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BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor and is highly prone to metastasis. OS can metastasize to the lymph node (LN) through the lymphatics, and the metastasis of tumor cells reestablishes the immune landscape of the LN, which is conducive to the growth of tumor cells. However, the mechanism of LN metastasis of osteosarcoma and remodeling of the metastatic lymph node (MLN) microenvironment is not clear. METHODS: Single-cell RNA sequencing of 18 samples from paracancerous, primary tumor, and lymph nodes was performed. Then, new signaling axes closely related to metastasis were identified using bioinformatics, in vitro experiments, and immunohistochemistry. The mechanism of remodeling of the LN microenvironment in tumor cells was investigated by integrating single-cell and spatial transcriptomics. RESULTS: From 18 single-cell sequencing samples, we obtained 117,964 cells. The pseudotime analysis revealed that osteoblast(OB) cells may follow a differentiation path from paracancerous tissue (PC) â primary tumor (PT) â MLN or from PC â PT, during the process of LN metastasis. Next, in combination of bioinformatics, in vitro and in vivo experiments, and immunohistochemistry, we determined that ETS2/IBSP, a new signal axis, might promote LN metastasis. Finally, single-cell and spatial dissection uncovered that OS cells could reshape the microenvironment of LN by interacting with various cell components, such as myeloid, cancer-associated fibroblasts (CAFs), and NK/T cells. CONCLUSIONS: Collectively, our research revealed a new molecular mechanism of LN metastasis and clarified how OS cells influenced the LN microenvironment, which might provide new insight for blocking LN metastasis.
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Neoplasias Óseas , Ganglios Linfáticos , Metástasis Linfática , Osteosarcoma , Análisis de la Célula Individual , Transcriptoma , Microambiente Tumoral , Osteosarcoma/patología , Osteosarcoma/genética , Humanos , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Animales , Ratones , Línea Celular Tumoral , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Adenoma's detection rates have been reported to vary with the participation status of endoscopic nurses during colonoscopy. This meta-analysis was conducted to determine whether the participation of endoscopy nurses during colonoscopy contributed to the improved detection rate of polyps and adenomas. METHODS: We retrieved English original research from PubMed, Embase, Web of Science, and Cochrane library databases and Chinese original research from the CNKI Data database. We searched for randomized controlled trials (RCTs) comparing the effect of participation of endoscopy nurses during colonoscopy of colorectal polyps and adenomas on polyp detection rates to that of nonparticipation. RevMan5.4 software was used to perform the meta-analysis. RESULTS: This meta-analysis included 11 randomized controlled trials involving 8278 patients. The results showed no significant difference between colonoscopies performed by nurses and endoscopists, but colonoscopies performed by two nurses significantly improved the detection rate of polyps and adenomas. In the random effects model, there was a significant difference in PDR between the single-observation and dual-observation groups (RR, 1.27; 95%CI, 1.05, 1.54; Z = 2.51; P = 0.01). The ADR difference between the single observation group and the double observation group was statistically significant (RR, 1.15; 95%CI, 1.05, 1.26; Z = 2.91; P = 0.004). CONCLUSION: Endoscopy nurses' participation in colonoscopy can improve the detection rate of polyps and adenomas, However, more research is needed to confirm the results.
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Adenoma , Pólipos , Humanos , Adenoma/diagnóstico , Colonoscopía , Bases de Datos Factuales , Ensayos Clínicos Controlados Aleatorios como Asunto , Enfermeras y EnfermerosRESUMEN
Apostasia fujianica belongs to the genus Apostasia and is part of the basal lineage in the phylogenetic tree of the Orchidaceae. Currently, there are only ten reported complete mitochondrial genomes in orchids, which greatly hinders the understanding of mitochondrial evolution in Orchidaceae. Therefore, we assembled and annotated the mitochondrial genome of A. fujianica, which has a length of 573,612 bp and a GC content of 44.5%. We annotated a total of 44 genes, including 30 protein-coding genes, 12 tRNA genes, and two rRNA genes. We also performed relative synonymous codon usage (RSCU) analysis, repeat sequence analysis, intergenomic transfer (IGT) analysis, and Ka/Ks analysis for A. fujianica and conducted RNA editing site analysis on the mitochondrial genomes of eight orchid species. We found that most protein-coding genes are under purifying selection, but nad6 is under positive selection, with a Ka/Ks value of 1.35. During the IGT event in A. fujianica's mitogenome, the trnN-GUU, trnD-GUC, trnW-CCA, trnP-UGG, and psaJ genes were identified as having transferred from the plastid to the mitochondrion. Compared to other monocots, the family Orchidaceae appears to have lost the rpl10, rpl14, sdh3, and sdh4 genes. Additionally, to further elucidate the evolutionary relationships among monocots, we constructed a phylogenetic tree based on the complete mitogenomes of monocots. Our study results provide valuable data on the mitogenome of A. fujianica and lay the groundwork for future research on genetic variation, evolutionary relationships, and breeding of Orchidaceae.
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Genoma Mitocondrial , Orchidaceae , Filogenia , Orchidaceae/genética , Orchidaceae/clasificación , Genoma Mitocondrial/genética , Evolución Molecular , ARN de Transferencia/genética , Composición de Base , Edición de ARN/genética , Uso de CodonesRESUMEN
The WUSCHEL-related homeobox (WOX) transcription factor plays a vital role in stem cell maintenance and organ morphogenesis, which are essential processes for plant growth and development. Dendrobium chrysotoxum, D. huoshanense, and D. nobile are valued for their ornamental and medicinal properties. However, the specific functions of the WOX gene family in Dendrobium species are not well understood. In our study, a total of 30 WOX genes were present in the genomes of the three Dendrobium species (nine DchWOXs, 11 DhuWOXs, and ten DnoWOXs). These 30 WOXs were clustered into ancient clades, intermediate clades, and WUS/modern clades. All 30 WOXs contained a conserved homeodomain, and the conserved motifs and gene structures were similar among WOXs belonging to the same branch. D. chrysotoxum and D. huoshanense had one pair of fragment duplication genes and one pair of tandem duplication genes, respectively; D. nobile had two pairs of fragment duplication genes. The cis-acting regulatory elements (CREs) in the WOX promoter region were mainly enriched in the light response, stress response, and plant growth and development regulation. The expression pattern and RT-qPCR analysis revealed that the WOXs were involved in regulating the floral organ development of D. chrysotoxum. Among them, the high expression of DchWOX3 suggests that it might be involved in controlling lip development, whereas DchWOX5 might be involved in controlling ovary development. In conclusion, this work lays the groundwork for an in-depth investigation into the functions of WOX genes and their regulatory role in Dendrobium species' floral organ development.
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Dendrobium , Evolución Molecular , Regulación de la Expresión Génica de las Plantas , Proteínas de Homeodominio , Familia de Multigenes , Filogenia , Proteínas de Plantas , Dendrobium/genética , Dendrobium/crecimiento & desarrollo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Genes Homeobox , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Flores/genética , Flores/crecimiento & desarrollo , Regiones Promotoras GenéticasRESUMEN
Lipid accumulation in hepatocytes is the distinctive characteristic of nonalcoholic fatty liver disease. Serine/arginine-rich splicing factor 3 (SRSF3) is highly expressed in the liver and expression decreases in high-fat conditions. However, the role of SRSF3 in hepatic lipid metabolism needs to be clarified. Here, we showed that loss of SRSF3 was associated with lipid accumulation. We determined that SRSF3 regulated lipophagy, the process of selective degradation of lipid droplets by autophagy. Mechanistically, loss of SRSF3 impaired the fusion of the autophagosome and lysosome by promoting the proteasomal degradation of syntaxin 17 (STX17), a key autophagosomal SNARE protein. We found that ubiquitination of STX17 was increased and upregulation of seven in absentia homolog 1 was responsible for the increased posttranslational modification of STX17. Taken together, our data primarily demonstrate that loss of SRSF3 weakens the clearance of fatty acids by impairing lipophagy in the progression of nonalcoholic fatty liver disease, indicating a novel potential therapeutic target for fatty liver disease treatment.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Autofagia/genética , Ácidos Grasos/metabolismo , Hepatocitos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Factores de Empalme de ARN/metabolismo , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismo , Ubiquitinación , Proteínas Qa-SNARE/metabolismoRESUMEN
Osteoclasts (OCs) and regulatory CD4+ T cells (CD4+ Tregs) are important components in the tumor microenvironment (TME) of osteosarcoma. In this study, we collected six osteosarcoma samples from our previous study (GSE162454). We also integrated a public database (GSE152048), which included single cell sequencing data of 11 osteosarcoma patients. We obtained 138,192 cells and then successfully identified OCs and CD4+ Tregs. Based on the interaction gene set between OCs and CD4+ Tregs, patients from GSE21257 were distinguished into two clusters by consensus clustering analysis. Both the tumor immune microenvironment and survival prognosis between the two clusters were significantly different. Subsequently, five model genes were identified by protein-protein interaction network based on differentially upregulated genes of cluster 2. Quantitative RT-PCR was used to detect their expression in human osteoblast and osteosarcoma cells. A prognostic model was successfully established using these five genes. Kaplan-Meier survival analysis found that patients in the high-risk group had worse survival (p = 0.029). Therefore, our study first found that cell-cell communication between OCs and CD4+ Tregs significantly alters TME and is connected to poor prognosis of OS. The model we constructed can accurately predict prognosis for osteosarcoma patients.
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Neoplasias Óseas , Osteosarcoma , Humanos , Osteoclastos , Linfocitos T , Osteosarcoma/genética , Pronóstico , Microambiente Tumoral/genética , Neoplasias Óseas/genética , Linfocitos T CD4-PositivosRESUMEN
Osteoporosis is a systemic and metabolic bone disease that usually occurs in postmenopausal women, which mainly manifests as bone loss and increased bone fragility that both facilitate fracture. However, few drugs for osteoporosis have shown good efficacy and limited side effects. Vaccarin has demonstrated its antiosteoporosis effects by inhibiting the formation and osteolytic activities of osteoclasts in our previous investigation. In this study, multivariate statistical analysis and ultrahigh-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry were used to analyze the serum metabolites of ovariectomized mice treated with or without vaccarin. As a result, 9 serum metabolites were identified as biomarkers. The metabolic levels of 3 crucial biomarkers, namely, lysophosphatidylcholine [22â:â6, (4Z, 7Z, 10Z, 13Z, 16Z, 19Z)], 1-linoleoylglycerophosphocholine and 1-palmitoyl-Sn-glycero-3-phosphocholine, that were correlated with glycerophospholipid metabolism increased and then decreased significantly after vaccarin treatment. Molecular docking analysis and osteoclasts differentiation experiment further revealed that vaccarin may bind with phospholipase A2 and downregulated its activity to reduce the osteoclastogenesis. Therefore, the occurrence of osteoporosis is closely related with glycerophospholipid metabolism disorders, and vaccarin exerts antiosteoporosis effects by reducing the levels of glycerophospholipid metabolites.
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Metabolómica , Osteoporosis , Ratones , Femenino , Animales , Cromatografía Líquida de Alta Presión , Simulación del Acoplamiento Molecular , Biomarcadores , Glicerofosfolípidos , Osteoporosis/tratamiento farmacológicoRESUMEN
Objective: Autophagy is the catabolic process where the components of eukaryotes experience damage, and the affected or superfluous components undergo self-degradation. However autophagy can promote cancer cell apoptosis or facilitate cell growth. This work aimed to investigat the significance of autophagy-related genes (ARGs) in predicting the prognosis of breast cancer (BC) intervened with Cremastra. Methods: Active ingredients and action targets were obtained using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SwissTargetPrediction. Then, the BC transcriptome and clinical data were downloaded in The Cancer Genome Atlas (TCGA), whereas ARGs were collected in the Human Autophagy Database (HADb). Meanwhile, Perl and R software were used for data processing and analysis. Firstly, the transcriptome data of BC were mapped to ARGs to screen the BC-ARGs. Secondly, the above genes were mapped to the action targets of Cremastra, ARGs of Cremastra-intervened BC were then screened out. Moreover, an enrichment analysis of biological function was carried out. Univariate Cox regression was carried out on ARGs of BC for preliminarily selecting the independent prognostic genes and constructing the autophagy prognosis model. These genes were mapped to ARGs involved in Cremastra-intervened BC. Finally, those mapped genes were optimized by multi-factor Cox regression, and the key ARGs and potential compounds were obtained. Finally, all cases were classified as low- or high-risk group based on the median risk score. Receiver operating characteristic (ROC) curve, Kaplan-Meier (K-M) survival, independent prognosis and clinical correlation analyses were conducted for model evaluation and identification of factors to independently predict prognosis. Results: Altogether, 66 active components and 38 targets of the Cremastra-intervened autophagy of BC were screened and the autophagy prognosis model demonstrate good predictive performance. As suggested by the survival curve, low-risk patients had a markedly increased survival rate compared with high-risk patients (P < .01). Besides, the gene expression levels of the high-risk group increased with the increases in patients' risk scores. Upon univariate regression, 34 differentially expressed ARGs related to BC treatment were screened. Multivariate regression identified 4 key ARGs, which were mainly derived from glycosides, lignans, flavonoids, and dibenzyl compounds. Thereafter, key genes were subjected to correlation analysis between clinicopathological features and prognosis, among which BCL2 and TP63, showed independent prognostic value. Conclusions: In this study, an autophagy prognosis model was established, and BCL2 and TP63 were predicted for the Cremastra intervention of BC by Bioinformatics, which will be applied to further work.
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RATIONALE: Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated. OBJECTIVE: We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS. METHODS AND RESULTS: We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine-phosphoguanine sites (discovery: false discovery rate <0.005; replication: Bonferroni corrected P<0.05). The association of methylation levels at these cytosine-phosphoguanine sites with ACS was further validated in at least 1 of the 6 leukocyte subsets, with predominant contributions from CD8+ T cells, CD4+ T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including IL6R, FASLG, and CCL18; P<5.9×10-4), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell-mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine-phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol (Penrichment≤1×10-5). CONCLUSIONS: Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.
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Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/genética , Metilación de ADN/fisiología , Epigénesis Genética/fisiología , Estudio de Asociación del Genoma Completo/métodos , Síndrome Coronario Agudo/epidemiología , Anciano , Estudios de Casos y Controles , China/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: To retrospectively analyze the tumor resection method used in 20 patients with clavicular tumors and evaluate its clinical efficacy. METHODS: A total of 9 patients with clavicular benign tumors underwent intracapsular resection, and 11 patients with clavicular malignant tumors underwent tumor resection from May 2012 to May 2017. Of the 11 patients, 5 underwent clavicular reconstruction using the plate-cement complex. Surgical efficacy was assessed using the Musculoskeletal Tumor Society, Constant-Murley, and American Shoulder and Elbow Surgeons shoulder outcome scores preoperatively until 12 months postoperatively. RESULTS: The average duration of follow-up care was 33.7 (12-71) months. Of the 20 patients, 3 patients died, 3 survived with tumor recurrence or metastasis, and 14 survived with no tumor recurrence. Among the 5 patients who underwent resection of malignant clavicular tumors and reconstruction, 2 underwent a re-operation because of a loose screw and plate displacement. In the functional assessment of the shoulder joint, patients with benign and malignant clavicular tumors showed significantly higher scores postoperatively compared with preoperative scores. For malignant clavicular tumors, no significant improvement was observed when comparing the non-reconstruction and reconstruction groups. CONCLUSIONS: Surgery is an optimal treatment for clavicular tumors. In patients with benign clavicular tumors, simple intracapsular resection can achieve a satisfactory prognosis. Reconstruction of a clavicular defect after resection of a clavicular malignant tumor is not recommended.
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Neoplasias Óseas/cirugía , Clavícula/cirugía , Recurrencia Local de Neoplasia/cirugía , Adolescente , Adulto , Neoplasias Óseas/patología , Niño , Preescolar , Clavícula/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: This article aims to design low molecular weight chitosan (LMWC)-based conjugates of Rhein (RH) by means of an amino acid linker (Alanine) for improved solubility and enhanced bioavailability. SIGNIFICANCE: Rhein is a potential candidate for the therapy of kidney disease. However, the poor solubility, inadequate bioavailability, and lack of proper formulation restrict its clinical applicability. LMWC-drug conjugates offer the potential to improve the water-solubility of RH, increase its oral absorption, and thereby enhance its bioavailability. METHODS: The conjugates were synthesized via a carbodiimide reaction and confirmed using UV-vis, FTIR, and 1H-NMR spectroscopy. The water-solubility and in vitro release properties were evaluated. Free RH and RH-LMWC conjugates were administered at an equivalent oral gavage dose of RH at 35 mg/kg for pharmacokinetic studies in Sprague Dawley rats. RESULTS: The conjugates with RH content of 9.65% were successfully synthesized and featured a satisfactory water-solubility of 9.73 mg/mL, which exhibited a sustained release pattern over 72 h, and the enzymes present may promote the degradation of the conjugate to increase the release of Rhein. Oral administration of RH-LMWC conjugates to rats led to seven-folds and 3.1-folds increase in the T1/2 and AUC0-∞, respectively, as compared to RH suspension. CONCLUSION: The present work demonstrated that the RH-LMWC conjugates exhibited sustained release properties with outstanding oral bioavailability enhancements compared to administration of RH itself. Potentially, RH-LMWC conjugates may serve as a promising lead for developing a new platform for RH oral delivery.
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Antraquinonas/síntesis química , Antraquinonas/farmacocinética , Quitosano/síntesis química , Quitosano/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Administración Oral , Animales , Antraquinonas/administración & dosificación , Disponibilidad Biológica , Quitosano/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Masculino , Peso Molecular , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
The aim of this paper was to investigate the effect of emodin on gut microbiota in acute kidney injury rats( AKI). Rats were randomly divided into several groups: normal group,model group,low-dose of emodin group( 10 mg·kg~(-1)),medium-dose of emodin group( 25 mg·kg~(-1)),high-dose of emodin group( 50 mg·kg~(-1)) and control group( 5 mg·kg~(-1) of benazepril hydrochloride).The AKI model rats were established by intraperitoneal injection of small dose of gentamicin sulfate for 7 days. Two hours after intraperitoneal injection,except for the normal group and the model group,the other groups were given corresponding doses of drugs for 15 days. The serum levels of serum creatinine( SCr),urea nitrogen( BUN),plasma endotoxin level,24 h urinary protein and D-lactate in the plasma were determined by sarcosine oxidase,urease method,tal reagent method,bromo cresol chloroform method and double antibody sandwich enzyme-linked immunoadsorbent assay,respectively. Gut microbial communities were assayed by fluorescent quantitative PCR methods. HE staining was used to detect the pathological changes of the kidneys. Compared with the normal group,there were significant differences in body weight,urinary protein( UTP),bacterial endotoxin,urea nitrogen,creatinine,D-lactate in the plasma and four bacterial contents in the model group( P<0. 05). The urinary protein,urea nitrogen,D-lactate,creatinine and plasma bacterial endotoxin in control group and each emodin group were lower than those in model group,especially for high-dose of emodin( P<0. 01). Moreover,pathology resolution in high-dose emodin was better than other groups. Except for low-dose of emodin group,qRT-PCR data suggested that the amounts of Escherichia coli and Enterococcus in medication administration group were increased,while the amounts of Lactobacilli and Bifidobacterium were reduced compared with model group( P<0. 05),especially for high-dose of emodin( P<0. 01). There is a clear imbalance of gut microbiota in rats with AKI. Emodin could regulate the imbalance of gut microbiota,which might be one of the mechanisms of its effects on AKI rats.
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Lesión Renal Aguda , Microbioma Gastrointestinal , Animales , Nitrógeno de la Urea Sanguínea , Emodina , Riñón , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND/AIMS: Regulator of cullins-1 (ROC1) is a pivotal component of cullin-RING E3 ubiquitin ligases, which help to regulate distinct cellular processes by governing the degradation of various substrates. Because the role of ROC1 in gastric cancer is largely uncharacterized, we investigated the relationship between ROC1 expression and the prognosis of gastric cancer patients and explored the biological function of ROC1 and its underlying mechanisms in gastric cancer. METHODS: Kaplan-Meier and multivariate Cox regression analyses were used to evaluate the correlation between the carcinogenesis of gastric cancer and ROC1. SA-ß-gal staining and the senescence-associated secretory phenotype (SASP) were used to assess ROC1 silencing-induced cellular senescence. A xenograft zebrafish model was used to evaluate the effects of BCL-XL and ROC1 co-silencing on tumor formation in vivo. RESULTS: High ROC1 expression was correlated with poor prognosis and a low 5-year survival rate of gastric cancer patients. ROC1 depletion significantly inhibited the growth of gastric cancer cells by sequentially inducing p21-mediated cellular senescence and mitochondrial-dependent apoptosis. Functional studies revealed successive upregulation of c-Jun, BCL-XL, and p21 upon ROC1 knockdown. BCL-XL suppression via RNA interference or a BH3 mimetic (ABT-737 or ABT-263) efficiently enhanced the anti-tumor effects of ROC1 knockdown. Equally as important, BCL-XL silencing strengthened ROC1 knockdown-induced apoptosis by blocking p21-mediated senescence. CONCLUSIONS: The c-Jun/BCL-XL/p21 axis promotes senescence to resist ROC1 knockdown-induced apoptosis in gastric cancer cells. Targeted inactivation of BCL-XL could sensitize gastric cancer cells to ROC1 knockdown in clinical practice.
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A series of hydroxychalcone derivatives have been designed, synthesized and evaluated for human xanthine oxidase (XO) inhibitory activity. Most of the tested compounds acted moderate XO inhibition with IC50 values in the micromolar rang. Molecular docking and kinetic studies have been performed to explain the binding modes of XO with the selected compounds. In addition, in vitro antioxidant screening results indicated that some of the hydroxychalcones possessed good anti-free radical activities. Furthermore, the preferred compounds 16 and 18 were able to significantly inhibit hepatic xanthine oxidase activity and reduced serum uric acid level of hyperuricemic mice in vivo. In summary, compounds 16 and 18 with balanced activities of antioxidant, XO inhibition and serum uric acid reduction, which are promising candidates for the treatment of hyperuricemia and gout.
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Chalconas/química , Chalconas/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Hiperuricemia/tratamiento farmacológico , Xantina Oxidasa/antagonistas & inhibidores , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Chalconas/síntesis química , Chalconas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Hiperuricemia/sangre , Hiperuricemia/metabolismo , Ratones , Modelos Moleculares , Ácido Úrico/sangre , Ácido Úrico/metabolismo , Xantina Oxidasa/metabolismoRESUMEN
The aim of this work is to develop biodegradable nanoparticles for improved kidney bioavailability of rhein (RH). RH-loaded nanoparticles were prepared using an emulsification solvent evaporation method and fully characterized by several techniques. Kidney pharmacokinetics was assessed by implanting a microdialysis probe in rat's kidney cortex. Blood samples were simultaneously collected (via femoral artery) for assessing plasma pharmacokinetics. Optimized nanoparticles were small, with a mean particle size of 132.6 ± 5.95 nm, and homogeneously dispersed. The charge on the particles was nearly zero, the encapsulation efficiency was 62.71 ± 3.02%, and the drug loading was 1.56 ± 0.15%. In vitro release of RH from the nanoparticles showed an initial burst release followed by a sustained release. Plasma and kidney pharmacokinetics showed that encapsulation of RH into nanoparticles significantly increased its kidney bioavailability (AUCkidney/AUCplasma = 0.586 ± 0.072), clearly indicating that nanoparticles are a promising strategy for kidney drug delivery.
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Antraquinonas/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Riñón/metabolismo , Nanopartículas/química , Animales , Antraquinonas/química , Antraquinonas/metabolismo , Disponibilidad Biológica , Riñón/química , Nanopartículas/administración & dosificación , RatasRESUMEN
Intermittent hypoxia preconditioning (IHP) has been shown to protect neurons against ischemic stroke injury. Studying how proteins respond to IHP may identify targets that can help fight stroke. The objective of the present study was to investigate whether mitochondrial dihydrolipoamide dehydrogenase (DLDH) would respond to IHP and if so, whether such a response could be linked to neuroprotection in ischemic stroke injury. To do this, we subjected male rats to IHP for 20 days and measured the content and activity of DLDH as well as the three α-keto acid dehydrogenase complexes that contain DLDH. We also measured mitochondrial electron transport chain enzyme activities. Results show that DLDH content was indeed upregulated by IHP and this upregulation did not alter the activities of the three α-keto acid dehydrogenase complexes. Results also show that the activities of the five mitochondrial complexes (I-V) were not altered either by IHP. To investigate whether IHP-induced DLDH upregulation is linked to neuroprotection against ischemic stroke injury, we subjected both DLDH deficient mouse and DLDH transgenic mouse to stroke surgery followed by measurement of brain infarction volume. Results indicate that while mouse deficient in DLDH had exacerbated brain injury after stroke, mouse overexpressing human DLDH also showed increased brain injury after stroke. Therefore, the physiological significance of IHP-induced DLDH upregulation remains to be further investigated.
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Isquemia Encefálica/metabolismo , Dihidrolipoamida Deshidrogenasa/metabolismo , Mitocondrias/metabolismo , Animales , Isquemia Encefálica/patología , Hipoxia de la Célula , Dihidrolipoamida Deshidrogenasa/genética , Modelos Animales de Enfermedad , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Humanos , Precondicionamiento Isquémico , Ratones Transgénicos , Ratas , Regulación hacia ArribaRESUMEN
Chemotherapy, a primary treatment for osteosarcoma (OS), has limited knowledge regarding its impact on tumor immune microenvironment (TIME). Here, tissues from 6 chemotherapy-naive OS patients underwent single-cell RNA sequencing (scRNA-seq) and were analyzed alongside public dataset (GSE152048) containing 7 post-chemotherapy OS tissues. CD45+ (PTPRC+) cells were used for cell clustering and annotation. Changes in immune cell composition pre- and post-chemotherapy were characterized. Totally, 28,636 high-quality CD45+ (PTPRC+) cells were extracted. Following chemotherapy, the proportions of regulatory T cells (Tregs) and activated CD8 T cells decreased, while CD8 effector T cells increased. GO analysis indicated that differentially expressed genes (DEGs) in T cells were associated with cell activation, adaptive immune response, and immune response to tumor cells. Furthermore, the proportions of plasma cells increased, while naive B cells decreased. B cell surface receptors expression was upregulated, and GO analysis revealed DEGs of B cells were mainly enriched in B cell-mediated immunity and B cell activation. Moreover, M2 polarization of macrophages was suppressed post-chemotherapy. Overall, this study elucidates chemotherapy remodels the OS TIME landscape, triggering immune heterogeneity and enhancing anti-tumor properties.
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Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a high mortality rate. It is regarded as a significant public health issue because of its complicated pathophysiology, high metastasis, and recurrence rates. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Traditional treatment methods such as surgical resection, radiotherapy, chemotherapy, and interventional therapies have limited therapeutic effects for HCC patients with recurrence or metastasis. With the development of molecular biology and immunology, molecular signaling pathways and immune checkpoint were identified as the main mechanism of HCC progression. Targeting these molecules has become a new direction for the treatment of HCC. At present, the combination of targeted drugs and immune checkpoint inhibitors is the first choice for advanced HCC patients. In this review, we mainly focus on the cutting-edge research of signaling pathways and corresponding targeted therapy and immunotherapy in HCC. It is of great significance to comprehensively understand the pathogenesis of HCC, search for potential therapeutic targets, and optimize the treatment strategies of HCC.
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BACKGROUND AND OBJECTIVES: Cumulative lipid profile burden is designed to dynamically measure lipid accumulation, and its effect on hypertension has been poorly studied. Our main purpose was to investigate the effect of cumulative lipid profile burden on the incidence of essential hypertension (EH) and to investigate whether cumulative lipid burden mediates the pathogenesis of the effects of diet and obesity on EH. SUBJECTS AND METHODS: A total of 1295 participants were included in the study, which started in 2017. The average follow-up time was 2.98 years. A total of 240 EH patients occurred during the follow-up period. RESULTS: The HR (95% CI) of the highest quartile in cumulative Total cholesterol (TC), triglyceride (TG) and high density lipoprotein (HDL) burden were 1.747 (1.145 - 2.664), 1.502 (1.038 - 2.173), 0.615 (0.413 - 0.917) for incidence of EH respectively, compared to the respective reference groups. Participants with EH consumed more red meat and refined grains, and red meat was positively associated with cumulative TC burden. BMI and Waist-To-Height Ratio (WHtR) increased the incidence of EH, and obesity was positively correlated with cumulative TG burden. Mediating analysis showed that cumulative TG had a partial mediating effect in the causal relationship between obesity and EH, and Mendelian randomization (MR) also proved this result. Diet was not found to influence EHn through cumulative lipid profile burden. CONCLUSIONS: The cumulative TG burden partially mediates the effect of obesity on EH.
Asunto(s)
Hipertensión , Humanos , Estudios de Cohortes , Índice de Masa Corporal , Hipertensión/epidemiología , Hipertensión/etiología , Obesidad/complicaciones , Triglicéridos , Hipertensión Esencial , Dieta , China/epidemiología , HDL-ColesterolRESUMEN
Purpose: The prevalence of diabetes in China is increasing, influenced by economic and genetic factors, with varying rates across regions. The Hakka population in Ganzhou city has unique exposures compared to surrounding districts, while limited research reported the epidemiological characteristics of type 2 diabetes mellitus (T2DM) in this population. This study aims to investigate the prevalence and influencing factors of T2DM among the population, thereby establishing a robust foundation for disease prevention and control measures. Patients and Methods: In 2017, a multistage random sampling method selected 3028 individuals from Ganzhou City's permanent resident population. Physical examinations, blood tests, and questionnaire surveys were conducted for data collection, with binary logistic regression analysis used to examine factors affecting T2DM prevalence. Results: A total of 2978 valid samples were included in this study. The average age of the surveyed population was 52.83±7.88 years, comprising 966 males and 2012 females. The prevalence rates of T2DM were 11.8% and 12.9% in males and females, respectively, while the standardized prevalence rate was recorded as 9.1%. Logistic regression analysis revealed that age (Odds Ratio[OR]=1.05, 95% Confidence Interval [CI]:1.03-1.06), hypertension (OR=2.22, 95% CI:1.71-2.93), family history of diabetes (OR= 3.54, 95% CI: 2.58-4.85), overweight (OR=1.73, 95% CI: 1.20-2.48), high total cholesterol (OR=1.17, 95% CI:1.09-1.27), elevated low-density lipoprotein cholesterol (OR=1.19, 95% CI:1.00-1.40) and serum insulin (OR=1.05, 95% CI:1.03-1.06) were identified as significant risk factors for T2DM, Conversely, a higher level of high-density lipoprotein cholesterol (OR=0.55, 95% CI:0.36-0.84) was found to be inversely related to T2DM development. Conclusion: The prevalence of T2DM in Ganzhou city has significantly increased. The effective implementation of comprehensive management strategies aimed at addressing hypertension, overweight, dyslipidemia, and abnormal serum insulin level is essential for promoting overall well-being and efficiently controlling the prevalence of T2DM.