role in the development of DR. However, the specific mechanism of action between GLP-1RA and DR remains unclear. The aim of this study was thus to investigate the main mechanism involved in the protective effect of GLP-1RA on DR. Methods: Type 2 diabetic mice were fed a high-sugar, high-fat diet. Changes in the retinal structure were observed via HE staining and transmission electron microscopy. The expression of retinal GLP-1R, blood-retinal barrier- (BRB-) related proteins, inflammatory factors, and related pathway proteins were studied via Western blot or immunohistochemistry/immunofluorescence analysis. Results: GLP-1RA treatment reduced the blood glucose and lipid levels as well as the body weight of the diabetic mice while also improving retinal thickness, morphology, and vascular ultrastructure. Moreover, restored GLP-1R expression, increased Occludin and ZO-1 levels, and decreased albumin expression led to reduced retinal leakage and improved the BRB by inhibiting the RhoA/ROCK pathway. Conclusions: We found that the protective effect of GLP-1RA on the retina may be realized through the GLP-1R-ROCK-p-MLC signaling pathway.
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Diabetes Mellitus Experimental , Retinopatia Diabética , Camundongos , Animais , Barreira Hematorretiniana/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/prevenção & controle , Retinopatia Diabética/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Transdução de Sinais , Fatores de TranscriçãoRESUMO
The ameliorative effects on ulcerative colitis (UC) as well as the related mechanisms of the essential oil derived from the edible herb Zanthoxylum bungeanum Maxim (ZBEO) have been demonstrated herein. Based on GC-MS analysis, 45 volatile compounds in ZBEO were determined for its quality control. In vitro studies showed that after pretreatment with ZBEO, the disordered expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) and an anti-inflammatory cytokine (IL-10) on colon epithelial NCM460 cells induced by lipopolysaccharide (LPS) could be reversed. Additionally, oral administration of ZBEO significantly alleviated colitis in dextran sulfate sodium (DSS)-induced UC mice, including body weight loss, colon length shortening, disease activity index and colonic pathological damage. Furthermore, to uncover the anti-UC mechanisms of ZBEO, analysis of transcriptomes by next-generation sequencing technology was performed to explore the RNA genetic variation on colon tissues. Based on GO analysis and KEGG pathway analysis, a series of genetic pathways involved in the protective role of ZBEO against UC were determined. As a result, ZBEO treatment could decrease the expression of VCAM-1, TLR8, IL-1ß and IL-11 mRNA as verified by qRT-PCR, which are involved in these potential genetic pathways. In conclusion, ZBEO administration would be a medicinal or dietary supplementation strategy for ulcerative colitis treatment.
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Colite Ulcerativa , Óleos Voláteis , Zanthoxylum , Animais , Anti-Inflamatórios/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Interleucina-10/metabolismo , Interleucina-11/metabolismo , Interleucina-11/farmacologia , Interleucina-11/uso terapêutico , Interleucina-6/metabolismo , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Óleos Voláteis/uso terapêutico , RNA/farmacologia , RNA Mensageiro/metabolismo , Receptor 8 Toll-Like/metabolismo , Transcriptoma , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula VascularRESUMO
Objective: To observe the protective effect of gynostemma glycosides on retinal ganglion cells in rats with chronically high intraocular pressure. Materials and Methods: A total of 60 rats were randomly divided into group A (the blank group, 10 rats) and chronic high IOP model group (50 rats). The IOP model group (IOP above 22 mmHg) was then randomly divided into an additional 5 groups (10 rats per group): group B (negative control group) treated with normal saline; group C treated with gynostemma glycosides 25 mg/(kg-d); group D treated with gynostemma glycosides 50 mg/(kg-d); group E treated with gynostemma glycosides 100 mg/(kg-d); and group F (positive control group) treated with VitB1 and VitB12. The eyes of each rat were monitored from day 1 to 14 (D1-D14). On day 14, rats were euthanized, after which retinal tissue and optic nerve were examined using real-time PCR, western blot, HE staining, LFB staining, and TUNEL assay. Results: Groups A, C, D, E, and F had significantly lower expression of CD11b, GFAP, Brn3α, and more TUNEL cells than in group B (all P < 0.05). Moreover, the relative expression of STAT3 mRNA and JAK2 (mRNA and protein) in groups A, C, D, E, and F was significantly lower than in group B (P < 0.05), while in group E, the expression was lower than in group D (P < 0.05). Conclusion: Gynostemma glycosides protect retinal ganglion cells in rats with chronically high intraocular pressure possibly associated with the STAT3/JAK2 signaling pathway.
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The small nucleolar RNA (snoRNA) is a type of small non-coding RNA widely distributed in the nucleoli of eukaryotic cells, promoting cancer development. The aim of this study was to assess box C/D snoRNA 89 (SNORD89) dysregulations in endometrial cancer. According to the TCGA database as well as the International Federation of Gynecology and Obstetrics (FIGO), higher SNORD89 expression is found in endometrial cancer tissues. In addition, the SNORD89 expression level was higher in endometrial carcinoma with lymph node metastasis than in endometrial carcinoma without lymph node metastasis. By interacting with the conservative chaperone protein methylase fibrillarin (Fbl), SNORD89 inhibits the translation process of the Bim gene, leading to a decrease in Bim protein. Cancer-promoting effect of SNORD89 can be reversed by Fbl knockdown or Bim overexpressing. What's more, ASO-mediated silencing of SNORD89 could inhibit endometrial cancer cell proliferation and migration ability. Taken together, SNORD89 can modify Bim through 2'-O-methylation and affect downstream signaling pathways to promote endometrial cancer occurrence and development. The role of methylation modification in the prevention and treatment of endometrial cancer provides a new understanding and SNORD89 may be a new diagnostic and therapeutic target for endometrial cancer.