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Authors = Zhenkun Xu

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13 pages, 3556 KiB  
Article
High-Temperature Tensile Grain Evolution and Mechanical Properties of Additively Manufactured TA15 Aerospace Titanium Alloy
by Pengfei Li, Zhenkun Dong, Qingtao Yang, Hao Xu, Dehai Kong and Minghui Hu
Metals 2025, 15(6), 677; https://doi.org/10.3390/met15060677 - 18 Jun 2025
Cited by 1 | Viewed by 357
Abstract
This study investigates the grain characteristics and high-temperature tensile properties of an additively manufactured (AM) TA15 titanium alloy. Directed energy deposition (DED) was utilized for its high material efficiency and design flexibility to explore the alloy’s applicability in aerospace manufacturing, where TA15 is [...] Read more.
This study investigates the grain characteristics and high-temperature tensile properties of an additively manufactured (AM) TA15 titanium alloy. Directed energy deposition (DED) was utilized for its high material efficiency and design flexibility to explore the alloy’s applicability in aerospace manufacturing, where TA15 is valued for its excellent high-temperature performance. A comparative analysis between DED and hot-rolled TA15 alloys was conducted at 25 °C and 600 °C to examine the influence of grain size and crystallographic texture on mechanical behavior. The AM TA15 alloy exhibited superior tensile properties at both temperatures compared to its hot-rolled counterpart. Microstructural analysis revealed finer grain size, stronger α-phase diffraction intensity, and altered grain boundary misorientation in the AM alloy after high-temperature testing, accompanied by improved plasticity. These findings highlight the potential of thermal process optimization and microstructural tailoring to enhance the high-temperature performance of AM TA15, offering valuable insights for the fabrication of critical aerospace components. Full article
(This article belongs to the Special Issue Machining, Grinding, and Laser Processing of Metallic Materials)
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19 pages, 5055 KiB  
Article
Parametric Study of Inverse Heat Source Model Based on Molten Pool Morphology for Selective Laser Melting
by Longchao He, Ruixiang Bai, Zhenkun Lei, Da Liu, Hao Jiang, Yaoxing Xu and Jinjing Zhu
Coatings 2025, 15(5), 497; https://doi.org/10.3390/coatings15050497 - 22 Apr 2025
Viewed by 360
Abstract
Selective laser melting is a commonly employed additive manufacturing technique that facilitates the fabrication of intricate geometries through the laser-induced melting of powder materials. The quality of the produced parts is significantly influenced by the molten pool morphology, which is affected by parameters [...] Read more.
Selective laser melting is a commonly employed additive manufacturing technique that facilitates the fabrication of intricate geometries through the laser-induced melting of powder materials. The quality of the produced parts is significantly influenced by the molten pool morphology, which is affected by parameters such as laser power, scanning rate, and powder characteristics. However, the selection of unknown parameters within the heat source model significantly impacts the simulation outcomes and must be carefully considered. This study addresses this issue by proposing an inversion method for accurately determining the parameters of the Goldak double ellipsoid heat source model using molten pool morphology as a reference. A pattern search algorithm combined with Bayesian inference was employed to invert and estimate the heat source parameters. The results demonstrated that the inversed parameters significantly improved the prediction accuracy of molten pool geometry. The inverse parameters χ0, χ1, and χ2 were 1.17, 1.00, and 2.08, respectively. The study provides valuable insights into the use of image-based methods for parameter inversion and offers a more reliable tool for improving the precision of simulations. These findings have important implications for optimizing processing conditions and enhancing the overall quality of additively-manufactured components. Full article
(This article belongs to the Special Issue Laser Surface Engineering and Additive Manufacturing)
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18 pages, 8595 KiB  
Article
Paeoniflorin Attenuates Limb Ischemia by Promoting Angiogenesis Through ERα/ROCK-2 Pathway
by Mengyao Li, Qianyi Wang, Sinan Zhu, Wei Sun, Xiuyun Ren, Zhenkun Xu, Xinze Li, Shaoxia Wang, Qi Liu, Lu Chen and Hong Wang
Pharmaceuticals 2025, 18(2), 272; https://doi.org/10.3390/ph18020272 - 19 Feb 2025
Cited by 2 | Viewed by 894
Abstract
Background: Peripheral artery disease (PAD) is a high-risk vascular condition, and vascular remodeling has become a promising therapeutic approach. Paeoniflorin (PF) is the main bioactive compound in the roots of Paeonia lactiflora Pall, which is commonly used to treat a range of cardiovascular [...] Read more.
Background: Peripheral artery disease (PAD) is a high-risk vascular condition, and vascular remodeling has become a promising therapeutic approach. Paeoniflorin (PF) is the main bioactive compound in the roots of Paeonia lactiflora Pall, which is commonly used to treat a range of cardiovascular disorders. However, the mechanisms underlying the ameliorating effects of PF on PAD remain unclear. Therefore, the purpose of this study was to explore the therapeutic efficiency of PF on PAD and determine its mechanisms. Methods: The blood flow of mice was detected with a laser Doppler dot scanning imaging system. HE staining was used to observe the morphological changes of ischemic muscle. The changes in the serologic indexes were detected with an automatic biochemical assay, and the capillary density of ischemic gastrocnemius was detected with a Lectin immunofluorescence assay. The expression of angiogenesis-related proteins in ischemic gastrocnemius was detected with Western blotting, and the proportion of macrophages and neutrophils in total cells was detected with flow cytometry. Results: PF significantly increased blood flow, capillary density and protein expressions of vascular endothelial growth factor A (VEGFA), matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 2 (MMP9), and estrogen receptor α (ERα) in mouse ischemic tissue in a PAD model. PF enhances the migration of endothelial cells and promotes the formation of tubular structures, involving the ERα/ROCK2 signaling pathway. Furthermore, PF was found to promote the phenotypic transformation of macrophages and alleviated grave inflammatory responses during vascular remodeling. Conclusions: We determined that PF as a potent compound in promoting angiogenesis and mitigating inflammatory responses during revascularization. Full article
(This article belongs to the Section Pharmacology)
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13 pages, 6473 KiB  
Article
Simulation of the Static Sealing Performance of Rubber Packer Cylinders in a Supercritical–CO2 Environment
by Zhenkun Zhu, Meng Cai, Lining Cui, Xingliang Song, Xiaoyu Xu, Chuanbo Cong, Haicheng Li and Qiming Gao
Energies 2024, 17(13), 3305; https://doi.org/10.3390/en17133305 - 5 Jul 2024
Cited by 1 | Viewed by 1161
Abstract
The aim of this study was to solve the problems associated with the sealing and tearing failure of rubber packer cylinders during CO2 downhole injection. Using Comsol Multiphysics 6.0 software, a rubber cylinder model in a supercritical CO2 (SC–CO2) [...] Read more.
The aim of this study was to solve the problems associated with the sealing and tearing failure of rubber packer cylinders during CO2 downhole injection. Using Comsol Multiphysics 6.0 software, a rubber cylinder model in a supercritical CO2 (SC–CO2) environment was established. The thermal analogy method was used to simulate the CO2 diffusion and rubber cylinder swelling process. We analyzed the deformation and stress of the rubber cylinder that was caused by temperature and pressure, with CO2 as the swelling agent. The results show that in the SC–CO2 environment, under the influence of CO2 diffusion and the consequent swelling, the rubber cylinder body is prone to large deformations, and the maximum shear stress is significantly increased, leading to the shear failure of the rubber cylinder. Reducing the initial seating pressure can alleviate the impact of deformation, whereas reducing the maximum contact pressure can cause the rubber cylinder to lose its seal. We also analyzed the influence of various factors on the maximum contact stress of the rubber cylinder, providing a theoretical basis and technical support for improving the sealing performance of rubber packer cylinders in an SC–CO2 environment. Full article
(This article belongs to the Special Issue Development of Unconventional Oil and Gas Fields)
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19 pages, 7479 KiB  
Article
Aerodynamic Performance and Numerical Analysis of the Coaxial Contra-Rotating Propeller Lift System in eVTOL Vehicles
by Jie Xu, Jiaming Yu, Xinjiang Lu, Zhenkun Long, Yuteng Xu and Hao Sun
Mathematics 2024, 12(7), 1056; https://doi.org/10.3390/math12071056 - 1 Apr 2024
Cited by 4 | Viewed by 3500
Abstract
Electric vertical takeoff and landing (eVTOL) vehicles possess high payload transportation capabilities and compact design features. The traditional method of increasing propeller size to cope with high payload is no longer applicable. Therefore, this study proposes the use of coaxial counter-rotating propellers as [...] Read more.
Electric vertical takeoff and landing (eVTOL) vehicles possess high payload transportation capabilities and compact design features. The traditional method of increasing propeller size to cope with high payload is no longer applicable. Therefore, this study proposes the use of coaxial counter-rotating propellers as the lift system for eVTOL vehicles, consisting of two coaxially mounted, counter-rotating bi-blade propellers. However, if the lift of a single rotating propeller is linearly increased without considering the lift loss caused by the downwash airflow generated by the upper propeller and the torque effect of the lift system, it will significantly impact performance optimization and safety in the eVTOL vehicles design process. To address this issue, this study employed the Moving Reference Frame (MRF) method within Computational Fluid Dynamics (CFD) technology to simulate the lift system, conducting a detailed analysis of the impact of the upper propeller’s downwash flow on the aerodynamic performance of the lower propeller. In addition, the aerodynamic performance indicators of coaxial counter-rotating propellers were quantitatively analyzed under different speed conditions. The results indicated significant lift losses within the coaxial contra-rotating propeller system, which were particularly notable in the lift loss of the lower propeller. Moreover, the total torque decreased by more than 93.8%, and the torque was not completely offset; there was still a small torsional effect in the coaxial counter-rotating propellers. The virtual testing method of this study not only saves a significant amount of time and money but also serves as a vital reference in the design process of eVTOL vehicles. Full article
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14 pages, 2602 KiB  
Article
Dynamic Modeling and Altitude Control for Flying Cars Based on Active Disturbance Rejection Control
by Jie Xu, Xinjiang Lu, Wei Luo, Hao Sun, Zhenkun Long and Yuteng Xu
Appl. Sci. 2024, 14(7), 2754; https://doi.org/10.3390/app14072754 - 25 Mar 2024
Cited by 1 | Viewed by 1684
Abstract
Flying cars offer huge advantages due to their deformable structure, which can adapt to external environments and mission requirements. They represent a novel system that can realize vertical takeoff and landing. However, the structure of a flying car is complicated, placing higher requirements [...] Read more.
Flying cars offer huge advantages due to their deformable structure, which can adapt to external environments and mission requirements. They represent a novel system that can realize vertical takeoff and landing. However, the structure of a flying car is complicated, placing higher requirements on modeling accuracy and control effectiveness. Thus, in this paper, a dynamic model of a flying car is proposed by combining a car body, motor, and propellers. Then, a double-loop controller based on active disturbance rejection control is proposed to accurately control its flight altitude. Utilizing the extended state observer, external wind and other disturbances are regarded as an extended state, which can be dynamically observed and compensated to significantly improve tracking accuracy. The effectiveness of the proposed controller is validated through detailed simulations and flight experiments. The proposed controller significantly improves control accuracy and disturbance rejection capability. Full article
(This article belongs to the Special Issue Research and Development of Intelligent Robot)
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17 pages, 5046 KiB  
Article
The Effects of Acute Exposure to Ammonia on Oxidative Stress, Hematological Parameters, Flesh Quality, and Gill Morphological Changes of the Large Yellow Croaker (Larimichthys crocea)
by Meijie Guo, Zhenkun Xu, Hongzhi Zhang, Jun Mei and Jing Xie
Animals 2023, 13(15), 2534; https://doi.org/10.3390/ani13152534 - 6 Aug 2023
Cited by 21 | Viewed by 2515
Abstract
Ammonia is considered to be the major chemical pollutant causing fish poisoning in aquaculture. This research aimed to evaluate the impact of acute ammonia exposure on the large yellow croaker’s meat quality, gill morphology, liver oxidative stress, and hematological parameters. The fish were [...] Read more.
Ammonia is considered to be the major chemical pollutant causing fish poisoning in aquaculture. This research aimed to evaluate the impact of acute ammonia exposure on the large yellow croaker’s meat quality, gill morphology, liver oxidative stress, and hematological parameters. The fish were exposed to total ammonia nitrogen concentrations of 0, 2.96, 5.92, and 8.87 mg/L for 48 h, respectively. The findings demonstrated that all ammonia-exposed fish had higher liver lactate dehydrogenase and glutamic oxalate transaminase activities. The glucose, blood urea nitrogen, and creatinine levels in 8.87 mg/L total ammonia nitrogen (TAN) were higher than other samples. The total protein, albumin, and triglyceride levels in serum decreased significantly in ammonia-exposed samples. After 48 h of ammonia exposure, superoxide dismutase activities showed a 76.1%, 118.0%, and 156.8% increase when fish were exposed to 2.96, 5.92, and 8.87 mg/L TAN, respectively. Catalase activities and glutathione contents were considerably higher (p < 0.05) in all ammonia-treated samples compared to 0 mg/L TAN. The ammonia-treated gill lamellae become thicker, shorter, and curved. Additionally, the ammonia exposure resulted in the accumulation of free amino acids and the loss of nucleotides. The inosine monophosphate and adenosine monophosphate contents in the flesh were decreased after 12 h of exposure to 2.96, 5.92, and 8.87 mg/L ammonia compared to the control group. Overall, large yellow croakers exposed to ammonia for 6 h presented not only changes in serum composition but also oxidative stress, liver and gill tissue damage and flesh quality deterioration. Full article
(This article belongs to the Special Issue The Effects of Pollution and Other Stressors on Fish Health)
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14 pages, 1997 KiB  
Article
The Association of Metabolomic Profiles of a Healthy Lifestyle with Heart Failure Risk in a Prospective Study
by Yuanyuan Ma, Maomao Chu, Zuqiang Fu, Qian Liu, Jingjia Liang, Jin Xu, Zhenkun Weng, Xiu Chen, Cheng Xu and Aihua Gu
Nutrients 2023, 15(13), 2934; https://doi.org/10.3390/nu15132934 - 28 Jun 2023
Cited by 3 | Viewed by 2801
Abstract
Lifestyle has been linked to the incidence of heart failure, but the underlying biological mechanisms remain unclear. Using the metabolomic, lifestyle, and heart failure data of the UK Biobank, we identified and validated healthy lifestyle-related metabolites in a matched case-control and cohort study, [...] Read more.
Lifestyle has been linked to the incidence of heart failure, but the underlying biological mechanisms remain unclear. Using the metabolomic, lifestyle, and heart failure data of the UK Biobank, we identified and validated healthy lifestyle-related metabolites in a matched case-control and cohort study, respectively. We then evaluated the association of healthy lifestyle-related metabolites with heart failure (HF) risk and the added predictivity of these healthy lifestyle-associated metabolites for HF. Of 161 metabolites, 8 were identified to be significantly related to healthy lifestyle. Notably, omega-3 fatty acids and docosahexaenoic acid (DHA) positively associated with a healthy lifestyle score (HLS) and exhibited a negative association with heart failure risk. Conversely, creatinine negatively associated with a HLS, but was positively correlated with the risk of HF. Adding these three metabolites to the classical risk factor prediction model, the prediction accuracy of heart failure incidence can be improved as assessed by the C-statistic (increasing from 0.806 [95% CI, 0.796–0.816] to 0.844 [95% CI, 0.834–0.854], p-value < 0.001). A healthy lifestyle is associated with significant metabolic alterations, among which metabolites related to healthy lifestyle may be critical for the relationship between healthy lifestyle and HF. Healthy lifestyle-related metabolites might enhance HF prediction, but additional validation studies are necessary. Full article
(This article belongs to the Section Nutrition and Metabolism)
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20 pages, 3529 KiB  
Communication
A Comprehensive Mass Spectrometry-Based Workflow for Clinical Metabolomics Cohort Studies
by Zhan Shi, Haohui Li, Wei Zhang, Youxiang Chen, Chunyan Zeng, Xiuhua Kang, Xinping Xu, Zhenkun Xia, Bei Qing, Yunchang Yuan, Guodong Song, Camila Caldana, Junyuan Hu, Lothar Willmitzer and Yan Li
Metabolites 2022, 12(12), 1168; https://doi.org/10.3390/metabo12121168 - 24 Nov 2022
Cited by 8 | Viewed by 3669
Abstract
As a comprehensive analysis of all metabolites in a biological system, metabolomics is being widely applied in various clinical/health areas for disease prediction, diagnosis, and prognosis. However, challenges remain in dealing with the metabolomic complexity, massive data, metabolite identification, intra- and inter-individual variation, [...] Read more.
As a comprehensive analysis of all metabolites in a biological system, metabolomics is being widely applied in various clinical/health areas for disease prediction, diagnosis, and prognosis. However, challenges remain in dealing with the metabolomic complexity, massive data, metabolite identification, intra- and inter-individual variation, and reproducibility, which largely limit its widespread implementation. This study provided a comprehensive workflow for clinical metabolomics, including sample collection and preparation, mass spectrometry (MS) data acquisition, and data processing and analysis. Sample collection from multiple clinical sites was strictly carried out with standardized operation procedures (SOP). During data acquisition, three types of quality control (QC) samples were set for respective MS platforms (GC-MS, LC-MS polar, and LC-MS lipid) to assess the MS performance, facilitate metabolite identification, and eliminate contamination. Compounds annotation and identification were implemented with commercial software and in-house-developed PAppLineTM and UlibMS library. The batch effects were removed using a deep learning model method (NormAE). Potential biomarkers identification was performed with tree-based modeling algorithms including random forest, AdaBoost, and XGBoost. The modeling performance was evaluated using the F1 score based on a 10-times repeated trial for each. Finally, a sub-cohort case study validated the reliability of the entire workflow. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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20 pages, 10191 KiB  
Article
Road Network Extraction from SAR Images with the Support of Angular Texture Signature and POIs
by Na Sun, Yongjiu Feng, Xiaohua Tong, Zhenkun Lei, Shurui Chen, Chao Wang, Xiong Xu and Yanmin Jin
Remote Sens. 2022, 14(19), 4832; https://doi.org/10.3390/rs14194832 - 28 Sep 2022
Viewed by 2594
Abstract
Urban road network information is an important part of modern spatial information infrastructure and is crucial for high-precision navigation map production and unmanned driving. Synthetic aperture radar (SAR) is a widely used remote-sensing data source, but the complex structure of road networks and [...] Read more.
Urban road network information is an important part of modern spatial information infrastructure and is crucial for high-precision navigation map production and unmanned driving. Synthetic aperture radar (SAR) is a widely used remote-sensing data source, but the complex structure of road networks and the noises in images make it very difficult to extract road information through SAR images. We developed a new method of extracting road network information from SAR images by considering angular (A) and texture (T) features in the sliding windows and points of interest (POIs, or P), and we named this method ATP-ROAD. ATP-ROAD is a sliding window-based semi-automatic approach that uses the grayscale mean, grayscale variance, and binary segmentation information of SAR images as texture features in each sliding window. Since POIs have much-duplicated information, this study also eliminates duplicated POIs considering distance and then selects a combination of POI linkages by discerning the direction of these POIs to initially determine the road direction. The ATP-ROAD method was applied to three experimental areas in Shanghai to extract the road network using China’s Gaofen-3 imagery. The experimental results show that the extracted road network information is relatively complete and matches the actual road conditions, and the result accuracy is high in the three different regions, i.e., 89.57% for Area-I, 96.88% for Area-II, and 92.65% for Area-III. Our method together with our extraction software can be applied to extract information about road networks from SAR images, providing an alternative for enriching the variety of road information. Full article
(This article belongs to the Special Issue Advances in SAR Image Processing and Applications)
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13 pages, 3872 KiB  
Article
Analysis of Acute Nitrite Exposure on Physiological Stress Response, Oxidative Stress, Gill Tissue Morphology and Immune Response of Large Yellow Croaker (Larimichthys crocea)
by Zhenkun Xu, Hongzhi Zhang, Meijie Guo, Dan Fang, Jun Mei and Jing Xie
Animals 2022, 12(14), 1791; https://doi.org/10.3390/ani12141791 - 12 Jul 2022
Cited by 28 | Viewed by 3382
Abstract
Nitrite is a common pollutant in aquaculture water, and nitrite toxicity that negatively affects aquatic species is common in aquaculture systems when the water quality is low. Therefore, the present research aimed to evaluate the effect of acute nitrite exposure on the hematological [...] Read more.
Nitrite is a common pollutant in aquaculture water, and nitrite toxicity that negatively affects aquatic species is common in aquaculture systems when the water quality is low. Therefore, the present research aimed to evaluate the effect of acute nitrite exposure on the hematological parameters, antioxidant enzymes, immune response, and gill morphology of large yellow croaker (Larimichthys crocea). The fish were randomly separated and exposed to four (i.e., 0, 29.36, 58.73, and 88.09 mg/L) nitrite concentrations for 48 h. The fish blood and gills were collected at 0, 12, 24, 36, and 48 h of nitrite exposure for further analysis. In hematological parameters, the results showed that the levels of hemoglobin, triglyceride, and total cholesterol in blood significantly decreased (p < 0.05) in all nitrite-treated samples after 12 h, while the contents of methemoglobin in blood significantly increased (p < 0.05) in these treatments. After 48 h of nitrite exposure, the levels of cortisol in serum showed a 94.5%, 132.1%, and 165.6% increase in fish exposed to 29.36, 58.73, and 88.09 mg/L nitrite, respectively. The nitrite (i.e., 29.36, 58.73, and 88.09 mg/L) exposure significantly increased (p < 0.05) the levels of antioxidant enzymes (i.e., catalase and glutathione) in the gill and serum after 12 h of exposure compared with the control. The lysozyme levels in serum decreased in the nitrite (i.e., 29.36, 58.73, and 88.09 mg/L) exposure samples. It was found that immunoglobulin levels in the 29.36, 58.73, and 88.09 mg/L nitrite-treated samples (i.e., 1.86, 1.58, and 0.74 μg/mL, respectively) were lower than that of the control (2.56 μg/mL). In addition, the surface of the gill lamellae displayed deformation and contraction after 48 h of nitrite, especially in the fish exposed to 88.09 mg/L nitrite. These results indicate that the nitrite exposure induced the oxidative stress, affected the immune response, and changed the gill morphology, leading to nitrite poisoning in large yellow croaker. Full article
(This article belongs to the Special Issue The Effects of Pollution and Other Stressors on Fish Health)
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19 pages, 979 KiB  
Review
Toxic Effects on Bioaccumulation, Hematological Parameters, Oxidative Stress, Immune Responses and Tissue Structure in Fish Exposed to Ammonia Nitrogen: A Review
by Zhenkun Xu, Jie Cao, Xiaoming Qin, Weiqiang Qiu, Jun Mei and Jing Xie
Animals 2021, 11(11), 3304; https://doi.org/10.3390/ani11113304 - 19 Nov 2021
Cited by 174 | Viewed by 12294
Abstract
Ammonia nitrogen is the major oxygen-consuming pollutant in aquatic environments. Exposure to ammonia nitrogen in the aquatic environment can lead to bioaccumulation in fish, and the ammonia nitrogen concentration is the main determinant of accumulation. In most aquatic environments, fish are at the [...] Read more.
Ammonia nitrogen is the major oxygen-consuming pollutant in aquatic environments. Exposure to ammonia nitrogen in the aquatic environment can lead to bioaccumulation in fish, and the ammonia nitrogen concentration is the main determinant of accumulation. In most aquatic environments, fish are at the top of the food chain and are most vulnerable to the toxic effects of high levels of ammonia nitrogen exposure. In fish exposed to toxicants, ammonia-induced toxicity is mainly caused by bioaccumulation in certain tissues. Ammonia nitrogen absorbed in the fish enters the circulatory system and affects hematological properties. Ammonia nitrogen also breaks balance in antioxidant capacity and causes oxidative damage. In addition, ammonia nitrogen affects the immune response and causes neurotoxicity because of the physical and chemical toxicity. Thence, the purpose of this review was to investigate various toxic effects of ammonia nitrogen, including oxidative stress, neurotoxicity and immune response. Full article
(This article belongs to the Special Issue Physiological Responses in Fishes)
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15 pages, 276 KiB  
Article
Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents
by Dongfeng Zhang, Yang Liu, Chunlin Zhang, Hao Zhang, Bin Wang, Jian Xu, Lei Fu, Dali Yin, Christopher B. Cooper, Zhenkun Ma, Yu Lu and Haihong Huang
Molecules 2014, 19(4), 4380-4394; https://doi.org/10.3390/molecules19044380 - 9 Apr 2014
Cited by 42 | Viewed by 8741
Abstract
Clofazimine, a member of the riminophenazine class, is one of the few antibiotics that are still active against multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). However, the clinical utility of this agent is limited by its undesirable physicochemical properties and skin pigmentation potential. [...] Read more.
Clofazimine, a member of the riminophenazine class, is one of the few antibiotics that are still active against multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). However, the clinical utility of this agent is limited by its undesirable physicochemical properties and skin pigmentation potential. With the goal of maintaining potent antituberculosis activity while improving physicochemical properties and lowering skin pigmentation potential, a series of novel riminophenazine derivatives containing a 2-methoxypyridylamino substituent at the C-2 position of the phenazine nucleus were designed and synthesized. These compounds were evaluated for antituberculosis activity against M. tuberculosis H37Rv and screened for cytotoxicity. Riminophenazines bearing a 3-halogen- or 3,4-dihalogen-substituted phenyl group at the N-5 position exhibited potent antituberculosis activity, with MICs ranging from 0.25~0.01 μg/mL. The 3,4-dihalogen- substituted compounds displayed low cytotoxicity, with IC50 values greater than 64 μg/mL. Among these riminophenazines, compound 15 exhibited equivalent in vivo efficacy against M. tuberculosis infection and reduced skin discoloration potential in an experimental mouse infection model as compared to clofazimine. Compound 15, as compared to clofazimine, also demonstrated improved physicochemical properties and pharmacokinetic profiles with a short half-life and less drug tissue accumulation. This compound is being evaluated as a potential drug candidate for the treatment of multidrug resistant tuberculosis. Full article
(This article belongs to the Section Medicinal Chemistry)
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