ABSTRACT
One of the independent risk factors for atrial fibrillation is diabetes mellitus (DM); however, the underlying mechanisms causing atrial fibrillation in DM are unknown. The underlying mechanism of Atrogin-1-mediated SK2 degradation and associated signaling pathways are unclear. The aim of this study was to elucidate the relationship among reactive oxygen species (ROS), the NF-κB signaling pathway, and Atrogin-1 protein expression in the atrial myocardia of DM mice. We found that SK2 expression was downregulated comitant with increased ROS generation and enhanced NF-κB signaling activation in the atrial cardiomyocytes of DM mice. These observations were mimicked by exogenously applicating H2O2 and by high glucose culture conditions in HL-1 cells. Inhibition of ROS production by diphenyleneiodonium chloride or silencing of NF-κB by siRNA decreased the protein expression of NF-κB and Atrogin-1 and increased that of SK2 in HL-1 cells with high glucose culture. Moreover, chromatin immunoprecipitation assay demonstrated that NF-κB/p65 directly binds to the promoter of the FBXO32 gene (encoding Atrogin-1), regulating the FBXO32 transcription. Finally, we evaluated the therapeutic effects of curcumin, known as a NF-κB inhibitor, on Atrogin-1 and SK2 expression in DM mice and confirmed that oral administration of curcumin for 4 weeks significantly suppressed Atrogin-1 expression and protected SK2 expression against hyperglycemia. In summary, the results from this study indicated that the ROS/NF-κB signaling pathway participates in Atrogin-1-mediated SK2 regulation in the atria of streptozotocin-induced DM mice.
Subject(s)
Diabetes Mellitus, Experimental , Heart Atria , Muscle Proteins , NF-kappa B , Reactive Oxygen Species , SKP Cullin F-Box Protein Ligases , Signal Transduction , Small-Conductance Calcium-Activated Potassium Channels , Animals , Mice , Atrial Fibrillation/etiology , Atrial Fibrillation/genetics , Atrial Fibrillation/metabolism , Atrial Fibrillation/physiopathology , Cell Line , Chromatin Immunoprecipitation , Curcumin/pharmacology , Curcumin/therapeutic use , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Gene Expression Regulation/drug effects , Glucose/pharmacology , Heart Atria/metabolism , Heart Atria/physiopathology , Hydrogen Peroxide/pharmacology , Hyperglycemia/genetics , Hyperglycemia/metabolism , Muscle Proteins/genetics , Muscle Proteins/metabolism , Myocardium , Myocytes, Cardiac , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Proteolysis , Reactive Oxygen Species/metabolism , RNA, Small Interfering , SKP Cullin F-Box Protein Ligases/genetics , SKP Cullin F-Box Protein Ligases/metabolism , Small-Conductance Calcium-Activated Potassium Channels/genetics , Small-Conductance Calcium-Activated Potassium Channels/metabolismABSTRACT
BACKGROUND: A number of models have been reported for predicting atrial fibrillation (AF) recurrence after catheter ablation. Although many machine learning (ML) models were developed among them, black-box effect existed widely. It was always difficult to explain how variables affect model output. We sought to implement an explainable ML model and then reveal its decision-making process in identifying patients with paroxysmal AF at high risk for recurrence after catheter ablation. METHODS: Between January 2018 and December 2020, 471 consecutive patients with paroxysmal AF who had their first catheter ablation procedure were retrospectively enrolled. Patients were randomly assigned into training cohort (70%) and testing cohort (30%). The explainable ML model based on Random Forest (RF) algorithm was developed and modified on training cohort, and tested on testing cohort. In order to gain insight into the association between observed values and model output, Shapley additive explanations (SHAP) analysis was used to visualize the ML model. RESULTS: In this cohort, 135 patients experienced tachycardias recurrences. With hyperparameters adjusted, the ML model predicted AF recurrence with an area under the curve of 66.7% in the testing cohort. Summary plots listed the top 15 features in descending order and preliminary showed the association between features and outcome prediction. Early recurrence of AF showed the most positive impact on model output. Dependence plots combined with force plots showed the impact of single feature on model output, and helped determine high risk cut-off points. The thresholds of CHA2DS2-VASc score, systolic blood pressure, AF duration, HAS-BLED score, left atrial diameter and age were 2, 130 mmHg, 48 months, 2, 40 mm and 70 years, respectively. Decision plot recognized significant outliers. CONCLUSION: An explainable ML model effectively revealed its decision-making process in identifying patients with paroxysmal atrial fibrillation at high risk for recurrence after catheter ablation by listing important features, showing the impact of every feature on model output, determining appropriate thresholds and identifying significant outliers. Physicians can combine model output, visualization of model and clinical experience to make better decision.
Subject(s)
Atrial Fibrillation , Catheter Ablation , Humans , Atrial Fibrillation/diagnosis , Atrial Fibrillation/surgery , Atrial Fibrillation/etiology , Treatment Outcome , Retrospective Studies , Risk Factors , Catheter Ablation/adverse effects , Catheter Ablation/methods , RecurrenceABSTRACT
BACKGROUND: Whether male and female patients with atrial fibrillation (AF) differ in their risk of recurrence after catheter ablation remains controversial. Large differences in baseline characteristics between males and females often affect study results. METHODS: Patients with drug-refractory paroxysmal AF who received their first catheter ablation procedure between January 2018 and December 2020 were retrospectively enrolled. Propensity score matching was used to adjust for age, body mass index, and AF duration. Our main concerns were sex differences in comorbidities, procedures, arrhythmia recurrences, and procedure-related complications. RESULTS: For this study, 352 patients (176 pairs) were matched, and baseline characteristics were comparable between the two groups. Intraprocedural sex differences were apparent as more male patients received cavotricuspid isthmus ablation (55.00% vs. 31.43%, p = .005). Full follow-up, 1-year, 2-year, and 3-year AF recurrence rates were comparable between male and female groups. Multivariable Cox regression showed that the recurrence risk of paroxysmal AF was similar between male and female patients. AF duration was the only potential risk factor and occurred for only male patients. There were no significant differences in the subgroup analyses. Procedure-related complications were comparable between the male and female groups. CONCLUSION: We did not observe differences in baseline characteristics, arrhythmia recurrences, or procedure-related complications between male and female patients. Sex differences were reflected mainly in the finding that male patients received more cavotricuspid isthmus ablations, and atrial fibrillation duration was the only potential risk factor for recurrence and only for male patients.
Subject(s)
Atrial Fibrillation , Catheter Ablation , Humans , Male , Female , Treatment Outcome , Retrospective Studies , Propensity Score , Sex Characteristics , Catheter Ablation/methods , RecurrenceABSTRACT
OBJECTIVES: During physical transfection, an electrical field or mechanical force is used to induce cell transfection. We tested if the disruption of a dense actin layer underneath the membrane of a suspended cell enhances cell transfection. RESULTS: A bubble generator was used to electromechanically stimulate suspended cells. To clarify the influence of the actin layer (the actin cortex) on cell transfection efficiency, we used an actin polymerization inhibitor (cytochalasin D) to disrupt the actin cortex before electromechanical stimulation. Without cytochalasin D treatment, signals from the overall actin cortex decreased after electromechanical stimulation. With cytochalasin D treatment, there was localized F-actin aggregation under static conditions. After electromechanical stimulation, there was a partial loss (localized disruption), but no overall disruption, of the actin cortex. With the pretreatment with cytochalasin D, the transfection efficiency of plasmids (4.7, 8.3, or 11 kbp) into NIH/3T3 or UMR-106 cells increased significantly after exposure to electromechanical stimulation. CONCLUSIONS: Localized distribution of the actin cortex before exposure to electromechanical stimulation is crucial for inducing a partial loss of the cortex, which improves transfection efficiency and large plasmid delivery.
Subject(s)
Actins , Actins/genetics , Actins/metabolism , Cytochalasin D/pharmacology , Transfection , MembranesABSTRACT
Tin selenide (SnSe) holds great potential for abundant future applications, due to its exceptional properties and distinctive layered structure, which can be modified using a variety of techniques. One of the many tuning techniques is pressure manipulating using the diamond anvil cell (DAC), which is a very efficient in situ and reversible approach for modulating the structure and physical properties of SnSe. We briefly summarize the advantages and challenges of experimental study using DAC in this review, then introduce the recent progress and achievements of the pressure-induced structure and performance of SnSe, especially including the influence of pressure on its crystal structure and optical, electronic, and thermoelectric properties. The overall goal of the review is to better understand the mechanics underlying pressure-induced phase transitions and to offer suggestions for properly designing a structural pattern to achieve or enhanced novel properties.
ABSTRACT
PURPOSE: Recent studies have shown that circular RNAs (circRNAs) are closely related to the occurrence and development of gastric cancer. In this paper, we analyzed the value of hsa_circ_0003195 in diagnosis and prognosis of gastric cancer. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to determine the level of hsa_circ_0003195 in 100 paired gastric cancer tissues and paracancerous tissues, 74 paired fasting plasma from gastric cancer patients before and 10 days after operation, and 74 fasting plasmas from healthy controls. A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic value. The survival analysis and Cox proportional-hazards model were used to evaluate the efficiency of hsa_circ_0003195 in predicting overall survival (OS) in patients with gastric cancer. RESULTS: The expression of hsa_circ_0003195 was down-regulated in gastric cancer tissues and plasma from patients with gastric cancer. The expression level of hsa_circ_0003195 was correlated with differentiation, TNM stages, lymphatic metastasis, and distal metastasis. The area under the ROC curve (AUC) of tissue and plasma hsa_circ_0003195 was 0.684 and 0.695, respectively. The plasma hsa_circ_0003195 can be used as predictors of survival of patients with gastric cancer. CONCLUSION: Hsa_circ_0003195 may be a new diagnostic and prognostic marker of gastric cancer.
Subject(s)
Stomach Neoplasms , Biomarkers, Tumor/genetics , Humans , Lymphatic Metastasis , Prognosis , RNA, Circular , Stomach Neoplasms/diagnosis , Stomach Neoplasms/geneticsABSTRACT
OBJECTIVE: To obtain the elastic quantitative and semi-quantitative indexes of solid breast masses using ultrasound linear array probes with two different frequencies, and to construct prediction models and evaluate their diagnostic values. METHODS: A total of 92 patients who were scheduled for surgical treatment on solid breast masses were enrolled in this study. Linear array probes with two frequencies, 9-3 MHz (L9 group) and 14-5 MHz (L14 group), were used for sound touch elastography and strain elastography before surgery, and the maximum elasticity value (Emax), average elasticity value (Emean), minimum elasticity value (Emin), standard deviation (SD)(in kPa), elasticity ratio (E), and strain ratio to fat (SRf) were recorded and calculated for the breast mass (A) and surrounding tissues (Shell). The elastic characteristic indexes of the L9 group and L14 group were compared, and the prediction models of these two groups were constructed using Logistic regression method. RESULTS: The diagnostic performance of the prediction model based on L9 group was better than the model based on L14 group (AUC: 0.904 vs. 0.810, P = 0.0343, z = 2.116) and the best single index EMax-shell-L9 (P = 0.0398, z = 2.056). The sensitivity of L9 based model was 85.19% and the specificity was 84.21%. CONCLUSION: The prediction model based on quantitative and semi-quantitative elastic ultrasound indexes from L9-3 probe exhibited better performance, which could improve the diagnostic accuracy for malignant breast tumors.
Subject(s)
Breast Neoplasms , Elasticity Imaging Techniques , Humans , Female , Breast/diagnostic imaging , Breast/pathology , Elasticity Imaging Techniques/methods , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Microsurgery , Ultrasonography, Mammary/methods , Sensitivity and Specificity , Diagnosis, DifferentialABSTRACT
BACKGROUND: Considering that current peritoneal dialysis has its own shortcomings, In this study, the Seldinger technique was modified to explore the relationship between different catheter placement methods of peritoneal dialysis and short-term postoperative complications. METHODS: We retrospectively analyzed the data of 157 patients who received peritoneal dialysis in the Department of Nephrology of our hospital from January 2017 to December 2019. According to different catheter placement methods, the patients were divided into three groups: 111 cases of open surgery technique, 23 cases of Seldinger technique, and 23 cases of modified Seldinger technique (ultrasound-guided Veress needle puncture). The general data, laboratory indexes, and abdominal infection and catheter-related complications within one month postoperatively were collected. RESULTS: There were 48 (31.0 %) cases of complications in 157 patients within one month postoperatively, which were mainly catheter-related complications (45 cases, 29.0 %). The incidence of catheter tip peritoneal drift (catheter migration) in the three groups was 27.3 %, 39.1 %, and 9.1 %, respectively, with no significant difference between groups (P = 0.069). Univariate logistic regression analysis showed that the systolic blood pressure, history of abdominal and pelvic surgery, creatinine, and modified Seldinger technique were possible impact factors of catheter migration (P < 0.10). After fully adjusting for confounding factors, Compared with the open surgery group, the modified Seldinger method group significantly reduced the risk of catheter migration with an OR of 0.161 (95 % confidence interval: 0.027-0.961, P = 0.045); However, the difference between the Seldinger method group and the open surgery group was not significant, with an OR of 1.061 (95 % confidence interval: 0.308-3.649, P = 0.926). Curve fitting showed that the average incidence of catheter migration in the three groups was 27.3 % (95% CI: 15.9-42.7 %), 28.5 % (95% CI: 10.7-56.9 %), and 5.7 % (95% CI: 1.0-27.0 %); the modified Seldinger method has the lowest average incidence of catheter migration. CONCLUSIONS: Modified Seldinger technique can significantly reduce catheter-related short-term complications after peritoneal dialysis, and it is especially effective in reducing the incidence of catheter migration. Modified Seldinger technique is a safe and feasible method for the placement of a peritoneal dialysis catheter.
Subject(s)
Catheterization/adverse effects , Catheterization/methods , Kidney Failure, Chronic/therapy , Peritoneal Dialysis/adverse effects , Peritoneal Dialysis/methods , Adolescent , Adult , Aged , Aged, 80 and over , Equipment Failure , Female , Foreign-Body Migration/prevention & control , Humans , Male , Middle Aged , Postoperative Complications , Retrospective Studies , Risk Factors , Ultrasonography , Young AdultABSTRACT
OBJECTIVE: To explore the efficacy and short-term complications of a modified technique to percutaneously insert a peritoneal dialysis catheter. METHODS: We reviewed the outcomes of 94 patients who underwent peritoneal dialysis catheterization between October 2017 and April 2020. Of these, 47 cases were placed by a conventional Seldinger technique, whereas 47 cases were placed by a modified technique based on the Seldinger method. The success rates of the catheter insertion and three-month postoperative complications were compared between these two groups. RESULTS: The catheter insertion success rates were comparable between the two groups: 93.6% in the conventional technique group and 97.9% in the modified technique group (p = 0.307). The incidence of postoperative catheter migration was lower using the modified technique (4.3%) than the conventional technique (18.3%) (p = 0.037). None of the patients in the modified technique group had postoperative dialysate leakage, whereas this occurred in 9.0% of patients in the conventional technique group (p = 0.036). There were no statistically significant differences in the incidence of postoperative bleeding, infection, or visceral damage between the two groups. CONCLUSIONS: The modified Seldinger technique for percutaneous peritoneal dialysis catheter insertion reduced the short-term postoperative complications of catheter migration and dialysate leakage, with a comparable successful catheter insertion rate compared with the conventional Seldinger technique.
Subject(s)
Catheterization/methods , Catheters, Indwelling , Peritoneal Dialysis/instrumentation , Punctures/methods , Adult , Female , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
A low carbon yield is a major limitation for the use of cellulose-based filaments as carbon fiber precursors. The present study aims to investigate the use of an abundant biopolymer chitosan as a natural charring agent particularly on enhancing the carbon yield of the cellulose-derived carbon fiber. The ionic liquid 1,5-diazabicyclo[4.3.0]non-5-enium acetate ([DBNH]OAc) was used for direct dissolution of cellulose and chitosan and to spin cellulose-chitosan composite fibers through a dry-jet wet spinning process (Ioncell). The homogenous distribution and tight packing of cellulose and chitosan revealed by X-ray scattering experiments enable a synergistic interaction between the two polymers during the pyrolysis reaction, resulting in a substantial increase of the carbon yield and preservation of mechanical properties of cellulose fiber compared to other cobiopolymers such as lignin and xylan.
Subject(s)
Chitosan , Carbon , Carbon Fiber , CelluloseABSTRACT
Self-referential processing has been proven to be effective in improving source memory. However, it is unclear whether different types of source information would be consistently enhanced when an item is self-referentially processed. In two experiments, the authors examined the influence of the self (compared with other-referencing and semantic processing) as well as learning intention (incidental/intentional learning) on memory for two types of source information (spatial location and colour) that differ in the amount of cognitive resources they require to be encoded in memory. Results show that self-referencing has enhanced memory for spatial location of words whatever this information is learned intentionally or incidentally, whereas it cannot facilitate memory for the colour of words under the intentional learning condition, nor can it under the incidental condition. These findings suggest that self-referential processing is beneficial in memory improvement but not all-powerful, a source self-reference effect is subject to source information type.
Subject(s)
Learning , Memory/physiology , Mental Recall/physiology , Recognition, Psychology , Adult , Color , Female , Humans , Male , Neuropsychological Tests , Spatial Memory/physiology , Young AdultABSTRACT
Herein we investigate the stabilization behavior of a cellulose-lignin composite fibre towards application as a new bio derived precursor for carbon fibres. Carbon fibre materials are in high demand as we move towards a lower emission high-efficiency society. However, the most prominent current carbon fibre precursor is an expensive fossil-based polymer. Over the past decade significant research has focused on using renewable and bio derived alternatives. By blending cellulose and lignin and spinning a fibre with a continuous bi-component matrix a new approach to overcome the current limitations of both these precursors is proposed. A thorough study is conducted here on understanding the stabilization of the new precursors which is a critical step in the carbon fibre process. We show that stabilization times of the composite fibre are significantly reduced in comparison to pure lignin and improvements in mass yield compared to pure cellulose fibres are observed.
ABSTRACT
To obtain nanometer thin film thickness fastly and accurately, a formula of linear fitting method based on the periodic Kiessig fringes for thickness determination is applied, and a series of SiO2 nanometer films on Si substrate with the film thickness ranging from 10 to 120 nm have been calculated with the formula. These samples are prepared with thermal atomic layer deposition (T-ALD) process and film thickness is measured with grazing incidence X-ray reflection (GIXRR) technique, in addition, the linear fitting procedure and several influencing factors among it are studied, all of the work is based on the reflectivity curve from GIXRR experiment. While at the same time, another fitting method based on a soft named Global Fit2.0 is brought into this study to compare the two obtained thicknesses from two kinds of analysis methods. In the end a novel method for film thickness determination-empirical curve is presented. The results show that: during the linear fitting process, the peak position series have a main effect on thickness determination, thickness will increase when the peak position adds up; Besides, any peak's corresponding reflection angle also has a significant effect on the thickness determination, it is expressed in the form of interference fringe period, thickness will decrease while the interference fringe period increases, however, the errors from either peak series or fringe period can be further weakened with trial and error method, calibration procedure of critical angle and interference fringe period individually. Choosing the same sample with random thickness, no matter using the linear fitting and soft fitting method, the two gained film thicknesses are consistent and the thickness deviation is less than 0.1 nm, which illustrates the accuracy of linear fitting method for thickness determination. An empirical relationship between film thickness and interference fringe period is then put forward on the foundation of the accurate thickness determination, according this curve, the target film thickness is directly got by putting an interference fringe period in the empirical curve. This novel method not only avoids the messy procedure of choosing peak position series or their corresponding angles during linear fitting process, but also avoids the complex task of building a correct structure for soft fitting process; it is of great significance in confirming thin film thickness with quick speed and high accuracy.
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Toxic organic pollutants in wastewater have seriously damaged human health and ecosystems. Photocatalytic degradation is a potential and efficient tactic for wastewater treatment. Among the entire carbon family, biochar has been developed for the adsorption of pollutants due to its large specific surface area, porous skeleton structure, and abundant surface functional groups. Hence, combining adsorption and photocatalytic decomposition, TiO2-biochar photocatalysts have received considerable attention and have been extensively studied. Owing to biochar's adsorption, more active sites and strong interactions between contaminants and photocatalysts can be achieved. The synergistic effect of biochar and TiO2 nanomaterials substantially improves the photocatalytic capacity for pollutant degradation. TiO2-biochar composites have numerous attractive properties and advantages, culminating in infinite applications. This review discusses the characteristics and preparation techniques of biochar, presents in situ and ex situ synthesis approaches of TiO2-biochar nanocomposites, explains the benefits of TiO2-biochar-based compounds for photocatalytic degradation, and emphasizes the strategies for enhancing the photocatalytic efficiency of TiO2-biochar-based photocatalysts. Finally, the main difficulties and future advancements of TiO2-biochar-based photocatalysis are highlighted. The review gives an exhaustive overview of recent progress in TiO2-biochar-based photocatalysts for organic contaminants removal and is expected to encourage the development of robust TiO2-biochar-based photocatalysts for sewage remediation and other environmentally friendly uses.
ABSTRACT
Background: Skin defects caused by open hand trauma are difficult to treat clinically and severely affect the recovery of hand function. Autologous platelet-rich plasma (PRP) has been widely used in the treatment of refractory chronic wounds, but its use in hand trauma skin defects remains scarce. Methods: This study compared the outcomes of 27 patients treated with PRP to 31 patients undergoing skin flap transplantation for hand wounds. We assessed several parameters, including healing times, duration of surgery, postoperative pain (VAS score), intraoperative amputation length, finger function, sensation restoration, nail bed preservation, and hospitalization expenses. Results: PRP-treated patients showed a mean healing time of 21.59 ± 3.17 days. Surgical times were significantly shorter in the PRP group (22.04 ± 7.04 min) compared to the flap group (57.45 ± 8.15 min, P < 0.0001). PRP patients experienced longer postoperative healing times (20.15 ± 2.16 days) than those in the skin flap group (12.84 ± 1.08 days, P < 0.0001), but reported lower pain scores (1.3 ± 1.44 vs 2.55 ± 2.06, P = 0.0119). Range of Motion (ROM) at the proximal interphalangeal joint was better in the PRP group (96.26° ± 6.69) compared to the flap group (86.16° ± 15.24, P = 0.0028). Sensory outcomes favored the PRP group, with a two-point discrimination of 2.37 ± 1.34 mm versus 2.52 ± 1.27 mm in the flap group (P = 0.0274). Costs were lower in the PRP group ($2081.6 ± 258.14 vs $2680.18 ± 481.15, P < 0.0001). Conclusion: PRP treatment for skin defects from hand trauma is effective, offering advantages in terms of reduced surgical time, pain, and cost, with comparable or superior functional outcomes to flap transplantation. Despite longer healing times, PRP may represent a preferable option for open hand injuries, preserving more nail beds and resulting in better sensation and joint motion.
ABSTRACT
Spinal cystic echinococcosis (CE) is a rare but malignant zoonosis that can cause disability or even death in more than half of patients. Due to the complex pathological features, it is not curable by conventional drugs and surgery, so new therapeutic targets urgently need to be discovered. In this study, we clarify the occurrence of the phenomenon of spinal encapsulation angiogenesis and explore its underlying molecular mechanisms. A co-culture system was established by protoscoleces (PSCs) with human umbilical vein endothelial cells (HUVECs) which showed a high expression level of Nrf2. A short hairpin RNA (shRNA) and Sulforaphane (SFN) affecting the expression of Nrf2 were used to treat HUVECs. The results showed that Nrf2 could promote the tube formation of HUVECs. Nrf2 also exerts a protective effect against HUVECs, which is achieved by promoting NQO1 expression to stabilize ROS levels. Furthermore, autophagy activation significantly promotes angiogenesis in the spinal echinococcosis model (SEM) as a result of Nrf2 regulation of oxidative stress. These results suggest that the ROS/Nrf2/autophagy axis can induce angiogenesis and may be a potential target for the treatment of spinal cystic echinococcosis.
Subject(s)
Autophagy , Echinococcosis , Human Umbilical Vein Endothelial Cells , NF-E2-Related Factor 2 , Neovascularization, Pathologic , Oxidative Stress , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Oxidative Stress/drug effects , Oxidative Stress/physiology , Humans , Autophagy/drug effects , Autophagy/physiology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Animals , Neovascularization, Pathologic/metabolism , Echinococcosis/metabolism , Mice , Coculture Techniques , Male , AngiogenesisABSTRACT
Spinal echinococcosis is one of the most overlooked zoonotic parasitic diseases worldwide. There is currently no safe and effective treatment to eradicate it, and research based on the physiological-metabolic signature of the disease is lacking. Herein, we repurposed agrimol B as a potent anti-hydatid compound and validated its pharmacological mechanism based on arginine uptake as a target through multi-omics sequencing. This herbal component suppressed energy metabolism and activated ROS aggregation by inducing mitochondrial membrane potential depolarization, which subsequently triggered autophagy-dependent apoptosis leading to parasite death. Moreover, we discovered that arginine deprivation induced metabolic changes led to a shift from ornithine to nitrogen oxide synthesis, thus boosting the iNOS enzyme-regulated dominant metabolic pathway. The excess NO targeted the mitochondrial respiratory chain complex IV to disrupt energy metabolic homeostasis and induced a downstream pathological waterfall effect to kill the hydatid. A novel metabolic regulatory mechanism targeting mitochondrial damage for arginine starvation therapy was discovered. Finally, arginine depletion was found to be superior to the anti-spinal echinococcosis effect of albendazole and accompanied by the potential for disc protection. This study unveils the role of arginine in the physiological metabolism of Echinococcus granulosus and reveals the value of targeting arginine metabolism as a potential therapy. In addition, agrimol B is proposed as a promising therapeutic strategy for spinal echinococcosis to block arginine uptake and break this parasite's metabolic balance.
Subject(s)
Apoptosis , Arginine , Autophagy , Echinococcosis , Energy Metabolism , Nitric Oxide Synthase Type II , Arginine/metabolism , Animals , Autophagy/drug effects , Autophagy/physiology , Nitric Oxide Synthase Type II/metabolism , Energy Metabolism/drug effects , Energy Metabolism/physiology , Echinococcosis/drug therapy , Echinococcosis/metabolism , Echinococcosis/parasitology , Apoptosis/drug effects , Apoptosis/physiology , Mice , Echinococcus granulosus/drug effects , Echinococcus granulosus/metabolism , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
Due to the pathological production of liver disease in utility particularly complexity, the morbidity and mortality of liver disease including viral hepatitis, liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC) are rapidly increasing worldwide. Considering its insidious onset, rapid progression and drug resistance, finding an effective therapy is particularly worthwhile. Phyllanthus urinaria L. (P. urinaria), an ethnic medicine, can be applied at the stages of viral hepatitis, liver fibrosis/cirrhosis and HCC, which demonstrates great potential in the treatment of liver disease. Currently, there are numerous reports on the application of P. urinaria in treating liver diseases, but a detailed analysis of its metabolites and a complete summary of its pharmacological mechanism are still scarce. In this review, the phytochemical metabolites and ethnopharmacological applications of P. urinaria are summarized. Briefly, P. urinaria mainly contains flavonoids, lignans, tannins, phenolic acids, terpenoids and other metabolites. The mechanisms of P. urinaria are mainly reflected in reducing surface antigen secretion and interfering with DNA polymerase synthesis for anti-viral hepatitis activity, reducing hepatic stellate cells activity, inflammation and oxidative stress for anti-liver fibrosis/cirrhosis activity, as well as preventing tumor proliferation, invasion and angiogenesis for anti-HCC activity via relevant signaling pathways. Accordingly, this review provides insights into the future application of natural products in the trilogy of liver diseases and will provide a scientific basis for further research and rational utilization of P. urinaria.
ABSTRACT
The present study was designed to observe the protection of Grateloupia filicina polysaccharide (GFP) against hepatotoxicity induced by Dioscorea bulbifera L in mice and its underlying mechanism. GFP was intragastrically (ig) given to mice at various doses. After 6 days, the mice were treated with ethyl acetate extract of Dioscorea bulbifera L (EF, ig). Serum levels of alanine/aspartate aminotransferase (ALT/AST), alkaline phosphatase (ALP), total bilirubin (TB) were measured, and liver histological evaluation was conducted. Furthermore, reductions of liver glutathione (GSH) amount and glutamate cysteine ligase (GCL) activity were tested. The expressions of GCL-c, GCL-m, and HO-1 (heme oxygenase-1) in liver were observed by Western-blot. The results showed that GFP (600 mg x kg(-1)) decreased EF-induced the increase of serum ALT, AST and TB, and GFP (400, 600 mg x kg(-1)) inhibited EF-induced the increase of serum ALP. Liver histological evaluation showed that the liver injury induced by EF was relieved after treated with GFP. GFP further increased liver GSH amount and reversed EF-induced the decrease of GCL activity. The Western-blot result showed that GFP augmented EF-induced the increase of HO-1, and reversed EF-induced the decrease of GCL-c. In conclusion, GFP can act against the oxidative stress liver injury induced by Dioscorea bulbifera L in mice.
Subject(s)
Chemical and Drug Induced Liver Injury/metabolism , Dioscorea/toxicity , Heterocyclic Compounds, 4 or More Rings/toxicity , Polysaccharides/pharmacology , Rhodophyta/chemistry , Alanine Transaminase/blood , Alkaline Phosphatase/blood , Animals , Aspartate Aminotransferases/blood , Bilirubin/blood , Chemical and Drug Induced Liver Injury/blood , Glutamate-Cysteine Ligase/metabolism , Glutathione/metabolism , Heme Oxygenase-1/metabolism , Heterocyclic Compounds, 4 or More Rings/antagonists & inhibitors , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred ICR , Oxidative Stress/drug effects , Plants, Medicinal/chemistry , Polysaccharides/isolation & purification , Random AllocationABSTRACT
PURPOSE: To address the difficulties of M-mode ultrasound images classification in pneumothorax diagnosis and the shortcomings of existing neural network algorithms in this field, we proposed an M-mode ultrasound images classification model based on Disturbed Meta-Pseudo-Labels (D-MPL). METHODS: An M-mode ultrasound image augmentation system was designed to make the model more robust and generalizable. In D-MPL, teacher-generated pseudo-labeling was first taught to students through a soft mask, and additional disturbance data were added to the teacher network. As the loss of the teacher network continues to decline, disturbance data were injected to improve the generalization of the model to cope with image differences across patients in clinical settings. RESULTS: We compared the proposed model with four commonly used models, including MPL, EfficientnetB2, Inception V3, and Resnet101, in order to confirm its efficacy. Our model has an average specificity of 98.28%, sensitivity of 98.22%, F1-score of 98.23%, and AUC of 98.10%, according to the experiment findings, and its comprehensive performance is better than the above four models. CONCLUSION: The results demonstrated our model's superiority over the competition and its greater. The model proposed in this study is expected to assist doctors in the diagnosis of pneumothorax as an auxiliary mean.