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PURPOSE: Osteosarcoma, a highly malignant primary bone tumor primarily affecting adolescents, frequently develops resistance to initial chemotherapy, leading to metastasis and limited treatment options. Our study aims to uncover novel therapeutic targets for metastatic and recurrent osteosarcoma. METHODS: In this study, we proved the potential of modulating the YAP1-regulated glutamine metabolic pathway to augment the response of OS to DFMO. We initially employed single-cell transcriptomic data to gauge the activation level of polyamine metabolism in MTAP-deleted OS patients. This was further substantiated by transcriptome sequencing data from recurrent and non-recurrent patient tissues, confirming the activation of polyamine metabolism in progressive OS. Through high-throughput drug screening, we pinpointed CIL56, a YAP1 inhibitor, as a promising candidate for a combined therapeutic strategy with DFMO. In vivo, we utilized PDX and CDX models to validate the therapeutic efficacy of this drug combination. In vitro, we conducted western blot analysis, qPCR analysis, immunofluorescence staining, and PuMA experiments to monitor alterations in molecular expression, distribution, and tumor metastasis capability. We employed CCK-8 and colony formation assays to assess the proliferative capacity of cells in the experimental group. We used flow cytometry and reactive oxygen probes to observe changes in ROS and glutamine metabolism within the cells. Finally, we applied RNA-seq in tandem with metabolomics to identify metabolic alterations in OS cells treated with a DFMO and CIL56 combination. This enabled us to intervene and validate the role of the YAP1-mediated glutamine metabolic pathway in DFMO resistance. RESULTS: Through single-cell RNA-seq data analysis, we pinpointed a subset of late-stage OS cells with significantly upregulated polyamine metabolism. This upregulation was further substantiated by transcriptomic profiling of recurrent and non-recurrent OS tissues. High-throughput drug screening revealed a promising combination strategy involving DFMO and CIL56. DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO's anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839. This underscores the significant potential of targeting the YAP1-mediated glutamine metabolic pathway to enhance efficacy of DFMO. CONCLUSION: Our findings elucidate YAP1-mediated glutamine metabolism as a crucial bypass mechanism against DFMO, following the inhibition of polyamine metabolism. Our study provides valuable insights into the potential role of DFMO in an "One-two Punch" therapy of metastatic and recurrent osteosarcoma.
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Purpose: This study aims to explore the metabolic signature of aging retina and identify the potential metabolic biomarkers for the diagnosis of retinal aging. Methods: Retinal samples were collected from both young (two months) and aging (14 months) mice to conduct an unbiased metabolic profiling. Liquid chromatography-tandem mass spectrometry analysis was conducted to screen for the metabolic biomarkers and altered signaling pathways associated with retinal aging. Results: We identified 166 metabolites differentially expressed between young and aged retinas using a threshold of orthogonal projection to latent structures discriminant analysis variable importance in projection >1 and P < 0.05. These metabolites were significantly enriched in several metabolic pathways, including purine metabolism, citrate cycle, phenylalanine, tyrosine and tryptophan biosynthesis, glycerophospholipid metabolism, and alanine, aspartate and glutamate metabolism. Among these significantly enriched pathways, glycerophospholipid metabolites emerged as promising candidates for retinal aging biomarkers. We assessed the potential of these metabolites as biomarkers through an analysis of their sensitivity and specificity, determined by the area under the receiver-operating characteristic (ROC) curves. Notably, the metabolites like PC (15:0/22:6), PC (17:0/14:1), LPC (P-16:0), PE (16:0/20:4), and PS (17:0/16:1) demonstrated superior performance in sensitivity, specificity, and accuracy in predicting retinal aging. Conclusions: This study sheds light on the molecular mechanisms underlying retinal aging by identifying distinct metabolic profiles and pathways. These findings provide a valuable foundation for developing future clinical applications in diagnosing, identifying, and treating age-related retinal degeneration. Translational Relevance: This study sheds light on novel metabolic profiles and biomarkers in aging retinas, potentially paving the way for targeted interventions in preventing, diagnosing, and treating age-related retinal degeneration and other retinal diseases.
Subject(s)
Aging , Biomarkers , Mice, Inbred C57BL , Retina , Tandem Mass Spectrometry , Animals , Aging/metabolism , Retina/metabolism , Mice , Biomarkers/metabolism , Chromatography, Liquid , ROC Curve , Metabolic Networks and Pathways , Metabolome , Metabolomics/methodsABSTRACT
Background: The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha (ERα) signaling and promoting cellular differentiation in models of human osteosarcoma (OSA). Whether this pathway can be targeted in canine OSA patients is unknown. Methods: Canine OSA tumor samples were tested for ERα expression and ESR1 promoter methylation. Human (MG63.3) and canine (MC-KOS) OSA cell lines and murine xenografts were treated with DAC in vitro and in vivo, respectively. Samples were assessed using mRNA sequencing and tissue immunohistochemistry. Results: ESR1 is methylated in a subset of canine OSA patient samples and the MC-KOS cell line. DAC treatment led to enhanced differentiation as demonstrated by increased ALPL expression, and suppressed tumor growth in vitro and in vivo. Metastatic progression was inhibited, particularly in the MG63.3 model, which expresses higher levels of DNA methyltransferases DNMT1 and 3B. DAC treatment induced significant alterations in immune response and cell cycle pathways. Conclusion: DAC treatment activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in human and canine OSA. Additional DAC-altered pathways and species- or individual-specific differences in DNMT expression may also play a role in DAC treatment of OSA.
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Background: Microcirculatory perfusion disorder and inflammatory response are critical links in acute kidney injury (AKI). We aim to construct anti-vascular cell adhesion molecule-1(VCAM-1) targeted microbubbles (TM) to monitor renal microcirculatory perfusion and inflammatory response. Methods: TM carrying VCAM-1 polypeptide was constructed by biological coupling. The binding ability of TM to human umbilical vein endothelial cells (HUVECs) was detected. Bilateral renal ischemia-reperfusion injury (IRI) models of mice were established to evaluate microcirculatory perfusion and inflammatory response using TM. Thirty-six mice were randomly divided into six groups according to the different reperfusion time (0.5, 2, 6, 12, and 24 h) and sham-operated group (Sham group). The correlation of TM imaging with serum and histopathological biomarkers was investigated. Results: TM has advantages such as uniform distribution, regular shape, high stability, and good biosafety. TM could bind specifically to VCAM-1 molecule expressed by tumor necrosis factor-alpha (TNF-α)-treated HUVECs. In the renal IRI-AKI model, the area under the curve (AUC) of TM significantly decreased both in the renal cortical and medullary after 2 h of reperfusion compared with the Sham group (p < 0.05). Normalized intensity difference (NID) of TM at different reperfusion time was all higher than that of blank microbubbles (BM) and the Sham group (p < 0.05). Ultrasound molecular imaging of TM could detect AKI early before commonly used renal function markers, histopathological biomarkers, and BM imaging. AUC of TM was negatively correlated with serum creatinine (Scr), blood urea nitrogen (BUN), and Cystatin C (Cys-C) levels, and NID of TM was linearly correlated with VCAM-1, TNF-α, and interleukin-6 (IL-6) expression (p < 0.05). Conclusions: Ultrasound molecular imaging based on TM carrying VCAM-1 polypeptide can accurately evaluate the changes in renal microcirculatory perfusion and inflammatory response, which might be a promising modality for early diagnosis of AKI.
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INTRODUCTION: Diabetic retinopathy (DR) is a common vascular complication of diabetes mellitus and a leading cause of vision loss worldwide. Endothelial cell (EC) heterogeneity has been observed in the pathogenesis of DR. Elucidating the underlying mechanisms governing EC heterogeneity may provide novel insights into EC-specific therapies for DR. RESEARCH DESIGN AND METHODS: We used the single-cell data from the Gene Expression Omnibus database to explore EC heterogeneity between diabetic retinas and non-diabetic retinas and identify the potential genes involved in DR. CCK-8 assays, EdU assays, transwell assays, and tube formation assays were conducted to determine the role of the identified gene in angiogenic effects. RESULTS: Our analysis identified three distinct EC subpopulations in retinas and revealed that Mitochondria-localized glutamic acid-rich protein (Mgarp) gene is potentially involved in the pathogenesis of DR. Silencing of Mgarp significantly suppressed the proliferation, migration, and tube formation capacities in retinal endothelial cells. CONCLUSIONS: This study not only offers new insights into transcriptomic heterogeneity and pathological alteration of retinal ECs but also holds the promise to pave the way for antiangiogenic therapy by targeting EC-specific gene.
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Diabetic Retinopathy , Endothelial Cells , Gene Expression Profiling , Single-Cell Analysis , Diabetic Retinopathy/genetics , Diabetic Retinopathy/pathology , Endothelial Cells/pathology , Endothelial Cells/metabolism , Humans , Animals , Cell Proliferation , Retina/pathology , Retina/metabolism , Transcriptome , Cell Movement/genetics , Mice , Angiogenesis Inhibitors/therapeutic use , Neovascularization, Pathologic/genetics , Mitochondrial Proteins/genetics , Cells, CulturedABSTRACT
Hepatocellular carcinoma (HCC), a widely prevalent malignancy strongly linked to inflammation, remains a significant public health concern. Triggering receptor expressed on myeloid cells 1 (TREM1), a modulator of inflammatory responses identified in recent years, has emerged as a crucial facilitator in cancer progression. Despite its significance, the precise regulatory mechanism of TREM1 in HCC metastasis remains unanswered. In the present investigation, we observed aberrant upregulation of TREM1 in HCC tissues, which was significantly linked to poorer overall survival. Inhibition of TREM1 expression resulted in a significant reduction in HCC Huh-7 and MHCC-97H cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process. Furthermore, inhibiting TREM1 decreased protein expressions of toll-like receptor 2/4 (TLR2/4) and major myeloid differentiation response gene 88 (MyD88), leading to the inactivation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. Notably, these effects were reversed by treatment with TLR2-specific agonist (CU-T12-9), indicating a potential crosstalk between TREM1 and TLR2/4. Mechanistic studies revealed a direct interaction between TREM1 and both TLR2 and TLR4. In vivo studies demonstrated that inhibition of TREM1 suppressed the growth of HCC cells in the orthotopic implant model and its metastatic potential in the experimental lung metastasis model. Overall, our findings underscore the role of TREM1 inhibition in regulating EMT and metastasis of HCC cells by inactivating the TLR/PI3K/AKT signaling pathway, thereby providing deeper mechanistic insights into how TREM1 regulates metastasis during HCC progression.
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BACKGROUND: The treatment of oral leukoplakia (OLK) with aminolaevulinic acid photodynamic therapy (ALA-PDT) is widespread. Nonetheless, there is variation in efficacy. Therefore, this study constructed a model for predicting the short-term efficacy and recurrence of OLK after ALA-PDT. METHODS: The short-term efficacy and recurrence of ALA-PDT were calculated by statistical analysis, and the relevant influencing factors were analyzed by Logistic regression and COX regression model. Finally, prediction models for total response (TR) rate, complete response (CR) rate and recurrence in OLK patients after ALA-PDT treatment were established. Features from pathology sections were extracted using deep learning autoencoder and combined with clinical variables to improve prediction performance of the model. RESULTS: The logistic regression analysis showed that the non-homogeneous (OR: 4.911, P: 0.023) OLK and lesions with moderate to severe epithelial dysplasia (OR: 4.288, P: 0.042) had better short-term efficacy. The area under receiver operating characteristic curve (AUC) of CR, TR and recurrence predict models after the ALA-PDT treatment of OLK patients is 0.872, 0.718, and 0.564, respectively. Feature extraction revealed an association between inflammatory cell infiltration in the lamina propria and recurrence after PDT. Combining clinical variables and deep learning improved the performance of recurrence model by more than 30 %. CONCLUSIONS: ALA-PDT has excellent short-term efficacy in the management of OLK but the recurrence rate was high. Prediction model based on clinicopathological characteristics has excellent predictive effect for short-term efficacy but limited effect for recurrence. The use of deep learning and pathology images greatly improves predictive value of the models.
Subject(s)
Aminolevulinic Acid , Deep Learning , Leukoplakia, Oral , Photochemotherapy , Photosensitizing Agents , Humans , Leukoplakia, Oral/drug therapy , Photochemotherapy/methods , Photosensitizing Agents/therapeutic use , Female , Male , Aminolevulinic Acid/therapeutic use , Middle Aged , Aged , Adult , Neoplasm Recurrence, Local/drug therapyABSTRACT
Mesenchymal stroma cells derived from oral tissues are known as dental stem cells (DSCs). Owing to their unique therapeutic niche and clinical accessibility, DSCs serve as a promising treatment option for bone defects and oral tissue regeneration. DSCs exist in a hypoxic microenvironment in vivo, which is far lower than the current 20% oxygen concentration used in in vitro culture. It has been widely reported that the application of an oxygen concentration less than 5% in the culture of DSCs is beneficial for preserving stemness and promoting proliferation, migration, and paracrine activity. The paracrine function of DSCs involves the secretome, which includes conditioned media (CM) and soluble bioactive molecules, as well as extracellular vesicles extracted from CM. Hypoxia can play a role in immunomodulation and angiogenesis by altering the protein or nucleic acid components in the secretory group, which enhances the therapeutic potential of DSCs. This review summarizes the biological characteristics of DSCs, the influence of hypoxia on DSCs, the impact of hypoxia on the secretory group of DSCs, and the latest progress on the use of DSCs secretory group in tissue regeneration based on hypoxia pretreatment. We highlighted the multifunctional biological effect of hypoxia culture on tissue regeneration and provided a summary of the current mechanism of hypoxia in the pretreatment of DSCs.
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BACKGROUND: Mounting evidence indicates that complement components play a crucial role in cancer progression. Recent findings indicate that certain complement components display a significant rise in expression within esophageal squamous cell carcinoma (ESCC). However, the specific tumorigenic functions of these components remain unclear. This study focuses on investigating the expression pattern of C1r, elucidating a role for C1r in ESCC, as well as exploring underlying mechanisms controlled by C1r. METHODS: The expression of C1r in ESCC tissues, malignant epithelial cells, and its relationship with survival were analyzed using the Gene Expression Omnibus (GEO) database and tissue microarrays. Single-cell RNA sequencing (scRNA-seq) was used to study the expression of C1r in malignant epithelial cells. C1r knockdown or C1r overexpression in cultured ESCC cells were used to assess the effects of C1r on proliferation, migration, invasion, cell-matrix adhesion, apoptosis, and growth of xenografted tumors in immunocompromised (nude) mice. Western blotting was used to detect the expression of MMP-1 and MMP-10 in C1r knockdown or C1r overexpressing ESCC cells. RESULTS: C1r was highly expressed in ESCC tissues, malignant epithelial cells, and cultured ESCC cell lines. High C1r expression indicated a poor prognosis. Knockdown of C1r significantly suppressed the proliferation, migration, invasion, cell-matrix adhesion, and promoted apoptosis in cultured ESCC cells. Additionally, knockdown of C1r markedly inhibited tumor growth in nude mice. Overexpression of C1r had the opposite effects. C1r induced the expression of MMP-1 and MMP-10. CONCLUSIONS: C1r is highly expressed in ESCC and promotes the progression of this tumor type. Our findings suggest that C1r may serve as a novel prognostic biomarker and therapeutic target in ESCC.
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Biomarkers, Tumor , Cell Proliferation , Complement C1r , Disease Progression , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Mice, Nude , Humans , Animals , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Esophageal Neoplasms/metabolism , Prognosis , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Complement C1r/genetics , Complement C1r/metabolism , Cell Proliferation/genetics , Cell Movement/genetics , Apoptosis/genetics , Mice , Male , Female , Gene Expression Regulation, Neoplastic , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 1/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathologyABSTRACT
Serum amyloid A1 (SAA1), an inflammation-related molecule, is associated with the malignant progression of many tumors. This study aimed to investigate the role of SAA1 in the progression of esophageal squamous cell carcinoma (ESCC) and its molecular mechanisms. The expression of SAA1 in ESCC tissues and cell lines was analyzed using bioinformatics analysis, western blotting, and reverse transcription-quantitative PCR (RTâqPCR). SAA1-overexpressing or SAA1-knockdown ESCC cells were used to assess the effects of SAA1 on the proliferation, migration, apoptosis of cancer cells and the growth of xenograft tumors in nude mice. Western blotting, immunofluorescence and RTâqPCR were used to investigate the relationship between SAA1 and ß-catenin and SAA1 and sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 1 (S1PR1). SAA1 was highly expressed in ESCC tissues and cell lines. Overexpression of SAA1 significantly promoted the proliferation, migration and the growth of tumors in nude mice. Knockdown of SAA1 had the opposite effects and promoted the apoptosis of ESCC cells. Moreover, SAA1 overexpression promoted the phosphorylation of ß-catenin at Ser675 and increased the expression levels of the ß-catenin target genes MYC and MMP9. Knockdown of SAA1 had the opposite effects. S1P/S1PR1 upregulated SAA1 expression and ß-catenin phosphorylation at Ser675 in ESCC cells. In conclusion, SAA1 promotes the progression of ESCC by increasing ß-catenin phosphorylation at Ser675, and the S1P/S1PR1 pathway plays an important role in its upstream regulation.
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Choroidal neovascularization (CNV) is a hallmark of neovascular age-related macular degeneration (nAMD) and a major contributor to vision loss in nAMD cases. However, the identification of specific cell types associated with nAMD remains challenging. Herein, we performed single-cell sequencing to comprehensively explore the cellular diversity and understand the foundational components of the retinal pigment epithelium (RPE)/choroid complex. We unveiled 10 distinct cell types within the RPE/choroid complex. Notably, we observed significant heterogeneity within endothelial cells (ECs), fibroblasts, and macrophages, underscoring the intricate nature of the cellular composition in the RPE/choroid complex. Within the EC category, four distinct clusters were identified and EC cluster 0 was tightly associated with choroidal neovascularization. We identified five clusters of fibroblasts actively involved in the pathogenesis of nAMD, influencing fibrotic responses, angiogenic effects, and photoreceptor function. Additionally, three clusters of macrophages were identified, suggesting their potential roles in regulating the progression of nAMD through immunomodulation and inflammation regulation. Through CellChat analysis, we constructed a complex cell-cell communication network, revealing the role of EC clusters in interacting with fibroblasts and macrophages in the context of nAMD. These interactions were found to govern angiogenic effects, fibrotic responses, and inflammatory processes. In summary, this study reveals noteworthy cellular heterogeneity in the RPE/choroid complex and provides valuable insights into the pathogenesis of CNV. These findings will open up potential avenues for deep understanding and targeted therapeutic interventions in nAMD.
Subject(s)
Choroid , Choroidal Neovascularization , Disease Models, Animal , Macrophages , Retinal Pigment Epithelium , Single-Cell Analysis , Animals , Mice , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/pathology , Choroidal Neovascularization/metabolism , Choroidal Neovascularization/pathology , Choroidal Neovascularization/genetics , Choroid/pathology , Choroid/metabolism , Macrophages/metabolism , Macrophages/pathology , Transcriptome , Mice, Inbred C57BL , Fibroblasts/metabolism , Fibroblasts/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Cell Communication/physiology , Wet Macular Degeneration/genetics , Wet Macular Degeneration/metabolism , Gene Expression ProfilingABSTRACT
BACKGROUND AND AIMS: We aimed to explore the effect of PCSK9 inhibitor based on the background of statin on carotid intraplaque neovascularization (IPN) assessed by serial contrast-enhanced ultrasound (CEUS) analysis in Chinese patients with premature coronary artery disease (PCAD). METHODS: 41 patients were included to receive treatments with biweekly evolocumab (n = 22) or placebo (n = 19) in addition to statin therapy for 52 weeks. All patients were newly diagnosed with PCAD and treatments were initiated at baseline of the observations. Baseline and 52-week CEUS were acquired to measure the max plaque height (MPH) and IPN. The primary outcome was the 52-week IPN changes, the secondary endpoints included the 52-week MPH changes and major adverse cardiovascular events. RESULTS: The mean ± SD age of the participants was 46.76 ± 8.56 years, and 61% (25/41) of patients were on statins before the start of the study. There was no statistically significant difference in the history of statins treatment and the initiated lipid-lowering therapy of atorvastatin and rosuvastatin between groups (p > 0.05). At 52 weeks, the evolocumab group showed a lower LDL level (0.84 ± 0.45 mmol/L vs. 1.58 ± 0.51 mmol/L, p < 0.001) and a greater decrease in percent reduction of LDL-C level (-65% vs. -32%) and a higher percent of achieving lipid-lowering target (95% vs. 53%, p < 0.05) compared with the placebo group. At 52 weeks, IPN (evolocumab group: 0.50 ± 0.60 vs. 1.50 ± 0.80, p < 0.001; placebo group: 0.79 ± 0.54 vs. 1.26 ± 0.65, p < 0.05) and MPH (evolocumab group: 2.01 ± 0.44 mm vs. 2.57 ± 0.90 mm, p < 0.05, placebo group: 2.21 ± 0.58 mm vs. 2.92 ± 0.86 mm, p < 0.05) reduced significantly in both groups from baseline to 52-week follow-up. IPN and MPH were decreased by both treatments. Still, there was no significant difference in delta (52 weeks - baseline) MPH by an ANOVA analysis between the two groups [evolocumab group: -0.56 mm (2.01 mm-2.57 mm); placebo group: -0.71 mm (2.21 mm-2.92 mm), p > 0.05]. In the evolocumab group, the change in the mean reduction of IPN from baseline [-1.00 (0.50-1.50) vs. -0.47 (0.79-1.26), p < 0.05] and the incidence of patients with carotid IPN decrease were significantly greater reduction (90% vs. 58%, p < 0.05). CONCLUSIONS: If compared to placebo, the PCSK9 inhibitor evolocumab combined with statins resulted in a greater decrease in LDL-C and plaque neovascularization in Chinese patients with PCAD.
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Antibodies, Monoclonal, Humanized , Anticholesteremic Agents , Coronary Artery Disease , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Plaque, Atherosclerotic , Humans , Adult , Middle Aged , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Coronary Artery Disease/complications , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/drug therapy , Proprotein Convertase 9 , Anticholesteremic Agents/adverse effects , Cholesterol, LDL , Plaque, Atherosclerotic/drug therapy , Treatment OutcomeABSTRACT
Objective: To probe into the influence of Helicobacter pylori (Hp) infection on glucose metabolism, lipid metabolism, and inflammatory cytokines in patients with nonalcoholic fatty liver disease (MASLD). Methods: A total of 140 MASLD patients admitted to our Hospital between June 2020 and May 2021 were selected as the research objects. Based on the presence or absence of Hp infection, they were divided into the study group (73 cases with infection) and control group (67 cases without infection). Glucose metabolism indicators [fasting blood glucose (FBG), 2-hour postprandial glucose (2hPG), fasting insulin (FINS), glycated hemoglobin (HbAlc)], lipid metabolism indicators [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], and inflammatory indicators [interleukin-37 (IL-37), interleukin-18 (IL-18)] were measured and compared between the two groups. Results: In terms of glucose metabolism indicators, the study group exhibited higher levels of FBG (5.84±0.49 vs 5.40±0.51, t=2.535, P=0.012), 2hPG (7.26±1.30 vs 6.50±1.53, t=3.321, P<0.001), and FINS (11.13±4.13 vs 9.12±3.72, t=3.224, P<0.001), and Insulin resistance index (HOMA-IR) (2.97±0.35 VS 2.13±0.54, t=3.761, P<0.001) and a lower level of HbAlc (5.25±0.56 vs 6.12±0.57, t=5.473, P<0.001) compared to the control group. Regarding lipid metabolism indicators, the study group exhibited higher levels of TC (5.64±1.49 vs 5.01±1.32, t=3.332, P<0.001), TG (1.89±0.34 vs 1.32±0.43, t=3.411, P<0.001), and LDL-C (3.31±0.43 vs 2.12±0.29, t=4.142, P<0.001), and a lower level of HDL-C (1.45±0.21 vs 1.78±0.42, t=4.347, P<0.001) compared to the control group. As for the inflammatory indicators, the study group exhibited higher levels of IL-37 (45.56±6.02 vs 34.02±3.28, t=9.332, P<0.001) and IL-18 (73.57±5.82 vs 60.34±4.84, t=10.141, P<0.001) compared to the control group. Conclusion: It is crucial to place appropriate emphasis on the impact of Hp infection on the glucose metabolism, lipid metabolism, and inflammatory response in MASLD patients, warranting careful consideration during the treatment of these patients.
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Remifentanilinduced hyperalgesia (RIH) is characterized by the emergence of stimulationinduced pain, including phenomena such as allodynia and thermal hyperalgesia following remifentanil infusion. As a sequencespecific DNA binding transcription factor, PAX6 positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system. It was hypothesized that puerarin could relieve RIH via targeting PAX6 to regulate transcription of transient receptor potential cation channel subfamily V Member 1 (TRPV1). A total of 32 rats were randomly divided into five groups, namely control group, RI group, RI + 10 mg/kg puerarin group (RI + puerarin10), RI + 20 mg/kg puerarin group (RI + puerarin20), and RI + 40 mg/kg puerarin group (RI + puerarin40). Mechanical and thermal hyperalgesia were tested at 24, 2, 6, 24 and 48 h after remifentanil infusion. Following the sacrifice of rats after the last behavioral test, western blot was used to detect the expression levels of TRPV1 in the tissues; Immunofluorescence staining and western blotting were used to detect the expression of PAX6 in the spinal cord. PharmMapper and JASPAR were used to predict the binding sites of puerarin/PAX6/TRPV1. Chromatin immunoprecipitationPCR and dual luciferase reporter assay were used to verify the targeting relationship between PAX6 and TRPV1. Immunofluorescence was used to detect the expression levels of TRPV1 and pNR2B. The results revealed that puerarin (10, 20, 40 mg/kg) dosedependently reduced thermal and mechanical hyperalgesia from 2 to 48 h after remifentanil infusion. Remifentanil infusion remarkably stimulated the expression of phosphorylated (p)NR2B. Nevertheless, the increased amount of pNR2B by RIH was dosedependently suppressed by puerarin in rats. In conclusion, puerarin was revealed to attenuate postoperative RIH via targeting PAX6 to regulate the transcription of TRPV1.
Subject(s)
Hyperalgesia , Isoflavones , Animals , Rats , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Hyperalgesia/genetics , Isoflavones/pharmacology , Isoflavones/therapeutic use , Pain, Postoperative/drug therapy , Pain, Postoperative/etiology , Piperidines/pharmacology , Rats, Sprague-Dawley , Remifentanil/adverse effects , PAX6 Transcription Factor/drug effects , PAX6 Transcription Factor/metabolism , TRPV Cation Channels/drug effects , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolismABSTRACT
Mulberry (Morus alba L.), a kind of common fruits widely cultivated worldwide, has been proven various biological activities. However, its potential role in the progression of knee osteoarthritis (KOA) remains unclear. This study aims to investigate the potential protective effects of crude polysaccharide extracted from mulberry fruit, referred to as a complex blend of polysaccharides and other unidentified extracted impurities, on KOA progression. The KOA rats were established by injection of 1 mg sodium monoiodoacetate into knee, and administrated with crude mulberry polysaccharide (Mup) by gastric gavage for 4 weeks. Furthermore, intestinal bacteria clearance assay (IBCA) and fecal microbiota transplantation were conducted for the evaluation of the effect of gut microbiota (GM) on KOA. Our findings demonstrated that Mup, particularly at a dosage of 200 mg/kg, effectively improved abnormal gait patterns, reduced the level of inflammation, mitigated subchondral bone loss, restored compromised joint surfaces, alleviated cartilage destruction, and positively modulated the dysregulated profile of GM in KOA rats. Moreover, IBCA compromised the protective effects of Mup, while transplantation of fecal bacteria from Mup-treated rats facilitated KOA recovery. Collectively, our study suggested that Mup had the potential to ameliorate the progression of KOA, potentially through its modulation of GM profile.
Subject(s)
Gastrointestinal Microbiome , Morus , Osteoarthritis, Knee , Rats , Animals , Osteoarthritis, Knee/drug therapy , Fruit , Polysaccharides/pharmacology , Polysaccharides/therapeutic useABSTRACT
Background: Statin treatment can reduce atherosclerotic plaque as detected via invasive intracoronary methods. However, few studies have evaluated the effect of moderate-intensity statin therapy on carotid intraplaque neovascularization (IPN) using semiquantitative indices. This study thus aimed to assess the effect of statin on the carotid IPN of coronary artery disease with contrast-enhanced ultrasound (CEUS). Methods: In this noncontrol, retrospective, cohort study, 35 inpatients who underwent coronary angiography, serial CEUS, and laboratory evaluations were consecutively enrolled from June 2020 to December 2022 at the Department of Cardiology, Chinese PLA General Hospital. All patients were administered moderate-intensity statin during serial CEUS, and continuous and categorical assessment of IPN and maximum plaque height (MPH) of carotid plaque was performed. Patients with a target low-density lipoprotein cholesterol (LDL-C) <1.8 mmol/L at 12-month follow-up were compared with those who did not reach the LDL-C 1.8 mmol/L target. Results: From baseline to 12-month follow-up, there were significant differences in the LDL-C levels between patients (2.71±1.29 vs. 1.35±0.83 mmol/L), those with 12-month follow-up LDL-C <1.8 mmol/L (2.58±1.24 vs. 1.08±0.52 mmol/L), and those with 12-month follow-up LDL-C ≥1.8 mmol/L (3.24±1.44 vs. 2.56±0.85 mmol/L) all P values <0.05, with decreases of 41%, 49%, and 11% from baseline, respectively. The mean MPH (12 months to baseline) decreased from 2.47±0.63 to 2.22±0.60 mm (P<0.05), and the IPN also decreased from 1.15±0.62 to 0.58±0.56, representing a reduction of 0.57±0.59 from baseline (P<0.001). In the LDL-C <1.8 mmol/L patients, there were significant differences between baseline and 12 months in MPH (2.37±0.56 vs. 2.03±0.52 mm; P<0.05) and IPN (1.32±0.77 vs. 0.54±0.63; P<0.05) compared with those with a follow-up LDL-C ≥1.8 mmol/L. Patients with a follow-up LDL-C <1.8 mmol/L, compared with those with a follow-up LDL-C ≥1.8 mmol/L, showed a significantly greater reduction in MPH (-0.34±0.46 vs. -0.13±0.39; P<0.05) and IPN (-0.79±0.63 vs. -0.57±0.79; P<0.05). Additionally, patients with carotid IPN regression showed a higher percent change in LDL-C compared with those without carotid IPN regression (-53.31±23.20 vs. -29.55±19.47; P<0.05). Conclusions: Controlling the LDL-C to <1.8 mmol/L under moderate-intensity statin can stabilize and reduce carotid IPN as detected by the semiquantitative noninvasive CEUS.
ABSTRACT
OBJECTIVES: To explore the diagnostic value of contrast-enhanced ultrasound (CEUS) in the disease activity of idiopathic retroperitoneal fibrosis (IRPF). METHODS: This retrospective study included 148 CEUS examinations from 63 patients with IRPF treated in our hospital from April 2016 to September 2021. They were divided into two groups: IRPF active group (69 examinations) and inactive group (79 examinations). Uni- and multivariable analyses were used to identify independent risk factors for IRPF activity. Receiver operating characteristic (ROC) curves were drawn to establish different diagnostic models to evaluate the diagnostic value of IRPF activity. The z test was used to compare the differences of the area under the curves (AUCs). The value of CEUS in evaluating the variation of disease activity over time was also investigated between repeat patient studies. RESULTS: Univariate and multivariate logistic regression analyses revealed the thickness [odds ratio (OR) = 14.125, 95% confidence interval (CI) = 3.017-66.123] was the most significant independent risk factor for IRPF activity (P < 0.01). The best diagnostic model was model 3, which was established by CEUS score combined with thickness. The AUC was 0.944 (95%CI = 0.912-0.977), and the sensitivity and specificity were 89.86% and 86.08%, respectively. The diagnostic performance was not significantly improved after combining clinical symptom (back pain) and laboratory indicators [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]. Compared with before treatment, the CEUS score and thickness were significantly decreased after treatment (x2 = 14.580, P < 0.001 and z = 4.708, P < 0.001, respectively). CONCLUSION: CEUS has good diagnostic value for IRPF disease activity. Key points ⢠Thickness and contrast-enhanced ultrasound score were significantly higher in the active group than those in inactive group (P < 0.001). ⢠With thickness of 4 mm and contrast-enhanced ultrasound 2 score as optimal cut-off values, the sensitivity and specificity were 89.86%, 81.01% and 52.17%, 100.00%, respectively. ⢠During follow-up, when the disease progressed, the change of CEUS score was earlier than the change of thickness.
Subject(s)
Retroperitoneal Fibrosis , Humans , Retrospective Studies , Retroperitoneal Fibrosis/diagnostic imaging , Contrast Media , Ultrasonography , Sensitivity and SpecificityABSTRACT
The microcirculation hemodynamics change and inflammatory response are the two main pathophysiological mechanisms of renal ischemia-reperfusion injury (IRI) induced acute kidney injury (AKI). The treatment of microcirculation hemodynamics and inflammatory response can effectively alleviate renal injury and correct renal function. Picroside II (P II) has a wide range of pharmacological effects. Still, there are few studies on protecting IRI-AKI, and whether P II can improve renal microcirculation perfusion is still being determined. This study aims to explore the protective effect of P II on IRI-AKI and evaluate its ability to enhance renal microcirculation perfusion. In this study, a bilateral renal IRI-AKI model in mice was established, and the changes in renal microcirculation and inflammatory response were quantitatively evaluated before and after P II intervention by contrast-enhanced ultrasound (CEUS). At the same time, serum and tissue markers were measured to assess the changes in renal function. The results showed that after P II intervention, the levels of serum creatinine (Scr), blood urea nitrogen (BUN), serum cystatin C (Cys-C), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), and superoxide dismutase (SOD), as well as the time-to-peak (TTP), peak intensity (PI) and area under the curve (AUC), and the normalized intensity difference (NID) were all alleviated. In conclusion, P II can improve renal microcirculation perfusion changes caused by IRI-AKI, reduce inflammatory reactions during AKI, and enhance renal antioxidant stress capacity. P II may be a new and promising drug for treating IRI-AKI.