Development and Validation of a Biparametric MRI Deep Learning Radiomics Model with Clinical Characteristics for Predicting Perineural Invasion in Patients with Prostate Cancer.

RATIONALE AND OBJECTIVES: Perineural invasion (PNI) is an important prognostic biomarker for prostate cancer (PCa). This study aimed to develop and validate a predictive model integrating biparametric MRI-based deep learning radiomics and clinical characteristics for the non-invasive prediction of PNI in patients with PCa. MATERIALS AND METHODS: In this prospective study, 557 PCa patients who underwent preoperative MRI and radical prostatectomy were recruited and randomly divided into the training and the validation cohorts at a ratio of 7:3. Clinical model for predicting PNI was constructed by univariate and multivariate regression analyses on various clinical indicators, followed by logistic regression. Radiomics and deep learning methods were used to develop different MRI-based radiomics and deep learning models. Subsequently, the clinical, radiomics, and deep learning signatures were combined to develop the integrated deep learning-radiomics-clinical model (DLRC). The performance of the models was assessed by plotting the receiver operating characteristic (ROC) curves and precision-recall (PR) curves, as well as calculating the area under the ROC and PR curves (ROC-AUC and PR-AUC). The calibration curve and decision curve were used to evaluate the model's goodness of fit and clinical benefit. RESULTS: The DLRC model demonstrated the highest performance in both the training and the validation cohorts, with ROC-AUCs of 0.914 and 0.848, respectively, and PR-AUCs of 0.948 and 0.926, respectively. The DLRC model showed good calibration and clinical benefit in both cohorts. CONCLUSION: The DLRC model, which integrated clinical, radiomics, and deep learning signatures, can serve as a robust tool for predicting PNI in patients with PCa, thus aiding in developing effective treatment strategies.

Serum high mobility group box 1 as a potential biomarker for the progression of kidney disease in patients with type 2 diabetes.

Background: As a damage-associated molecular pattern protein, high mobility group box 1 (HMGB1) is associated with kidney and systemic inflammation. The predictive and therapeutic value of HMGB1 as a biomarker has been confirmed in various diseases. However, its value in diabetic kidney disease (DKD) remains unclear. Therefore, this study aimed to investigate the correlation between serum and urine HMGB1 levels and DKD progression. Methods: We recruited 196 patients with type 2 diabetes mellitus (T2DM), including 109 with DKD and 87 T2DM patients without DKD. Additionally, 60 healthy participants without T2DM were also recruited as controls. Serum and urine samples were collected for HMGB1 analysis. Simultaneously, tumor necrosis factor receptor superfamily member 1A (TNFR-1) in serum and kidney injury molecule (KIM-1) in urine samples were evaluated for comparison. Results: Serum and urine HMGB1 levels were significantly higher in patients with DKD than in patients with T2DM and healthy controls. Additionally, serum HMGB1 levels significantly and positively correlated with serum TNFR-1 (R 2 = 0.567, p<0.001) and urine KIM-1 levels (R 2 = 0.440, p<0.001), and urine HMGB1 has a similar correlation. In the population with T2DM, the risk of DKD progression increased with an increase in serum HMGB1 levels. Multivariate logistic regression analysis showed that elevated serum HMGB1 level was an independent risk factor for renal function progression in patients with DKD, and regression analysis did not change in the model corrected for multiple variables. The restricted cubic spline depicted a nonlinear relationship between serum HMGB1 and renal function progression in patients with DKD (p-nonlinear=0.007, p<0.001), and this positive effect remained consistent across subgroups. Conclusion: Serum HMGB1 was significantly correlated with DKD and disease severity. When the HMGB1 level was ≥27 ng/ml, the risk of renal progression increased sharply, indicating that serum HMGB1 can be used as a potential biomarker for the diagnosis of DKD progression.

Uprighting horizontally impacted third molars by super-elastic nickel-titanium wire in patients with an extracted first molar.

Protracting lower second molars and uprighting horizontally impacted third molars is a significant orthodontic challenge in patients who require the extraction of severely decayed first molars. Here, we describe the use of biomechanics to upright 90°-tilted lower third molars following second molar protraction. Herein, we introduce a technique for uprighting the lower third molars by (1) the placement of superelastic nickel titanium archwires, (2) bonding, and (3) repositioning of a buccal tube in a tilted position to compensate for the efficiency of Ni-Ti (nickel-titanium) wire. The treatment mechanics used for our two cases showed that even severely impacted third molars can be uprighted by routine continuous straight-wire techniques. This technique proved to be a simple, efficient and reliable treatment option for uprighting horizontally impacted third molars.

Can combined high-resolution vessel wall imaging and multiple post-labeling delay 3D pseudo-continuous arterial spin labeling differentiate moyamoya disease from atherosclerotic moyamoya syndrome?

PURPOSE: To investigate whether moyamoya disease (MMD) and atherosclerotic moyamoya syndrome (AS-MMS) differ in vascular morphology and perfusion characteristics using T1w-CUBE imaging and multiple post-labeling delay 3D pseudo-continuous arterial spin labeling imaging (MP 3D-PcASL), and to explore the potential of the combined techniques for accurate diagnosis of both diseases. METHOD: This prospective study enrolled 51 patients with moyamoya vasculopathy, including 26 with MMD and 25 with AS-MMS. All patients underwent digital subtraction angiography (DSA)/magnetic resonance angiography (MRA), T1w-CUBE imaging, and MP 3D-PCASL examinations. Morphological parameters, including the outer diameter, maximum wall thickness, luminal stenosis morphology, degree of wall enhancement, number of collateral vessels, and perfusion parameters, such as cerebral blood flow (CBF) and arterial transit time (ATT), were measured. After univariate analysis between the two groups, logistic regression models based on the derived parameters of T1w-CUBE imaging, MP 3D-PCASL, and combined imaging were implemented, and receiver operating characteristic (ROC) curves were generated to compare the discriminatory power of the different imaging methods for the diagnosis of MMD. RESULTS: With T1w-CUBE imaging, MMD showed a smaller outer diameter (2.76 ± 0.39 vs. 3.07 ± 0.49 mm) and maximum wall thickness (1.27 ± 0.19 vs. 1.49 ± 0.24 mm) than AS-MMS (both P < 0.05). Using MP 3D-pcASL, the resultant CBF (36.64 ± 14.28 vs. 28.77 ± 8.63 mL/100 g/min) was higher in MMD relative to AS-MMS, while an opposite pattern was shown for ATT (1.61 ± 0.09 vs. 1.72 ± 0.13 s; both P < 0.05). Robust diagnostic efficacies for disease differentiation, confirmed by high areas under the ROC curve (AUCs) (>0.808), were separately shown with T1w-CUBE and MP 3D-pcASL derived parameters. However, the combined multivariate logistic regression model showed optimaldiagnostic efficacy(AUC: 0.938; P < 0.05). CONCLUSIONS: Combined T1w-CUBE imaging and MP 3D-PCASL provides distinctive morphological and functional features to evaluate vessel walls and cerebral perfusion, and might help distinguish MMD from AS-MMS.

Regulation of autophagy by natural polyphenols in the treatment of diabetic kidney disease: therapeutic potential and mechanism.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease worldwide. Autophagy plays an important role in maintaining cellular homeostasis in renal physiology. In DKD, the accumulation of advanced glycation end products induces decreased renal autophagy-related protein expression and transcription factor EB (TFEB) nuclear transfer, leading to impaired autophagy and lysosomal function and blockage of autophagic flux. This accelerates renal resident cell injury and apoptosis, mediates macrophage infiltration and phenotypic changes, ultimately leading to aggravated proteinuria and fibrosis in DKD. Natural polyphenols show promise in treating DKD by regulating autophagy and promoting nuclear transfer of TFEB and lysosomal repair. This review summarizes the characteristics of autophagy in DKD, and the potential application and mechanisms of some known natural polyphenols as autophagy regulators in DKD, with the goal of contributing to a deeper understanding of natural polyphenol mechanisms in the treatment of DKD and promoting the development of their applications. Finally, we point out the limitations of polyphenols in current DKD research and provide an outlook for their future research.

Oxidative stress and inflammation in diabetic nephropathy: role of polyphenols.

Diabetic nephropathy (DN) often leads to end-stage renal disease. Oxidative stress demonstrates a crucial act in the onset and progression of DN, which triggers various pathological processes while promoting the activation of inflammation and forming a vicious oxidative stress-inflammation cycle that induces podocyte injury, extracellular matrix accumulation, glomerulosclerosis, epithelial-mesenchymal transition, renal tubular atrophy, and proteinuria. Conventional treatments for DN have limited efficacy. Polyphenols, as antioxidants, are widely used in DN with multiple targets and fewer adverse effects. This review reveals the oxidative stress and oxidative stress-associated inflammation in DN that led to pathological damage to renal cells, including podocytes, endothelial cells, mesangial cells, and renal tubular epithelial cells. It demonstrates the potent antioxidant and anti-inflammatory properties by targeting Nrf2, SIRT1, HMGB1, NF-κB, and NLRP3 of polyphenols, including quercetin, resveratrol, curcumin, and phenolic acid. However, there remains a long way to a comprehensive understanding of molecular mechanisms and applications for the clinical therapy of polyphenols.

Using machine learning models to predict the surgical risk of children with pancreaticobiliary maljunction and biliary dilatation.

PURPOSE: To develop machine learning (ML) models to predict the surgical risk of children with pancreaticobiliary maljunction (PBM) and biliary dilatation. METHODS: The subjects of this study were 157 pediatric patients who underwent surgery for PBM with biliary dilatation between January, 2015 and August, 2022. Using preoperative data, four ML models were developed, including logistic regression (LR), random forest (RF), support vector machine classifier (SVC), and extreme gradient boosting (XGBoost). The performance of each model was assessed via the area under the receiver operator characteristic curve (AUC). Model interpretations were generated by Shapley Additive Explanations. A nomogram was used to validate the best-performing model. RESULTS: Sixty-eight patients (43.3%) were classified as the high-risk surgery group. The XGBoost model (AUC = 0.822) outperformed the LR (AUC = 0.798), RF (AUC = 0.802) and SVC (AUC = 0.804) models. In all four models, enhancement of the choledochal cystic wall and an abnormal position of the right hepatic artery were the two most important features. Moreover, the diameter of the choledochal cyst, bile duct variation, and serum amylase were selected as key predictive factors by all four models. CONCLUSIONS: Using preoperative data, the ML models, especially XGBoost, have the potential to predict the surgical risk of children with PBM and biliary dilatation. The nomogram may provide surgeons early warning to avoid intraoperative iatrogenic injury.

Prediction of post-operative acute pancreatitis in children with pancreaticobiliary maljunction using machine learning model.

PURPOSE: This study aimed to develop a prediction model to identify risk factors for post-operative acute pancreatitis (POAP) in children with pancreaticobiliary maljunction (PBM) by pre-operative analysis of patient variables. METHODS: Logistic regression (LR), support vector machine (SVM), and extreme gradient boosting (XGBoost) models were established using the prospectively collected databases of patients with PBM undergoing surgery which was reviewed in the period comprised between August 2015 and August 2022, at the Children's Hospital of Soochow University. Primarily, the area beneath the receiver-operating curves (AUC), accuracy, sensitivity, and specificity were used to evaluate the model performance. The model was finally validated using the nomogram and clinical impact curve. RESULTS: In total, 111 children with PBM met the inclusion criteria, and 21 children suffered POAP. In the validation dataset, LR models showed the highest performance. The risk nomogram and clinical effect curve demonstrated that the LR model was highly predictive. CONCLUSION: The prediction model based on the LR with a nomogram could be used to predict the risk of POAP in patients with PBM. Protein plugs, age, white blood cell count, and common bile duct diameter were the most relevant contributing factors to the models.

Therapeutic potential of artemisinin and its derivatives in managing kidney diseases.

Artemisinin, an antimalarial traditional Chinese herb, is isolated from Artemisia annua. L, and has shown fewer side effects. Several pieces of evidence have demonstrated that artemisinin and its derivatives exhibited therapeutic effects on diseases like malaria, cancer, immune disorders, and inflammatory diseases. Additionally, the antimalarial drugs demonstrated antioxidant and anti-inflammatory activities, regulating the immune system and autophagy and modulating glycolipid metabolism properties, suggesting an alternative for managing kidney disease. This review assessed the pharmacological activities of artemisinin. It summarized the critical outcomes and probable mechanism of artemisinins in treating kidney diseases, including inflammatory, oxidative stress, autophagy, mitochondrial homeostasis, endoplasmic reticulum stress, glycolipid metabolism, insulin resistance, diabetic nephropathy, lupus nephritis, membranous nephropathy, IgA nephropathy, and acute kidney injury, suggesting the therapeutic potential of artemisinin and its derivatives in managing kidney diseases, especially the podocyte-associated kidney diseases.

Amide proton transfer-weighted magnetic resonance imaging for the diagnosis of symptomatic chronic intracranial artery stenosis: a feasibility study.

Background: Hemodynamic changes after intracranial artery stenosis (ICAS) or occlusion are important causes of metabolic alterations in tissue. This study aimed to explore the feasibility of using amide proton transfer-weighted (APTw) magnetic resonance imaging (MRI) to diagnose patients with symptomatic chronic ICAS based on pH variations caused by metabolite damage. Methods: Sixty-seven patients with clinically confirmed unilateral anterior circulation ICAS (≥70% arterial narrowing) and 20 healthy volunteers were recruited for the study. Each patient underwent an MRI examination including a T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence, spin-echo echo-planar diffusion-weighted imaging (DWI), three-dimensional pseudo-continuous arterial spin labeling (pcASL), and an APTw sequence. Areas with abnormal perfusion and APTw effects were defined as perfusion/pH matched areas; areas with abnormal perfusion but normal APTw effects were defined as perfusion/pH unmatched areas; the contralateral mirror areas were defined as the normal areas. Regions of interest (ROIs) were selected within these three areas, and the corresponding apparent diffusion coefficient (ADC), cerebral blood flow (CBF), and magnetization transfer ratio asymmetry (MTRasym) were measured. Results: High intraclass correlation coefficient (ICC) values (0.78≤ ICCs ≤0.97; P<0.05) were observed between the two radiologists who independently performed the data analysis. Significant differences were found in CBF and MTRasym between the perfusion/pH matched, perfusion/pH unmatched, and normal areas [F(2,64)=288.5, 163.5; both P<0.05], but the ADC values were comparable between the three [F(2,64)=2.11; P>0.05]. Spearman correlation analysis revealed no significant correlation between changes in MTRasym and CBF (P>0.05). Finally, APTw showed a robust performance in diagnosing symptomatic chronic ICAS, with an area under the receiver operating characteristic curve (ROC) of 0.953 (sensitivity 97.01%; specificity 85.07%; cut-off value 1.005%). Conclusions: The present study has demonstrated that metabolic alterations are present in patients with symptomatic chronic ICAS. Our findings illustrate that APTw imaging could potentially serve as an effective method to provide a robust clinical diagnosis for patients with symptomatic chronic ICAS.

Evaluating iron deposition in gray matter nuclei of patients with unilateral middle cerebral artery stenosis using quantitative susceptibility mapping.

Iron mediated oxidative stress is involved in the process of brain injury after long-term ischemia. While increased iron deposition in the affected brain regions was observed in animal models of ischemic stroke, potential changes in the brain iron content in clinical patients with cerebral ischemia remain unclear. Quantitative susceptibility mapping (QSM), a non-invasive magnetic resonance imaging technique, can be used to evaluate iron content in the gray matter (GM) nuclei reliably. In this study, we aimed to quantitatively evaluate iron content changes in GM nuclei of patients with long-term unilateral middle cerebral artery (MCA) stenosis/occlusion-related cerebral ischemia using QSM. Forty-six unilateral MCA stenosis/occlusion patients and 38 age-, sex- and education-matched healthy controls underwent QSM. Clinical variables of history of hypertension, diabetes, hyperlipidemia, hyperhomocysteinemia, smoking, and drinking in all patients were evaluated. The iron-related susceptibility of GM nucleus subregions, including the bilateral caudate nucleus (CN), putamen (PU), globus pallidus (GP), thalamus, substantia nigra (SN), red nucleus, and dentate nucleus, was assessed. Susceptibility was compared between the bilateral GM nuclei in patients and controls. Receiver operating characteristic curve analysis was used to evaluate the efficacy of QSM susceptibility in distinguishing patients with unilateral MCA stenosis/occlusion from healthy controls. Multiple linear regression analysis was used to evaluate the relationship between ipsilateral susceptibility levels and clinical variables. Except for the CN, the susceptibility in most bilateral GM nucleus subregions was comparable in healthy controls, whereas for patients with unilateral MCA stenosis/occlusion, the ipsilateral PU, GP, and SN exhibited significantly higher susceptibility than the contralateral side (all P < 0.05). Compared with controls, susceptibility of the ipsilateral PU, GP, and SN and of contralateral PU in patients were significantly increased (all P < 0.05). The area under the curve (AUC) was greater for the ipsilateral PU than for the GP and SN (AUC = 0.773, 0.662 and 0.681; all P < 0.05). Multiple linear regression analysis showed that the increased susceptibility of the ipsilateral PU was significantly associated with hypertension, of the ipsilateral GP associated with smoking, and of the ipsilateral SN associated with diabetes (all P < 0.05). Our findings provide support for abnormal iron accumulation in the GM nuclei after chronic MCA stenosis/occlusion and its correlation with some cerebrovascular disease risk factors. Therefore, iron deposition in the GM nuclei, as measured by QSM, may be a potential biomarker for long-term cerebral ischemia.

Irreversible Electroporation Enhanced by Radiofrequency Ablation: An In Vitro and Computational Study in a 3D Liver Tumor Model.

In the present study, we used a computational and experimental study in a 3D liver tumor model (LTM) to explore the tumor ablation enhancement of irreversible electroporation (IRE) by pre-heating with radiofrequency ablation (RFA) and elucidate the mechanism whereby this enhancement occurs. Three ablation protocols, including IRE alone, RFA45 → IRE (with the pre-heating temperature of 45 °C), and RFA60 → IRE (with the pre-heating temperature of 60 °C) were investigated. Both the thermal conductivity and electrical conductivity of the 3D LTM were characterized with the change in the pre-heating temperature. The results showed, compared to IRE alone, a significant increase in the tumor ablation volume (19.59 [Formula: see text] 0.61 vs. 15.29 ± 0.61 mm3, p = 0.002 and 22.87 [Formula: see text] 0.35 vs. 15.29 ± 0.61 mm3, p < 0.001) was observed with both RFA45 → IRE and RFA60 → IRE, leading to a decrease in lethal electric filed strength (8 and 17%, correspondingly). The mechanism can be attributed to the change of cell microenvironment by pre-heating and/or a synergistic effect of RFA and IRE. The proposed enhancing method might contribute to the improvement of interventional oncology in the treatment of large tumors close to critical organs (e.g., large blood vessels and bile ducts).

Can 3D Pseudo-Continuous Territorial Arterial Spin Labeling Effectively Diagnose Patients With Recanalization of Unilateral Middle Cerebral Artery Stenosis?

BACKGROUND: Unilateral middle cerebral artery (MCA) stenosis, as an independent risk factor for stroke, requires an intervention operation for vessel recanalization. Accurate perfusion measurement is thus essential after the operation. PURPOSE: To explore the feasibility of three-dimensional (3D) pseudo-continuous territorial arterial-spin-labeling (tASL) in evaluating MCA recanalization. STUDY TYPE: Prospective and longitudinal. SUBJECTS: Forty-seven patients with unilateral MCA stenosis or occlusion. FIELD STRENGTH/SEQUENCE: A 3.0 T, 3D time-of-flight fast-field-echo magnetic resonance (MR) angiography sequence, spin-echo echo-planar diffusion-weighted imaging sequence, 3D fast-spin-echo pseudo-continuous ASL (pcASL) and tASL sequences. ASSESSMENT: All patients underwent MR examination before and after MCA recanalization and scored using the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at admission and discharge. An mRS score <2 was defined as a good prognosis. 3D-pcASL and tASL cerebral blood flow (CBF) maps were obtained, and the corresponding Alberta Stroke Program Early CT Score (ASPECTS)-based scores were evaluated. STATISTICAL TESTS: The Kolmogorov-Smirnov test, intra-class correlation coefficient, paired t-test, receiver operating characteristic (ROC) curve, and multivariable logistic regression analysis. RESULTS: After recanalization, tASL derived absolute CBFs between the affected and contralateral sides were significantly higher than before the operation (mean: 34.3 ± 8.5 mL/100 g/min vs. 40.6 ± 9.2 mL/100 g/min, 42.6 ± 9.8 mL/100 g/min vs. 43.5 ± 9.9 mL/100 g/min, both P < 0.05). In ROC analysis, tASL provided good prognosis (area under ROC curve [AUC] = 0.829; 95% CI: 0.651-1.000, P < 0.05), while pcASL had lower prognostic value (AUC = 0.760; 95% CI: 0.574-0.946, P < 0.05). The NIHSS score before recanalization, pcASL, and tASL-based ASPECTS scores were significantly associated with good clinical outcome (P < 0.05). Multivariable analysis revealed that ASPECTS-based scores of pcASL and tASL before and after surgery were independent predictors of good clinical outcome (all P < 0.05). DATA CONCLUSION: tASL can determine hypoperfusion in the responsible vascular perfusion area and predict clinical outcome. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Iron Deposition in Gray Matter Nuclei of Patients With Intracranial Artery Stenosis: A Quantitative Susceptibility Mapping Study.

Purpose: This study aimed to use quantitative susceptibility mapping (QSM) to systematically investigate the changes of iron content in gray matter (GM) nuclei in patients with long-term anterior circulation artery stenosis (ACAS) and posterior circulation artery stenosis (PCAS). Methods: Twenty-five ACAS patients, 25 PCAS patients, and 25 age- and sex-matched healthy controls underwent QSM examination. Patients were scored using the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) to assess the degree of neural function deficiency. On QSM images, iron related susceptibility of GM nuclei, including bilateral caudate nucleus, putamen (PU), globus pallidus (GP), thalamus (TH), substantia nigra (SN), red nucleus, and dentate nucleus (DN), were assessed. Susceptibility was compared between bilateral GM nuclei in healthy controls, ACAS patients, and PCAS patients. Partial correlation analysis, with age as a covariate, was separately performed to assess the relationships of susceptibility with NIHSS and mRS scores. Results: There were no significant differences between the susceptibilities for left and right hemispheres in all seven GM nucleus subregions for healthy controls, ACAS patients, and PCAS patients. Compared with healthy controls, mean susceptibility of bilateral PU, GP, and SN in ACAS patients and of bilateral PU, GP, SN, and DN in PCAS patients were significantly increased (all P < 0.05). In addition, mean susceptibility of bilateral TH and SN in PCAS patients was significantly higher than in ACAS patients (both P < 0.05). With partial correlation analysis, mean susceptibility at bilateral PU of ACAS patients was significantly correlated with mRS score (r = 0.415, P < 0.05), and at bilateral PU in PCAS patients was correlated with NIHSS score (r = 0.424, P < 0.05). Conclusion: Our findings indicated that abnormal iron metabolism may present in different subregions of GM nuclei after long-term ACAS and PCAS. In addition, iron content of PU in patients with ACAS and PCAS was correlated with neurological deficit scores. Therefore, iron quantification measured by QSM susceptibility may provide a new insight to understand the pathological mechanism of ischemic stroke caused by ACAS and PCAS.

Obstructive sleep apnea syndrome and risk of renal impairment: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with a variety of systemic diseases. Among patients with chronic kidney diseases (CKD), the prevalence of OSAS is high. OSAS can induce progression of CKD. However, whether or not OSAS can cause renal damage in healthy people is not clear. Thus, the purpose of this meta-analysis was to elucidate whether or not there was an association between OSAS and early renal damage. METHODS: PubMed, Embase Database, Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Biology Medicine Database, Chinese Scientific Journals Database, and Wanfang Database were searched systematically. The relative risk (RR), weighted mean difference (WMD), and 95% confidence intervals (CI) were used to evaluate the relationship between OSAS and early renal damage. Funnel plot and Egger's test were used to evaluate publication bias, and trial sequential analysis (TSA) was employed to verify the sufficiency of the research conclusions. RESULTS: A total of 18 studies were analyzed comprising 4,567 participants. Compared with the healthy control group, levels of cystatin C (MD = 0.530, 95% CI 0.423, 0.637, P < 0.01) and proteinuria in patients with OSAS were significantly increased, while the levels of estimated glomerular filtration rate (eGFR) (MD = - 0.194, 95% CI - 0.268, - 0.121, P < 0.01) were significantly decreased. Furthermore, patients with OSAS also had an increased risk of CKD. Subgroup analysis showed that compared with patients without OSAS, the level of serum cystatin C in patients with OSAS was significantly increased independent of hypertension and diabetes, and the eGFR was significantly decreased in patients with moderate to severe OSAS and comorbid hypertension and/or diabetes. CONCLUSION: In this meta-analysis, OSAS was associated with a higher risk of early renal damage. Patients with OSAS and comorbid hypertension and/or diabetes appear to suffer from severe renal damage.

A Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F against Diabetic Kidney Disease.

BACKGROUND: Diabetic kidney disease (DKD) poses a major public-health burden globally. Tripterygium wilfordii Hook F (TwHF) is a widely employed herbal medicine in decreasing albuminuria among diabetic patients. However, a holistic network pharmacology strategy to investigate the active components and therapeutic mechanism underlying DKD is still unavailable. METHODS: We collected TwHF ingredients and their targets by traditional Chinese Medicine databases (TCMSP). Then, we obtained DKD targets from GeneCards and OMIM and collected and analyzed TwHF-DKD common targets using the STRING database. Protein-protein interaction (PPI) network was established by Cytoscape and analyzed by MCODE plugin to get clusters. In addition, the cytoHubba software was used to identify hub genes. Finally, all the targets of clusters were subjected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses via DAVID. RESULTS: A total of 51 active ingredients in TwHF were identified and hit by 88 potential targets related to DKD. Compounds correspond to more targets include kaempferol, beta-sitosterol, stigmasterol, and Triptoditerpenic acid B, which appeared to be high-potential compounds. Genes with higher degree including VEGFA, PTGS2, JUN, MAPK8, and HSP90AA1 are hub genes of TwHF against DKD, which are involved in inflammation, insulin resistance, and lipid homeostasis. Kaempferol and VEGFA were represented as the uppermost active ingredient and core gene of TwHF in treating DKD, respectively. DAVID results indicated that TwHF may play a role in treating DKD through AGE-RAGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, insulin resistance, and calcium signaling pathway (P < 0.05). CONCLUSION: Kaempferol and VEGFA were represented as the uppermost active ingredient and core gene of TwHF in treating DKD, respectively. The key mechanisms of TwHF against DKD might be involved in the reduction of renal inflammation by downregulating VEGFA.

Cyclin-Dependent Kinase 9 Inhibition Suppresses Necroptosis and Pyroptosis in the Progress of Endotoxemia.

The host innate immune response stands at the first line of defense against the outburst of pathogen invasion and their byproduct release. The balanced and coordinated expression of genes in normal immune responses is compromised in the progress of endotoxemia with exacerbated inflammation and massive cell death. In the present study, we identified cyclin-dependent kinase 9 (CDK9), the functional subunit of the positive transcription elongation factor b, as a master regulator of inflammatory gene transcription in the process of promoter-proximal pausing to productive elongation. Therapeutic pharmacological inhibition of CDK9 by flavopiridol (FVD) rescued mice from death in experimental models of fatal endotoxemia. In addition to alleviation of the cytokine storm in the circulation system following lethal endotoxin injection, FVD treatment significantly dampened the onset of inflammation in the livers and lungs and reduced the necroptosis and pyroptosis in livers. Moreover, CDK9 inhibition reduced inflammatory cytokine release and decreased cell death in the pro-inflammatory pyroptotic and necroptotic cell death pathway in monocytes in responses to lipopolysaccharide. In conclusion, CDK9 inhibition may affect the progress of endotoxemia by dampening inflammation and cell death including necroptosis and pyroptosis.

Non-Targeted Metabolomic Profiling of Coronary Heart Disease Patients With Taohong Siwu Decoction Treatment.

Traditional Chinese medicine is one of the complementary and alternative therapies to improve the prognosis of coronary heart disease (CHD). Taohong Siwu Decoction (THSWD), a classical traditional Chinese medication that promotes blood circulation, is clinically beneficial in CHD. However, the underlying mechanism of THSWD is still unclear. To comprehensively understand the material foundation of the "blood", it is significantly important to study the differential metabolites involved in the treatment of CHD with Chinese medicinal herb promoting blood circulation in TCM theory. Hence, this study investigated the metabolic profiles of the serum in CHD patients to determine the differential metabolites between the THSWD group and the placebo group. Eleven CHD patients were recruited and divided into two groups randomly and double-blindly. Serum samples were determined by performing non-targeted ultra-performance liquid chromatography with tandem mass spectrometry-based metabolomics. Pearson's correlation analysis was used to assess the association between identified metabolites and clinical serum indexes of CHD. Based on the result, a total of 513 metabolites were found in the serum of CHD patients, of which 27, involved in 29 metabolic pathways, were significantly different between the two groups. Among the differential metabolites, THSWD upregulated succinylcarnitine in fatty acid metabolism and 5'-methylthioadenosine in cysteine and methionine metabolism compared with the placebo group. However, THSWD downregulated pelargonic acid, involved in FA metabolism; succinate, involved in the tricarboxylic acid cycle; gluconic acid, gluconolactone, and d-glucose, involved in pentose phosphate pathway; glycerophosphocholine, involved in glycerophospholipid metabolism; 8,9-dihydroxyeicosatrienoic acid (8,9-DiHETrE), l-lysine, N-acetyl-l-aspartic acid, N-alpha-acetyl-l-asparagine, hippurate, indoxyl sulfate, and 3-ureidopropionate involved in amino acid metabolism compared with the placebo group. Moreover, succinylcarnitine, pelargonic acid, succinate, d-glucose, gluconic acid, l-lysine, N-alpha-acetyl-l-asparagine, 5'-methylthioadenosine, indoxyl sulfate, 8,9-DiHETrE, and 3-ureidopropionate were associated with total cholesterol or low-density lipoprotein. Succinylcarnitine, pelargonic acid, gluconolactone, N-acetyl-l-aspartic acid, N-alpha-acetyl-l-asparagine, hippurate, and 5'-methylthioadenosine were associated with activated partial thromboplastin time. Our findings indicated that glycerophosphocholine, 8,9-DiHETrE, 5'-methylthioadenosine, hippurate, indoxyl sulfate, and 3-ureidopropionate might constitute the partial material foundation of the "blood" in CHD patients treated with THSWD.

Ferroptosis as an emerging target in inflammatory diseases.

Cell survival or death is one critical issue in inflammatory responses. Ferroptosis, which is characterized by iron-dependent lethal lipid peroxidation, has been found to participate in the development of cancers, degenerative brain diseases and ischemia-reperfusion injuries. Incorporation of polyunsaturated fatty acids (PUFAs) into cellular membranes represents a vulnerability to invasion of microbials and sterile stimuli. In addition, the competition for iron in the battle between microbials and host cells underlies infection development. Although host cells have been equipped with complex antioxidant systems to combat lethal accumulation of lipid peroxidation, emerging evidence suggests several pathogens may target PUFAs in the cell membrane, and manipulate ferroptosis as a way for pathogen propagation. Moreover, ferroptosis takes part in the progression of sterile inflammations, such as cigarette smoke-induced chronic obstructive pulmonary disease, stroke and ischemia-reperfusion injuries. As iron-dependent oxidative stress and lipid peroxidation are common features for ferroptosis and inflammatory diseases, underlying mechanisms linking such pathological conditions will be discussed in this review. Progress in the research of ferroptosis may shed more light on the etiology and treatment of inflammatory diseases.