8,541 results on '"cathepsin"'
Search Results
2. Study on the causality of cathepsin on autoimmune diseases and cancer: evidence from mendelian randomization analysis.
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Gao, Xue, Zhao, Xinyu, Yang, Shuhan, Liu, Jianli, and Liu, Dan
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The genetic causality between cathepsin levels and autoimmune diseases (ADs) bidirectionally was investigated and the associated cancer risk was explored with Mendelian randomization. Mendelian randomization analyses were used to explore causal associations between cathepsin and 14 ADs. The final results came from a meta-analysis of two datasets to get a robust result. Furthermore, the potential carcinogenic effects of reduced cathepsin levels were explored. Sensitivity analyses were used to evaluate the robustness of the results. Based on the Mendelian randomization analysis, it was found that lower levels of specific cathepsins were associated with reduced risk of ADs. Reduced cathepsin E levels were linked to decreased susceptibility to psoriasis and a potential reduction in breast cancer risk. Reduced cathepsins G and L2 showed an inhibitory effect on psoriasis without increasing cancer risk. These results emphasized the genetic causal connection between cathepsin and ADs. Targeting cathepsins may be beneficial in treating ADs, but potential oncogenic effects must be considered to provide a basis for safer therapeutic strategies. [ABSTRACT FROM AUTHOR]
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- 2025
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3. Underlying Mechanism of Lysosomal Membrane Permeabilization in CNS Injury: A Literature Review.
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Xiang, Linyi, Lou, Junsheng, Zhao, Jiayi, Geng, Yibo, Zhang, Jiacheng, Wu, Yuzhe, Zhao, Yinuo, Tao, Zhichao, Li, Yao, Qi, Jianjun, Chen, Jiaoxiang, Yang, Liangliang, and Zhou, Kailiang
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Lysosomes play a crucial role in various intracellular pathways as their final destination. Various stressors, whether mild or severe, can induce lysosomal membrane permeabilization (LMP), resulting in the release of lysosomal enzymes into the cytoplasm. LMP not only plays a pivotal role in various cellular events but also significantly contributes to programmed cell death (PCD). Previous research has demonstrated the participation of LMP in central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE). However, the mechanisms underlying LMP in CNS injuries are poorly understood. The occurrence of LMP leads to the activation of inflammatory pathways, increased levels of oxidative stress, and PCD. Herein, we present a comprehensive overview of the latest findings regarding LMP and highlight its functions in cellular events and PCDs (lysosome-dependent cell death, apoptosis, pyroptosis, ferroptosis, and autophagy). In addition, we consolidate the most recent insights into LMP in CNS injury by summarizing and exploring the latest advances. We also review potential therapeutic strategies that aim to preserve LMP or inhibit the release of enzymes from lysosomes to alleviate the consequences of LMP in CNS injury. A better understanding of the role that LMP plays in CNS injury may facilitate the development of strategic treatment options for CNS injury. [ABSTRACT FROM AUTHOR]
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- 2025
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4. Inhibition of intracellular versus extracellular cathepsin D differentially alters the liver lipidome of mice with metabolic dysfunction‐associated steatohepatitis.
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Vermeulen, Isabeau, Li, Mengying, van Mourik, Hester, Yadati, Tulasi, Eijkel, Gert, Balluff, Benjamin, Godschalk, Roger, Temmerman, Lieve, Biessen, Erik A. L., Kulkarni, Aditya, Theys, Jan, Houben, Tom, Cillero‐Pastor, Berta, and Shiri‐Sverdlov, Ronit
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CATHEPSIN D , *DIETARY patterns , *SUBCUTANEOUS injections , *LIPOPROTEIN receptors , *LIPID metabolism - Abstract
The prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) progressing to metabolic dysfunction‐associated steatohepatitis (MASH), characterized by hepatic inflammation, has significantly increased in recent years due to unhealthy dietary practices and sedentary lifestyles. Cathepsin D (CTSD), a lysosomal protease involved in lipid homeostasis, is linked to abnormal lipid metabolism and inflammation in MASH. Although primarily intracellular, CTSD can be secreted extracellularly. Our previous proteomics research has shown that inhibition of extracellular CTSD results in more anti‐inflammatory effects and fewer potential side effects compared to intracellular CTSD inhibition. However, the correlation between reduced side effects and alterations in the hepatic lipid composition remains unknown. This study aims to investigate the correlation between intra‐ and extracellular CTSD inhibition and potential alterations in the hepatic lipid composition in MASH. Low‐density lipoprotein receptor knockout (Ldlr−/−) mice were fed a high‐fat diet for 10 weeks and received subcutaneous injections every 2 days of vehicle, intracellular CTSD inhibitor (GA‐12), or extracellular CTSD inhibitor (CTD‐002). Matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) was used to visualize and compare the lipid composition in liver tissues. Hepatic phosphatidylcholine remodeling was observed with both inhibitors, suggesting their therapeutic potential in treating MASH. Treatment with an intracellular CTSD inhibitor resulted in elevated levels of cardiolipin, reactive oxygen species, phosphatidylinositol, phosphatidylethanolamine, and lipids that are linked to mitochondrial dysfunction and inflammation, and induced more oxidative stress. The observed modifications in lipid composition demonstrate the clinical advantages of extracellular CTSD inhibition as a potentially beneficial therapeutic approach for MASH. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Vitamin consumption and the ontogenesis of cathepsins and antioxidant capacity in developing embryos of turbot, Scophthalmus maximus.
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Tong, Xuehong, Ran, Sudan, Feng, Yiqiu, Cao, Linxi, Wang, Yi, Wang, Yueqin, Zhuang, Yutian, and Zhang, Xuexue
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PSETTA maxima , *EMBRYOLOGY , *CATHEPSINS , *OXIDANT status , *GASTRULATION , *PROTEOLYSIS , *GLUTATHIONE peroxidase - Abstract
During embryonic development, vitamins are involved in energy metabolism and protein synthesis, while cathepsins and antioxidant defense play key roles in yolk degradation and protecting fish embryos from oxidative damage. This study aimed to investigate the consumption of vitamins (A, B1, B2, C, D, and E), ontogenesis of cathepsins, and antioxidant capacity in developing embryos of turbot. In this study, embryos were collected over time from 2.3 to 102.5 h (i.e., hatching) after fertilization for vitamins, cathepsins, and antioxidant capacity analyses. Results showed that the embryonic growth rate in the cleavage stage (CS) was faster than in other stages, while that in the segmentation stage (SS) was lower than in other stages. Embryos displayed higher demands on VA during blastula stage (BS), gastrula stage (GS), the early SS, and hatching day (HD), VB1 at CS; VB2 at BS, GS, SS, and HD; VD at CS and SS; VE at CS, BS, and the late SS; and Vc during entire periods. Cathepsins A (CA) showed a high level at early SS, suggesting its involvement in yolk degradation. Cathepsins B (CB) and cathepsins D (CD) were highly active at GS, suggesting an active apoptosis process. CA, CB, CD, and cathepsins L (CL) all kept low levels in CS, revealing low protein demand during the cleavage process. On the whole, the predominant antioxidant enzymes were superoxide dismutase (SOD) and malondialdehyde (MDA) from CS to SS; SOD, MDA, glutathione peroxidase (GSH-Px), and catalase (CAT) during SS; and GSH-Px and CAT during HD. In conclusion, the fastest growth rate and the slowest growth rate of embryos occurred in CS and SS, respectively, being consistent with energy allocation. Vitamin consumption and cathepsin ontogenesis were stage-specific. Oxidative damage on embryos was relatively less at CS, but larger at SS and HD. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Association of LVV-Hemorphin-7 with Sepsis and Shock: Roles of Cathepsin D and G in Hemoglobin Metabolism in a Prospective ICU Cohort Study.
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Wu, Yao-Kuang, Chung, Hsueh-Wen, Chen, Yi-Ting, Chen, Hsing-Chun, Chen, I-Hung, and Su, Wen-Lin
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CATHEPSIN D ,SEPTIC shock ,INTENSIVE care units ,SEPSIS ,LOGISTIC regression analysis - Abstract
Background: Sepsis is a leading cause of mortality in intensive care units (ICUs). Cell-free hemoglobin (CFH) released during sepsis interacts with lysosomal enzymes from neutrophils and macrophages. This study aims to examine the association of LVV-hemorphin-7 (LVV-H7), cathepsin D, and cathepsin G with sepsis and shock in ICU patients. Methods: A prospective observational cohort study was conducted in the medical ICU of a tertiary referral hospital in Taiwan. The patients with an acute increasing sequential organ failure assessment (SOFA) score ≥ 2 between 2022 and 2023. Blood samples from 40 healthy controls were obtained from the hospital biobank. CFH metabolites, including LVV-H7 and lysosomal enzyme cathepsin D and cathepsin G, were compared between the sepsis (definite and probable) and non-sepsis (possible sepsis) groups. Multivariate logistic regression analyzed factors associated with sepsis and shock. Results: Among 120 patients, 75 were classified as septic and 45 as non-septic. Significant differences were observed in CFH, cathepsin D, cathepsin G, and LVV-H7 levels between sepsis and non-sepsis groups. LVV-H7 was a significant predictor for sepsis (adjusted OR [aOR] 1.009, 95% CI 1.005–1.013; p < 0.001) and shock (aOR 1.005, 95% CI 1.002–1.008; p < 0.05). Cathepsin G predicted non-shock (aOR 0.917, 95% CI 0.848–0.991; p < 0.05), while cathepsin D predicted septic shock (aOR 1.001, 95% CI 1.000–1.002; p < 0.05). Conclusions: LVV-H7, cathepsin D, and cathepsin G are associated with the classification of sepsis and shock episodes in critically ill patients with elevated SOFA scores. [ABSTRACT FROM AUTHOR]
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- 2024
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7. 组织蛋白酶与骨密度的因果关系: 双向孟德尔随机化分析.
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姜 楠, 符浩楠, 郝宇涵, 陈祉霖, 朱芷晴, 徐 峰, and 于 栋
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BONE density , *MENDELIAN randomization , *SINGLE nucleotide polymorphisms , *MIDDLE-aged persons , *AGE groups , *INSTRUMENTAL variables (Statistics) - Abstract
BACKGROUND: Previous studies have indicated that cathepsin K can intervene with the occurrence and development of osteoporosis by regulating bone mineral density in middle-aged and older adults. However, whether there is a causal relationship between the cathepsin family and bone mineral density in other populations remains unknown. OBJECTIVE: To investigate the causal relationship between cathepsin and bone mineral density. METHODS: Genetic loci associated with eight cathepins were extracted from the IEU Open GWAS database as instrumental variables, and bone mineral density values in five age groups acted as an outcome. The causal relationship between cathepin and bone mineral density was assessed by two-way Mendelian randomization analysis. Heterogeneity of the genetic instrumental variables was assessed using Cochran’s Q test, pleiotropy was assessed using the MR-Egger intercept test, and the sensitivity of single nucleotide polymorphisms used as instrumental variables to the causal effect of exposure and outcome was assessed using the leave-one-out method. RESULTS AND CONCLUSION: The results of the inverse variance weighting method with positive Mendelian randomization showed that cathepin H was negatively associated with bone mineral density in people aged 45-60 years [odds ratio (95% confidence interval)=0.965(0.94-0.99), P=0.04]; cathepin Z was negatively associated with bone mineral density in people aged 30-45 year [odds ratio (95% confidence interval)=1.06 (1.00-1.11), P=0.03]. The results of sensitivity analysis showed a stable causal relationship, and MR-Egger intercept analysis did not detect potential horizontal pleiotropy. The inverse Mendelian randomization results showed that bone mineral density had no significant inverse effect on cathepin. The above results confirm that cathepin can affect bone mineral density in some age groups, which may increase the risk of osteoporosis and should be given more attention. [ABSTRACT FROM AUTHOR]
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- 2025
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8. 溶酶体的代谢调节及调控肉嫩化机制的研究进展.
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董玉珊, 杜 瑞, 苏日娜, 姚丽丽, 杜雪蓉, 李晨龙, 吴俊琴, 侯艳茹, and 罗玉龙
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P53 protein ,REACTIVE oxygen species ,CATHEPSINS ,LYSOSOMES ,OXIDATIVE stress - Abstract
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- 2025
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9. The modulatory effects of Lonicera caerulea L. extract and omega-3 on sarcopenia via regulating PI3K and FOXO signaling pathways in rats
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Radwa Wahid Mohamed and Nourhan Gamal El-Rahmany
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cathepsin ,dexamethasone ,muscle atrophy ,atrogin-1 ,haskap berry ,nuclear factor kappa b ,oxidative damage ,Medicine (General) ,R5-920 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Introduction: Sarcopenia is an inflammatory disease caused by a disruption of muscle homeostasis. Lonicera caerulea L. (Haskap berry) (HB) extract and omega-3 (ω−3) possess antioxidant and anti-inflammatory activities. This study assesses the potential ameliorating effects of HB extract and ω−3 supplementation on dexamethasone (DEXA)-induced sarcopenia. Methods: Rats were divided into five groups; the negative control group was injected with saline (i.p.); groups 2, 3, 4, and 5 were injected with DEXA (2 mg/kg/d, i.p.); groups 3 and 4 also received 400 mg/kg/d and 100 mg/kg/d of HB extract and ω−3, respectively, while group 5 received both treatments daily for 21 days. The ameliorative effects of treatments were investigated by measuring lysosomal proteolytic enzyme cathepsin activity, phosphatidylinositol 3 kinase (PI3K) activity, nuclear factor kappa beta (NF-κB) level, and heme oxygenase-1 (HO-1) activity. The gene expression levels of muscle ring-finger protein (MuRF) and forkhead box O (FOXO) transcription factor were also evaluated. Biochemical and histological examinations were done on muscle tissues. Results: DEXA caused a significant elevation (P
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- 2024
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10. Mendelian randomisation analysis to explore the association between cathepsins and bipolar disorder
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Chenshuang Dong, Yecheng Han, Siqiao Chen, and Guiling Wang
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Mendelian randomization ,Type I bipolar disorder ,Type II bipolar disorder ,Cathepsin ,Cerebral dopamine neurotrophic factor ,Psychiatry ,RC435-571 - Abstract
Abstract Introduction Bipolar disorder is a psychiatric condition characterized by the coexistence of depression and mania. Diagnosis of this disorder can be challenging due to limited pathologic and experimental tools. Treatment compliance is often poor due to medication side effects. Although cathepsin is known to play a significant role in diseases such as tumors and osteoporosis, its role in psychiatric disorders is not yet fully understood. Objective The aim of this study was to investigate the relationship between cathepsin in the blood circulation and bipolar disorder. Methods The causal relationship between cathepsin and different subtypes of bipolar affective disorder was explored using bidirectional Mendelian randomization analysis and multivariate analysis. Results It was found that cathepsin H level was a protective factor for type II bipolar disorder. No potential causal relationship was found between cathepsin H and type I bipolar disorder, but cathepsin B changes with the development of type I bipolar disorder. A causal relationship was found between cathepsin H and cerebral dopamine neurotrophic factor. Conclusions In conclusion, cathepsin H may be a diagnostic target for bipolar II disorder and may play a guiding role in clinical diagnosis. Cathepsin H may have an effect on BD through cerebral dopamine neurotrophic factor.
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- 2024
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11. Searching for novel cellular targets for MASLD and HCC within the humble lysosomal cathepsins
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Alejandro del Castillo-Cruz, Maria Fernández-Fernández, and Anna Moles
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cathepsin ,lysosome ,protease ,masld ,mash ,hcc ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Metabolic-associated steatotic liver disease (MASLD) and its pathological version, metabolic dysfunction-associated steatohepatitis (MASH), are becoming the main leading causes of chronic liver disease almost worldwide and are the fastest growing aetiology of hepatocellular carcinoma (HCC), especially in the Western countries. The combination of high incidence and morbidity with limited treatment options for both MASH and HCC highlights an urgent need for the discovery of novel therapeutic candidates to inform drug development. The importance of lysosomes and cathepsins, their most abundant hydrolases, has been overlooked for decades. They were considered organelles only involved in the recycling of macromolecules, with cathepsins simply being their effectors. Contrary to this traditional view, recent findings have shed new light on the lysosome and its enzymes as drivers of essential cellular processes, such as apoptosis and autophagy. Bringing lysosomal activity and the regulation of cathepsins into the spotlight of MASH and HCC research can open new avenues for the development of novel drugs based on targeting cathepsin-driven lysosomal activity and its associated pathological processes. This review comprehensively summarises the current knowledge on the role and contribution of lysosomal cathepsins to MASLD/MASH and HCC progression.
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- 2024
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12. Mendelian randomisation analysis to explore the association between cathepsins and bipolar disorder.
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Dong, Chenshuang, Han, Yecheng, Chen, Siqiao, and Wang, Guiling
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BLOOD circulation disorders , *DRUG side effects , *CATHEPSIN B , *BIPOLAR disorder , *AFFECTIVE disorders , *HYPOMANIA - Abstract
Introduction: Bipolar disorder is a psychiatric condition characterized by the coexistence of depression and mania. Diagnosis of this disorder can be challenging due to limited pathologic and experimental tools. Treatment compliance is often poor due to medication side effects. Although cathepsin is known to play a significant role in diseases such as tumors and osteoporosis, its role in psychiatric disorders is not yet fully understood. Objective: The aim of this study was to investigate the relationship between cathepsin in the blood circulation and bipolar disorder. Methods: The causal relationship between cathepsin and different subtypes of bipolar affective disorder was explored using bidirectional Mendelian randomization analysis and multivariate analysis. Results: It was found that cathepsin H level was a protective factor for type II bipolar disorder. No potential causal relationship was found between cathepsin H and type I bipolar disorder, but cathepsin B changes with the development of type I bipolar disorder. A causal relationship was found between cathepsin H and cerebral dopamine neurotrophic factor. Conclusions: In conclusion, cathepsin H may be a diagnostic target for bipolar II disorder and may play a guiding role in clinical diagnosis. Cathepsin H may have an effect on BD through cerebral dopamine neurotrophic factor. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Causal effect of immune cells, metabolites, cathepsins, and vitamin therapy in diabetic retinopathy: a Mendelian randomization and crosssectional study.
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Huijun Zhou, Jingzhi Wang, and Xuehao Cui
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VITAMIN B6 ,VITAMIN E ,GENOME-wide association studies ,PROTEOLYTIC enzymes ,VITAMIN B1 ,DIABETIC retinopathy - Abstract
Background: Diabetic retinopathy (DR) is a major microvascular complication of diabetes and a leading cause of blindness worldwide. The pathogenesis of DR involves complex interactions between metabolic disturbances, immune cells, and proteolytic enzymes such as cathepsins (CATs). Despite various studies, the precise roles of different CATs, metabolites, and vitamins in DR remain unclear. Method: In this study, we employed Mendelian Randomization (MR) to assess causal relationships using genetic instruments selected based on genome-wide association studies (GWAS). We employed two-sample and mediation MR to explore the causal effects between nine CATs, immune cells, metabolites, vitamins, and DR. Additionally, the study also incorporated data from the NHANES survey to explore the associated relationship between vitamins and DR. We utilized cross-sectional data from the NHANES to analyze the association between vitamin intake and diabetic retinopathy (DR), adjusting for potential confounders to strengthen the validity of our findings. Results: The MR analysis identified CAT H as a significant risk factor for both NPDR and PDR, with no evidence of reverse causality. Additionally, 62 immune cell traits were found to have causal relationships with NPDR and 49 with PDR. Enrichment analysis revealed that metabolic pathways such as sphingolipid metabolism are crucial in DR progression. Vitamins B6 and E were significantly associated with a reduced risk of PDR. Cross-sectional data indicated that vitamins B1, B2, B6, B12, and E progressively decreased with DR severity. Conclusion: This study is the first to identify CAT H as a key risk factor for DR, while vitamins B6 and E showed significant protective effects, particularly against PDR. These findings suggest that CAT H, along with vitamins B6 and E, could serve as therapeutic targets for DR. Further validation through larger, multicenter studies is recommended to enhance the accuracy and applicability of these findings. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Cathepsins and neurological diseases: a Mendelian randomization study.
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Haitao Sun, Qingqing Tang, Xue Yan, Wanying Xie, Yueshan Xu, and Weimin Zhang
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ALZHEIMER'S disease ,CATHEPSIN D ,CATHEPSIN B ,AMYOTROPHIC lateral sclerosis ,PARKINSON'S disease - Abstract
Background: The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases. Methods: This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis. Results: We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p = 0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p = 0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p = 0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases. Conclusion: Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Comparación de la estimulación por microvibración versus inhibidores de catepsina K a nivel molecular y celular: una revisión sistemática.
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Salgado Martínez, Yomira, Villanueva Arriaga, Rosina Eugenia, García López, Salvador, and Molina Frechero, Nelly
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BONE remodeling , *BONE regeneration , *DRUG therapy , *MEDLINE , *REGENERATION (Biology) - Abstract
Introduction: Bone is constantly remodeling to maintain the structure of the bone tissue that composes it. This is susceptible to changes that can be both favorable and harmful, marked by certain variables such as age, sex, diseases, hormonal alterations, trauma, among others. Method: Due to the above, the idea was raised to study which treatment is better in the regeneration of bone tissue, comparing pharmacological treatments (cathepsin K inhibitors) against micro-vibratory stimulation or non-pharmacological treatment. Objective: To carry out a systematic review of treatments with micro-vibrations and cathepsin K inhibitors in relation to bone remodeling. To make a comparison between the effectiveness of treatment based on micro-vibrations and with cathepsin K inhibitors, a systematic review was carried out in nine databases (Wiley Online Library, Pubmed, Google Academic, Scopus, Science Direct, Scielo, Medline, EBSCO and SpringerLink). Results: Twenty articles were included in this study, which demonstrated that both treatments improve the bone remodeling process. Conclusions: Taking into consideration the systematic review carried out, it has been determined that the treatment of low-intensity, high-frequency micro-vibrations increases the outer cortex; however, the use of cathepsin k inhibitors promises innovative treatments in tissue regeneration. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Impaired autophagy flux contributes to enhanced ischemia reperfusion injury in the diabetic heart
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Jialing Tang, Nanyoung Yoon, Keith Dadson, Hye Kyoung Sung, Yubin Lei, Thanh Q. Dang, Wing Yan Chung, Saher Ahmed, Ali A. Abdul-Sater, Jun Wu, Ren-Ke Li, James Jonkman, Trevor McKee, Justin Grant, Jeffrey D. Peterson, and Gary Sweeney
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Autophagy ,cardiac remodeling ,cathepsin ,diabetes ,fluorescence molecular tomography ,ischemia-reperfusion ,Cytology ,QH573-671 - Abstract
Myocardial ischemia/reperfusion (I/R) injury is exacerbated in diabetic individuals and animal models. We tested whether autophagy is an important cellular determinant of cell death. First, we utilized a cellular model of hypoxia reoxygenation (H/R) in H9c2 cells cultured in low or high glucose (HG) and tested cell death using flow cytometry to detect Annexin-V and propidium iodide, imaging cell viability ReadyProbe and lactate dehydrogenase release. We observed that cell death induced by H/R was enhanced by HG. Kinetic analysis of caspase-3 activity using a fluorescence reporter probe, stable expression of the VC3AI biosensor and western blotting indicated that H/R induced activation of caspase-3 was enhanced by HG. Temporal autophagy flux analysis using DapRed and DalGreen probes indicated an initial increase in response to H/R that was reduced upon prolonged (24h) R. HG suppressed this induction of autophagy. This was verified using LC3 HiBiT reporter assay, tandem-fluorescent LC3, and western blotting. Lysosomal cathepsin activity was also elevated at 6h and suppressed at 24h R. Autophagy-deficient cells were generated via CRISPR-mediated knockout of atg7 and the effect of combined HG and H/R treatment on caspase activation and cell death was elevated in comparison with wild type cells. We then performed coronary artery ligation surgery to induce ischemia, followed by reperfusion, in wild-type or streptozotocin (STZ)-induced hyperglycemic mice. Non-invasive 3-dimensional imaging using fluorescence molecular tomography combined with computerized tomography was employed to monitor spatio-temporal activation of cardiac autophagy and apoptosis. Upon systemic injection of a near infra-red cathepsin activatable probe we found that hyperglycemic mice had lower activity in the infarct region after I/R versus wild type. In parallel, we observed a higher extent of I/R-induced apoptosis, detected with an annexin-V probe, in hyperglycemic mice. Collectively, these results revealed that impaired autophagic flux in the presence of high glucose levels exacerbates I/R injury.Abbreviation: satg7, autophagy-related 7; FMT, fluorescence molecular tomography; HG, high glucose; H/R, hypoxia/reoxygenation; I/R, ischemia/reperfusion; LC3, MAP1LC3; N, normoxia; NG, normal glucose; NIR, near-infrared; p62, SQSTM1; STZ, streptozotocin.
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- 2024
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17. Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases.
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Sampognaro, Paul J, Arya, Shruti, Knudsen, Giselle M, Gunderson, Emma L, Sandoval-Perez, Angelica, Hodul, Molly, Bowles, Kathryn, Craik, Charles S, Jacobson, Matthew P, and Kao, Aimee W
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Lysosomes ,Humans ,Neurodegenerative Diseases ,Peptide Hydrolases ,tau Proteins ,DNA-Binding Proteins ,Mutation ,Half-Life ,alpha-Synuclein ,Autophagy ,Cathepsin ,Lysosome ,Mutations ,Neurodegeneration ,Protease ,TDP-43 ,Tau ,α-synuclein ,Aging ,Acquired Cognitive Impairment ,Dementia ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Brain Disorders ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,alpha-synuclein ,Genetics ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
BackgroundAutosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins.ResultsTo test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates.ConclusionsTogether, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.
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- 2023
18. Associations between multiple neurological biomarkers and distal sensorimotor polyneuropathy: KORA F4/FF4 study.
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Herder, Christian, Thorand, Barbara, Strom, Alexander, Rathmann, Wolfgang, Heier, Margit, Koenig, Wolfgang, Morrison, Helen, Ziegler, Dan, Roden, Michael, Peters, Annette, Bönhof, Gidon J., and Maalmi, Haifa
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PLATELET-derived growth factor receptors ,POLYNEUROPATHIES ,BIOMARKERS ,TYPE 2 diabetes ,PEOPLE with diabetes - Abstract
Aims: The aim of this study was to assess associations between neurological biomarkers and distal sensorimotor polyneuropathy (DSPN). Materials and Methods: Cross‐sectional analyses were based on 1032 participants aged 61–82 years from the population‐based KORA F4 survey, 177 of whom had DSPN at baseline. The prevalence of type 2 diabetes was 20%. Prospective analyses used data from 505 participants without DSPN at baseline, of whom 125 had developed DSPN until the KORA FF4 survey. DSPN was defined based on the examination part of the Michigan Neuropathy Screening Instrument. Serum levels of neurological biomarkers were measured using proximity extension assay technology. Associations between 88 biomarkers and prevalent or incident DSPN were estimated using Poisson regression with robust error variance and are expressed as risk ratios (RR) and 95% CI per 1‐SD increase. Results were adjusted for multiple confounders and multiple testing using the Benjamini–Hochberg procedure. Results: Higher serum levels of CTSC (cathepsin C; RR [95% CI] 1.23 (1.08; 1.39), pB‐H = 0.044) and PDGFRα (platelet‐derived growth factor receptor A; RR [95% CI] 1.21 (1.08; 1.35), pB‐H = 0.044) were associated with prevalent DSPN in the total study sample. CDH3, JAM‐B, LAYN, RGMA and SCARA5 were positively associated with DSPN in the diabetes subgroup, whereas GCP5 was positively associated with DSPN in people without diabetes (all pB‐H for interaction <0.05). None of the biomarkers showed an association with incident DSPN (all pB‐H>0.05). Conclusions: This study identified multiple novel associations between neurological biomarkers and prevalent DSPN, which may be attributable to functions of these proteins in neuroinflammation, neural development and myelination. [ABSTRACT FROM AUTHOR]
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- 2024
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19. ZYMOGRAPHY OF PROTEASES IN HONEY BEES (APIS MELLIFERA) INFECTED WITH NOSEMA CERANAE.
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DOGHUZLU, Mohammad Afrasiabi, NABIAN, Sedigheh, Nehzati PAGHALEH, Gholam Ali, TAHERI, Mohammad, ASADOLLAHI, Zahra, and AKHZARI, Soheila
- Subjects
PROTEOLYTIC enzymes ,HONEYBEE diseases ,NOSEMA ceranae ,SERINE proteinases ,IMMUNE system - Abstract
Copyright of Veterinarski Glasnik is the property of Veterinarski Glasnik and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2024
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20. Cathepsin-mediated regulation of alpha-synuclein in Parkinson's disease: a Mendelian randomization study.
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Liyu Lin, Zilun Wu, Haocheng Luo, and Yunxuan Huang
- Subjects
RNA metabolism ,RISK assessment ,MOLECULAR epidemiology ,SYNUCLEINS ,REPLICATION (Experimental design) ,PARKINSON'S disease ,MULTIVARIATE analysis ,META-analysis ,ODDS ratio ,PROTEOLYTIC enzymes ,CONFIDENCE intervals ,SENSITIVITY & specificity (Statistics) ,SEQUENCE analysis ,DISEASE risk factors - Abstract
Objective: The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this study, our objective is to investigate the causal link between cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction. Methods: Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data. Result: Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834-0.966, p = 0.004), while more cathepsin H (CTSH) (OR = 1.076, 95%CI: 1.007-1.149, p = 0.029) and more cathepsin S (CTSS) (OR = 1.076, 95%CI: 1.007-1.150, p = 0.030) associated with increasing PD risk. Meta-analyses validated these associations. Multivariate MR Results were consistent with those before adjustment. No significant results were observed in bidirectional MR analysis. In the investigation of the underlying mechanism, our findings demonstrate that CTSB significantly reduces the levels of alpha-synuclein (OR = 0.909, 95%CI: 0.841-0.983, p = 0.017). Concurrently, a genetically determined positive correlation between alpha-synuclein and PD is illuminated by both eQTL MR and colocalization analysis. Conclusion: In conclusion, this MR study yields robust evidence suggesting an association between elevated levels of CTSB and reduced PD risk, mediated by the downregulation of alpha-synuclein levels. Conversely, higher levels of CTSH and CTSS are associated with an increased risk of PD. These findings offer novel insights into the pathophysiological mechanisms of PD and identify potential drug targets for disease prevention and treatment warranting further clinical investigations. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels.
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Chen, Hengshu, Wang, Si, Zhang, Xiaoling, Hua, Xing, Liu, Meng, Wang, Yanan, Wu, Simiao, and He, Weihong
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Myocardial infarction (MI) results in prolonged ischemia and the subsequent cell death leads to heart failure which is linked to increased deaths or hospitalizations. New therapeutic targets are urgently needed to prevent cell death and reduce infarct size among patients with MI. Runt-related transcription factor-1 (RUNX1) is a master-regulator transcription factor intensively studied in the hematopoietic field. Recent evidence showed that RUNX1 has a critical role in cardiomyocytes post-MI. The increased RUNX1 expression in the border zone of the infarct heart contributes to decreased cardiac contractile function and can be therapeutically targeted to protect against adverse cardiac remodelling. This study sought to investigate whether pharmacological inhibition of RUNX1 function has an impact on infarct size following MI. In this work we demonstrate that inhibiting RUNX1 with a small molecule inhibitor (Ro5-3335) reduces infarct size in an in vivo rat model of acute MI. Proteomics study using data-independent acquisition method identified increased cathepsin levels in the border zone myocardium following MI, whereas heart samples treated by RUNX1 inhibitor present decreased cathepsin levels. Cathepsins are lysosomal proteases which have been shown to orchestrate multiple cell death pathways. Our data illustrate that inhibition of RUNX1 leads to reduced infarct size which is associated with the suppression of cathepsin expression. This study demonstrates that pharmacologically antagonizing RUNX1 reduces infarct size in a rat model of acute MI and unveils a link between RUNX1 and cathepsin-mediated cell death, suggesting that RUNX1 is a novel therapeutic target that could be exploited clinically to limit infarct size after an acute MI. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis
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Paloma Ruiz-Blázquez, María Fernández-Fernández, Valeria Pistorio, Celia Martinez-Sanchez, Michele Costanzo, Paula Iruzubieta, Ekaterina Zhuravleva, Júlia Cacho-Pujol, Silvia Ariño, Alejandro Del Castillo-Cruz, Susana Núñez, Jesper B. Andersen, Margherita Ruoppolo, Javier Crespo, Carmen García-Ruiz, Luigi Michele Pavone, Thomas Reinheckel, Pau Sancho-Bru, Mar Coll, José C. Fernández-Checa, and Anna Moles
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Fibrosis ,Protease ,Cathepsin ,Resolution ,Macrophage ,Internal medicine ,RC31-1245 - Abstract
Background and objectives: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. Methods: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. Results: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. Conclusions: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.
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- 2024
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23. Association of LVV-Hemorphin-7 with Sepsis and Shock: Roles of Cathepsin D and G in Hemoglobin Metabolism in a Prospective ICU Cohort Study
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Yao-Kuang Wu, Hsueh-Wen Chung, Yi-Ting Chen, Hsing-Chun Chen, I-Hung Chen, and Wen-Lin Su
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sepsis ,shock ,cathepsin ,LVV-hemorphin-7 ,sequential organ failure assessment score ,Biology (General) ,QH301-705.5 - Abstract
Background: Sepsis is a leading cause of mortality in intensive care units (ICUs). Cell-free hemoglobin (CFH) released during sepsis interacts with lysosomal enzymes from neutrophils and macrophages. This study aims to examine the association of LVV-hemorphin-7 (LVV-H7), cathepsin D, and cathepsin G with sepsis and shock in ICU patients. Methods: A prospective observational cohort study was conducted in the medical ICU of a tertiary referral hospital in Taiwan. The patients with an acute increasing sequential organ failure assessment (SOFA) score ≥ 2 between 2022 and 2023. Blood samples from 40 healthy controls were obtained from the hospital biobank. CFH metabolites, including LVV-H7 and lysosomal enzyme cathepsin D and cathepsin G, were compared between the sepsis (definite and probable) and non-sepsis (possible sepsis) groups. Multivariate logistic regression analyzed factors associated with sepsis and shock. Results: Among 120 patients, 75 were classified as septic and 45 as non-septic. Significant differences were observed in CFH, cathepsin D, cathepsin G, and LVV-H7 levels between sepsis and non-sepsis groups. LVV-H7 was a significant predictor for sepsis (adjusted OR [aOR] 1.009, 95% CI 1.005–1.013; p < 0.001) and shock (aOR 1.005, 95% CI 1.002–1.008; p < 0.05). Cathepsin G predicted non-shock (aOR 0.917, 95% CI 0.848–0.991; p < 0.05), while cathepsin D predicted septic shock (aOR 1.001, 95% CI 1.000–1.002; p < 0.05). Conclusions: LVV-H7, cathepsin D, and cathepsin G are associated with the classification of sepsis and shock episodes in critically ill patients with elevated SOFA scores.
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- 2024
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24. Differential effects of cholecalciferol and calcitriol on muscle proteolysis and oxidative stress in angiotensin II‐induced C2C12 myotube atrophy.
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Hirunsai, Muthita and Srikuea, Ratchakrit
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- *
CALCITRIOL , *VITAMIN D receptors , *OXIDATIVE stress , *CHOLECALCIFEROL , *MUSCULAR atrophy - Abstract
Renin–angiotensin system activation contributes to skeletal muscle atrophy in aging individuals with chronic diseases. We aimed to explore the effects of cholecalciferol (VD3) and calcitriol (1,25VD3) on signaling of muscle proteolysis and oxidative stress in myotubes challenged with angiotensin II (AII). The mouse C2C12 myotubes were assigned to vehicle, AII, AII + VD3, AII + 1,25VD3, and AII + losartan groups. The expression levels of muscle‐specific E3 ubiquitin ligase proteins, autophagy‐related proteins, and oxidative stress markers were investigated. We demonstrated the diverse effects of VD3 and 1,25VD3 on AII‐induced myotube atrophy. The myotube diameter was preserved by treatment with 100 nM VD3 and losartan, while 1 and 10 nM 1,25VD3 increased levels of FoxO3a, MuRF1, and atrogin‐1 protein expression in myotubes exposed to AII. Treatment with AII + 10 nM 1,25VD3 resulted in the upregulation of LC3B‐II, LC3B‐II/LC3B‐I, and mature cathepsin L, which are autophagic marker proteins. The p62/SQSTM1 protein was downregulated and vitamin D receptor was upregulated after treatment with AII + 10 nM 1,25VD3. A cellular redox imbalance was observed as AII + 10 nM 1,25VD3‐induced reactive oxygen species and NADPH oxidase‐2 overproduction, and these changes were associated with an inadequate response of antioxidant superoxide dismutase‐1 and catalase proteins. Collectively, these findings provide a translational perspective on the role of vitamin D3 in alleviating muscle atrophy related to high levels of AII. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Selective Intracellular Delivery of Antibodies in Cancer Cells with Nanocarriers Sensing Endo/Lysosomal Enzymatic Activity.
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Chen, Pengwen, Yang, Wenqian, Mochida, Yuki, Li, Shangwei, Hong, Taehun, Kinoh, Hiroaki, Kataoka, Kazunori, and Cabral, Horacio
- Abstract
The differential enzymatic activity in the endo/lysosomes of particular cells could trigger targeted endosomal escape functions, enabling selective intracellular protein delivery. However, this strategy may be jeopardized due to protein degradation during endosomal trafficking. Herein, using custom made fluorescent probes to assess the endosomal activity of cathepsin B (CTSB) and protein degradation, we found that certain cancer cells with hyperacidified endosomes grant a spatiotemporal window where CTSB activity surpass protein digestion. This inspired the engineering of antibody‐loaded polymeric nanocarriers having CTSB‐activatable endosomal escape ability. The nanocarriers selectively escaped from the endo/lysosomes in the cells with high endosomal CTSB activity and delivered active antibodies to intracellular targets. This study provides a viable strategy for cell‐specific protein delivery using stimuli‐responsive nanocarriers with controlled endosomal escape. [ABSTRACT FROM AUTHOR]
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- 2024
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26. An Unusual Two-Domain Thyropin from Tick Saliva: NMR Solution Structure and Highly Selective Inhibition of Cysteine Cathepsins Modulated by Glycosaminoglycans.
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Matoušková, Zuzana, Orsághová, Katarína, Srb, Pavel, Pytelková, Jana, Kukačka, Zdeněk, Buša, Michal, Hajdušek, Ondřej, Šíma, Radek, Fábry, Milan, Novák, Petr, Horn, Martin, Kopáček, Petr, and Mareš, Michael
- Subjects
- *
CATHEPSINS , *GLYCOSAMINOGLYCANS , *PROTEOLYSIS , *LYME disease , *TICK-borne encephalitis , *CASTOR bean tick - Abstract
The structure and biochemical properties of protease inhibitors from the thyropin family are poorly understood in parasites and pathogens. Here, we introduce a novel family member, Ir-thyropin (IrThy), which is secreted in the saliva of Ixodes ricinus ticks, vectors of Lyme borreliosis and tick-borne encephalitis. The IrThy molecule consists of two consecutive thyroglobulin type-1 (Tg1) domains with an unusual disulfide pattern. Recombinant IrThy was found to inhibit human host-derived cathepsin proteases with a high specificity for cathepsins V, K, and L among a wide range of screened cathepsins exhibiting diverse endo- and exopeptidase activities. Both Tg1 domains displayed inhibitory activities, but with distinct specificity profiles. We determined the spatial structure of one of the Tg1 domains by solution NMR spectroscopy and described its reactive center to elucidate the unique inhibitory specificity. Furthermore, we found that the inhibitory potency of IrThy was modulated in a complex manner by various glycosaminoglycans from host tissues. IrThy was additionally regulated by pH and proteolytic degradation. This study provides a comprehensive structure–function characterization of IrThy—the first investigated thyropin of parasite origin—and suggests its potential role in host–parasite interactions at the tick bite site. [ABSTRACT FROM AUTHOR]
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- 2024
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27. The host mannose-6-phosphate pathway and viral infection.
- Author
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Qincheng Liu, Weiqi Wang, Liwei Xu, Qisheng Zhang, and Hongna Wang
- Abstract
Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Differential effects of cholecalciferol and calcitriol on muscle proteolysis and oxidative stress in angiotensin II‐induced C2C12 myotube atrophy
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Muthita Hirunsai and Ratchakrit Srikuea
- Subjects
autophagy ,cathepsin ,muscle atrophy ,p62/SQSTM1 ,reactive oxygen species ,vitamin D ,Physiology ,QP1-981 - Abstract
Abstract Renin–angiotensin system activation contributes to skeletal muscle atrophy in aging individuals with chronic diseases. We aimed to explore the effects of cholecalciferol (VD3) and calcitriol (1,25VD3) on signaling of muscle proteolysis and oxidative stress in myotubes challenged with angiotensin II (AII). The mouse C2C12 myotubes were assigned to vehicle, AII, AII + VD3, AII + 1,25VD3, and AII + losartan groups. The expression levels of muscle‐specific E3 ubiquitin ligase proteins, autophagy‐related proteins, and oxidative stress markers were investigated. We demonstrated the diverse effects of VD3 and 1,25VD3 on AII‐induced myotube atrophy. The myotube diameter was preserved by treatment with 100 nM VD3 and losartan, while 1 and 10 nM 1,25VD3 increased levels of FoxO3a, MuRF1, and atrogin‐1 protein expression in myotubes exposed to AII. Treatment with AII + 10 nM 1,25VD3 resulted in the upregulation of LC3B‐II, LC3B‐II/LC3B‐I, and mature cathepsin L, which are autophagic marker proteins. The p62/SQSTM1 protein was downregulated and vitamin D receptor was upregulated after treatment with AII + 10 nM 1,25VD3. A cellular redox imbalance was observed as AII + 10 nM 1,25VD3‐induced reactive oxygen species and NADPH oxidase‐2 overproduction, and these changes were associated with an inadequate response of antioxidant superoxide dismutase‐1 and catalase proteins. Collectively, these findings provide a translational perspective on the role of vitamin D3 in alleviating muscle atrophy related to high levels of AII.
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- 2024
- Full Text
- View/download PDF
29. Development of a Novel Biomarker for the Progression of Idiopathic Pulmonary Fibrosis.
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Yeo, Hye Ju, Ha, Mihyang, Shin, Dong Hoon, Lee, Hye Rin, Kim, Yun Hak, and Cho, Woo Hyun
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- *
IDIOPATHIC pulmonary fibrosis , *ENZYME-linked immunosorbent assay , *GENE expression , *WESTERN immunoblotting - Abstract
The progression of idiopathic pulmonary fibrosis (IPF) is diverse and unpredictable. We identified and validated a new biomarker for IPF progression. To identify a candidate gene to predict progression, we assessed differentially expressed genes in patients with advanced IPF compared with early IPF and controls in three lung sample cohorts. Candidate gene expression was confirmed using immunohistochemistry and Western blotting of lung tissue samples from an independent IPF clinical cohort. Biomarker potential was assessed using an enzyme-linked immunosorbent assay of serum samples from the retrospective validation cohort. We verified that the final candidate gene reflected the progression of IPF in a prospective validation cohort. In the RNA-seq comparative analysis of lung tissues, CD276, COL7A1, CTSB, GLI2, PIK3R2, PRAF2, IGF2BP3, and NUPR1 were up-regulated, and ADAMTS8 was down-regulated in the samples of advanced IPF. Only CTSB showed significant differences in expression based on Western blotting (n = 12; p < 0.001) and immunohistochemistry between the three groups of the independent IPF cohort. In the retrospective validation cohort (n = 78), serum CTSB levels were higher in the progressive group (n = 25) than in the control (n = 29, mean 7.37 ng/mL vs. 2.70 ng/mL, p < 0.001) and nonprogressive groups (n = 24, mean 7.37 ng/mL vs. 2.56 ng/mL, p < 0.001). In the prospective validation cohort (n = 129), serum CTSB levels were higher in the progressive group than in the nonprogressive group (mean 8.30 ng/mL vs. 3.00 ng/mL, p < 0.001). After adjusting for baseline FVC, we found that CTSB was independently associated with IPF progression (adjusted OR = 2.61, p < 0.001). Serum CTSB levels significantly predicted IPF progression (AUC = 0.944, p < 0.001). Serum CTSB level significantly distinguished the progression of IPF from the non-progression of IPF or healthy control. [ABSTRACT FROM AUTHOR]
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- 2024
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30. Correlation of Plasma and Salivary Osteocalcin Levels with Nascent Metabolic Syndrome Components with and Without Pre/Diabetes Biochemical Parameters.
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Bulatova, Nailya R., Kasabri, Violet N., Albsoul, Abla M., Halaseh, Lana, and Suyagh, Maysa
- Subjects
SALIVA analysis ,OSTEOCALCIN ,CROSS-sectional method ,RESEARCH funding ,DESCRIPTIVE statistics ,FIBROBLAST growth factors ,BLOOD plasma ,METABOLIC syndrome ,DATA analysis software ,BIOMARKERS - Abstract
Objectives: This study aimed to compare and correlate plasma and salivary levels of cardiometabolic risk biomarkers' of pharmacotherapy (appraised using colorimetric assays), adiposity, and atherogenicity indices. Methods: 61 Nascent MetS subjects vs. 30 lean normoglycemic and healthy controls were recruited in Family Medicine outpatient clinics/Jordan University Hospital (a referral medical center). Fasting blood and saliva specimens were collected. Clinical and anthropometric variables were determined along with atherogenecity and adiposity indices. Results: Among nascent MetS (metabolic syndrome) recruits, almost half were normoglycemic, 43% were prediabetic and 8% were diabetic. Pronouncedly Glycemic (FPG and Alc) and lipid parameters (TG, HDL-C and non-HDL-C), adiposity indices (BMI, WHR, WtHR, Conicity-index, BAI, LAP, VAI) and atherogenicity indices (AIP, TC/HDL-C, LDL-C/HDL-C, non-HDL-C/HDL-C and TG/HDL-C) were higher in the nascent MetS group (P<0.05 vs. controls). Markedly among the plasma cardiometabolic risk biomarkers (P<0.05 vs. controls) in the nascent MetS group, adipolin, cathepsin S, ghrelin, irisin, LBP, leptin, and osteocalcin were higher but plasma FGF1 levels were oddly lower. Significantly (P<0.05 vs. controls) nascent MetS -linked salivary levels of adipolin and LBP were higher as opposed to the lower cathepsin S. Only osteocalcin, amongst 9 metabolic risk biomarkers studied, had remarkably significant correlation between plasma and saliva levels, in both total sample and MetS patients (P<0.05). Markedly in the nascent MetS only group, both plasma and salivary osteocalcin correlated with FPG and A1c (P<0.05); salivary osteocalcin correlated with BMI and LAP (P<0.05). Likewise, in the total sample plasma osteocalcin correlated significantly with BMI, BAI, WHt R, SBP, DBP, TG, LAP, VAI, TG/HDL-C and AIP (P<0.05), while salivary osteocalcin had substantial correlations only with FPG and A1c (P<0.05). Conclusion: Association of nascent MetS-related plasma and salivary osteocalcin levels and clinical characteristics and indices propagate salivary osteocalcin as a non-invasive marker for clinical control of MetS-/preDM. [ABSTRACT FROM AUTHOR]
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- 2024
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31. Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy.
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Smyth, P., Ferguson, L., Burrows, J. F., Burden, R. E., Tracey, S. R., Herron, Ú. M., Kovaleva, M., Williams, R., Porter, A. J., Longley, D. B., Barelle, C. J., and Scott, C. J.
- Subjects
ANTIGEN receptors ,MOLECULAR cloning ,CELL migration - Abstract
Aberrant activity of the cysteine protease Cathepsin S (CTSS) has been implicated across a wide range of pathologies. Notably in cancer, CTSS has been shown to promote tumour progression, primarily through facilitating invasion and migration of tumour cells and augmenting angiogenesis. Whilst an attractive therapeutic target, more efficacious CTSS inhibitors are required. Here, we investigated the potential application of Variable New Antigen Receptors (vNARs) as a novel inhibitory strategy. A panel of potential vNAR binders were identified following a phage display panning process against human recombinant proCTSS. These were subsequently expressed, purified and binding affinity confirmed by ELISA and SPR based approaches. Selected lead clones were taken forward and were shown to inhibit CTSS activity in recombinant enzyme activity assays. Further assessment demonstrated that our lead clones functioned by a novel inhibitory mechanism, by preventing the activation of proCTSS to the mature enzyme. Moreover, using an intrabody approach, we exhibited the ability to express these clones intracellularly and inhibit CTSS activity whilst lead clones were also noted to impede cell invasion in a tumour cell invasion assay. Collectively, these findings illustrate a novel mechanistic approach for inhibiting CTSS activity, with anti-CTSS vNAR clones possessing therapeutic potential in combating deleterious CTSS activity. Furthermore, this study exemplifies the potential of vNARs in targeting intracellular proteins, opening a range of previously “undruggable” targets for biologic-based therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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32. Effects of proteases on textural softening and changes in physical property of harpiosquillid mantis shrimp (Harpiosquilla raphidea) during the iced storage.
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Chanchi Prashanthkumar, Mallikarjun, Temdee, Wattana, Suyapoh, Watcharapol, Sornying, Peerapon, Palamae, Suriya, Patil, Umesh, Ma, Lukai, and Benjakul, Soottawat
- Subjects
- *
STOMATOPODA , *PROTEOLYTIC enzymes , *CATHEPSIN B , *SERINE proteinases , *MUSCLE proteins - Abstract
Summary: Rapid softening of texture is a major problem associated with quality loss and consumer rejection of harpiosquillid mantis shrimp (Harpiosquilla raphidea) (HMS). Effects of endogenous proteases in muscles and digestive tract on protein degradation and softening were investigated. Scanning electron microscopic and histological images indicated drastic destruction of muscle during iced storage. Based on autolysis, maximal activity was found at pH 8.5 and 55 °C, and serine proteases including trypsin were dominant. Cathepsin B and L + B in muscle were altered throughout storage, while trypsin remained constant in HMS meat for 1–3 days. Firmness and toughness decreased and coincided with augmented degradation of myofibrillar proteins and collagen. Trypsin from the digestive tract was contaminated into the abdomen during iced storage, therefore inducing drastic hydrolysis of muscle proteins. This phenomenon caused the undesirable pasty/mushy texture associated with the loss in firmness and toughness of meat within 3 days of storage. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
33. Type 2 Cystatins and Their Roles in the Regulation of Human Immune Response and Cancer Progression.
- Author
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Zhang, Zijun and Zhan, Fenghuang
- Subjects
- *
DISEASE progression , *BIOMARKERS , *CELL differentiation , *CYSTATINS , *PROTEASE inhibitors , *SECRETED frizzled-related proteins , *CANCER invasiveness , *INFLAMMATION , *IMMUNE system , *AUTOIMMUNE diseases , *METASTASIS - Abstract
Simple Summary: Type 2 cystatins are a group of small secreted protease inhibitors that regulate cysteine protease cathepsins and legumain. These enzymes regulate important cellular processes that are linked to the immune response and tumor progression, playing important roles in both autoimmune diseases and various types of cancers. This review aims to explore the roles of type 2 cystatins in immune regulation and cancer development, shedding light on their significance in maintaining health. Cystatins are a family of intracellular and extracellular protease inhibitors that inhibit cysteine cathepsins—a group of lysosomal cysteine proteases that participate in multiple biological processes, including protein degradation and post-translational cleavage. Cysteine cathepsins are associated with the development of autoimmune diseases, tumor progression, and metastasis. Cystatins are categorized into three subfamilies: type 1, type 2, and type 3. The type 2 cystatin subfamily is the largest, containing 10 members, and consists entirely of small secreted proteins. Although type 2 cystatins have many shared biological roles, each member differs in structure, post-translational modifications (e.g., glycosylation), and expression in different cell types. These distinctions allow the type 2 cystatins to have unique biological functions and properties. This review provides an overview of type 2 cystatins, including their biological similarities and differences, their regulatory effect on human immune responses, and their roles in tumor progression, immune evasion, and metastasis. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
- View/download PDF
34. Lysosomal-Cleavable Peptide Linkers in Antibody–Drug Conjugates.
- Author
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Balamkundu, Seetharamsing and Liu, Chuan-Fa
- Subjects
ANTIBODY-drug conjugates ,PEPTIDES ,LEUCOCYTE elastase ,AMINO acid sequence ,PLASMA stability - Abstract
Antibody–drug Conjugates (ADCs) are a powerful therapeutic modality for cancer treatment. ADCs are multi-functional biologics in which a disease-targeting antibody is conjugated to an effector payload molecule via a linker. The success of currently used ADCs has been largely attributed to the development of linker systems, which allow for the targeted release of cytocidal payload drugs inside cancer cells. Many lysosomal proteases are over expressed in human cancers. They can effectively cleave a variety of peptide sequences, which can be exploited for the design of ADC linker systems. As a well-established linker, valine-citrulline-p-aminobenzyl carbamate (ValCitPABC) is used in many ADCs that are already approved or under preclinical and clinical development. Although ValCitPABC and related linkers are readily cleaved by cathepsins in the lysosome while remaining reasonably stable in human plasma, many studies have shown that they are susceptible to carboxylesterase 1C (Ces1C) in mouse and rat plasma, which hinders the preclinical evaluation of ADCs. Furthermore, neutropenia and thrombocytopenia, two of the most commonly observed dose-limiting adverse effects of ADCs, are believed to result from the premature hydrolysis of ValCitPABC by human neutrophil elastase. In addition to ValCitPABC, the GGFG tetrapeptidyl-aminomethoxy linker is also cathepsin-cleavable and is used in the highly successful ADC drug, DS8201a. In addition to cathepsin-cleavable linkers, there is also growing interest in legumain-sensitive linkers for ADC development. Increasing plasma stability while maintaining lysosomal cleavability of ADC linkers is an objective of intensive current research. This review reports recent advances in the design and structure–activity relationship studies of various peptide/peptidomimetic linkers in this field. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
- View/download PDF
35. Fibrogenic and fibrolytic potential of differently activated human macrophages
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A. A. Maksimova, L. V. Sakhno, and A. A. Ostanin
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macrophages ,matrix metalloproteinase ,collagen ,cathepsin ,fibrosis ,anti-fibrotic activity ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Macrophages are involved in the regulation of fibrogenesis and turnover of the extracellular matrix. One way to perform this function is through the production of profibrotic and fibrolytic factors including fibronectin, laminin, collagen, and extracellular matrix proteases. The production of most of them has been well studied in experimental models; however, much remains unclear regarding human macrophages. Therefore, the aim of this study was to study the content of extracellular matrix proteases (MMP-2 and MMP-9, cathepsin L), their inhibitors (TIMP-1), and collagen (type I) in supernatants of differently activated human macrophages. We compared macrophages differentiated by M-CSF or GM-CSF and further polarized in M1 with lipopolysaccharide, in M2a with IL-4, and in M2c with dexamethasone. Macrophages was obtained from peripheral blood monocytes. The content of MMPs, TIMP, cathepsin, and collagen was determined using appropriate ELISA kits. The results obtained demonstrate that differentiation factors are more important for the production of the above factors compared to polarizing stimuli (lipopolysaccharide, IL-4, dexamethasone). Moreover, macrophages differentiated by M-CSF showed predominantly antifibrotic activity because of pronounced MMPs production, while GM-CSF-induced cultures, on the contrary, were characterized by profibrotic properties due to the high level of TIMP-1 and type I collagen. M1, M2a, and M2c, induced by M-CSF, differed only in MMP-2 production, and M2a produced this metalloproteinase more than other subtypes. In the case of GM-CSF-differentiated cells, a higher level of production of TIMP-1 and, to a lesser extent, type I collagen was characteristic of M1, whereas M2c have minimal concentration of them among GM-CSF-induced macrophage subtypes. Concerning the level of cathepsin L production was relatively constant and did not depend on the generation conditions (differentiation and polarizing signals). Thus, the data obtained help to identify macrophage subtypes with anti- or profibrotic potential and may be useful for the development of cell therapy for diseases associated with fibrogenesis dysregulation.
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- 2023
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36. Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases
- Author
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Paul J. Sampognaro, Shruti Arya, Giselle M. Knudsen, Emma L. Gunderson, Angelica Sandoval-Perez, Molly Hodul, Kathryn Bowles, Charles S. Craik, Matthew P. Jacobson, and Aimee W. Kao
- Subjects
Cathepsin ,Protease ,α-synuclein ,TDP-43 ,Tau ,Lysosome ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Autosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins. Results To test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates. Conclusions Together, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.
- Published
- 2023
- Full Text
- View/download PDF
37. Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy
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P. Smyth, L. Ferguson, J. F. Burrows, R. E. Burden, S. R. Tracey, Ú. M. Herron, M. Kovaleva, R. Williams, A. J. Porter, D. B. Longley, C. J. Barelle, and C. J. Scott
- Subjects
therapeutic ,cancer ,inhibitor ,vNAR ,cathepsin ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Aberrant activity of the cysteine protease Cathepsin S (CTSS) has been implicated across a wide range of pathologies. Notably in cancer, CTSS has been shown to promote tumour progression, primarily through facilitating invasion and migration of tumour cells and augmenting angiogenesis. Whilst an attractive therapeutic target, more efficacious CTSS inhibitors are required. Here, we investigated the potential application of Variable New Antigen Receptors (vNARs) as a novel inhibitory strategy. A panel of potential vNAR binders were identified following a phage display panning process against human recombinant proCTSS. These were subsequently expressed, purified and binding affinity confirmed by ELISA and SPR based approaches. Selected lead clones were taken forward and were shown to inhibit CTSS activity in recombinant enzyme activity assays. Further assessment demonstrated that our lead clones functioned by a novel inhibitory mechanism, by preventing the activation of proCTSS to the mature enzyme. Moreover, using an intrabody approach, we exhibited the ability to express these clones intracellularly and inhibit CTSS activity whilst lead clones were also noted to impede cell invasion in a tumour cell invasion assay. Collectively, these findings illustrate a novel mechanistic approach for inhibiting CTSS activity, with anti-CTSS vNAR clones possessing therapeutic potential in combating deleterious CTSS activity. Furthermore, this study exemplifies the potential of vNARs in targeting intracellular proteins, opening a range of previously “undruggable” targets for biologic-based therapy.
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- 2023
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38. The effect of amorphous calcium carbonate as a culture media supplement on embryonic development of murine sibling embryos.
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Arav, Amir, Natan, Yehudit, Hejja, Tamila, Blum, Yigal D, Poliansky, Ylena, and Patrizio, Pasquale
- Subjects
- *
EMBRYOLOGY , *CALCIUM carbonate , *CELL culture , *EMBRYOS , *EMBRYO implantation , *CATHEPSIN B - Abstract
Purpose: The aim of this study was to compare the addition in culture media of stabilized amorphous calcium carbonate (ACC) versus calcium chloride (CaCl2) or calcium carbonate in crystalline form (CCC) on growth rates among sibling mouse embryos. Methods: We evaluated the effect of different ACC concentrations on the rates of embryo compaction at 60 h, blastocyst rate at 84 h and percentage of fully hatched at 108 h following hCG injection. As ACC is stabilized by tripolyphosphate (TPP), we also evaluated the addition of TPP alone to the culture media. Finally, we compared supplemented ACC culture media to one-step SAGE and Irvine cleavage media. Results: The results revealed that ACC accelerates the compaction and blastocyst rates, as well as the percentage of fully hatched embryos in a dose-dependent manner, with an increased positive effect at 2.5 mM. The magnitude of the effect for ACC-supplemented media on the embryo developmental rate was between 30 to 40% (p < 0.01) faster for each stage, compared to both SAGE and Irvine one-step standard media. Embryos cultured with SAGE or Irvine media with or without supplementation of CaCl2 or CCC, did not produce the same improvements as observed with ACC. Conclusion: In conclusion, the ACC demonstrates a rapid modulation effect for restoring media optimal pH. ACC can inhibit cathepsin B activity during in vitro culture of fibroblast cells. The beneficial impact of ACC on cleavage mouse embryos is likely due to an improved buffering effect causing slower pH media variations, which may enhance quality and implantation potential of embryos following in vitro culture. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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39. Cathepsins and SARS‐CoV‐2 infection: From pathogenic factors to potential therapeutic targets.
- Author
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Zhao, Shuxuan, Jiang, Muzhou, Qing, Hong, and Ni, Junjun
- Subjects
- *
COVID-19 , *CATHEPSINS , *SARS-CoV-2 , *DRUG target , *COVID-19 treatment - Abstract
Coronavirus disease‐19 (COVID‐19) is caused by severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) infection. The COVID‐19 pandemic began in March 2020 and has wrought havoc on health and economic systems worldwide. Efficacious treatment for COVID‐19 is lacking: Only preventive measures as well as symptomatic and supportive care are available. Preclinical and clinical studies have indicated that lysosomal cathepsins might contribute to the pathogenesis and disease outcome of COVID‐19. Here, we discuss cutting‐edge evidence on the pathological roles of cathepsins in SARS‐CoV‐2 infection, host immune dysregulations, and the possible underlying mechanisms. Cathepsins are attractive drug targets because of their defined substrate‐binding pockets, which can be exploited as binding sites for pharmaceutical enzyme inhibitors. Accordingly, the potential modulatory strategies of cathepsin activity are discussed. These insights could shed light on the development of cathepsin‐based interventions for COVID‐19. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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40. Augmentation of Cathepsin Isoforms in Diabetic db/db Mouse Kidneys Is Associated with an Increase in Renal MARCKS Expression and Proteolysis.
- Author
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Gholam, Mohammed F., Bala, Niharika, Dogan, Yunus E., and Alli, Abdel A.
- Subjects
- *
SODIUM channels , *PROTEOLYSIS , *PROTEIN kinase C , *REGULATION of blood pressure , *CATHEPSIN B , *KIDNEYS - Abstract
The expression of the myristoylated alanine-rich C-kinase substrate (MARCKS) family of proteins in the kidneys plays an important role in the regulation of the renal epithelial sodium channel (ENaC) and hence overall blood pressure regulation. The function of MARCKS is regulated by post-translational modifications including myristoylation, phosphorylation, and proteolysis. Proteases known to cleave both ENaC and MARCKS have been shown to contribute to the development of high blood pressure, or hypertension. Here, we investigated protein expression and proteolysis of MARCKS, protein expression of multiple protein kinase C (PKC) isoforms, and protein expression and activity of several different proteases in the kidneys of diabetic db/db mice compared to wild-type littermate mice. In addition, MARCKS protein expression was assessed in cultured mouse cortical collecting duct (mpkCCD) cells treated with normal glucose and high glucose concentrations. Western blot and densitometric analysis showed less abundance of the unprocessed form of MARCKS and increased expression of a proteolytically cleaved form of MARCKS in the kidneys of diabetic db/db mice compared to wild-type mice. The protein expression levels of PKC delta and PKC epsilon were increased, while cathepsin B, cathepsin S, and cathepsin D were augmented in diabetic db/db kidneys compared to those of wild-type mice. An increase in the cleaved form of MARCKS was observed in mpkCCD cells cultured in high glucose compared to normal glucose concentrations. Taken together, these results suggest that high glucose may contribute to an increase in the proteolysis of renal MARCKS, while the upregulation of the cathepsin proteolytic pathway positively correlates with increased proteolysis of MARCKS in diabetic kidneys, where PKC expression is augmented. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
41. SARS-CoV-2 Omicron entry is type II transmembrane serine protease-mediated in human airway and intestinal organoid models.
- Author
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Mykytyn, Anna Z., Breugem, Tim I., Geurts, Maarten H., Beumer, Joep, Schipper, Debby, van Acker, Romy, van den Doel, Petra B., van Royen, Martin E., Jingshu Zhang, Clevers, Hans, Haagmans, Bart L., and Lamers, Mart M.
- Subjects
- *
SARS-CoV-2 Omicron variant , *SARS-CoV-2 , *SERINE , *SERINE proteinases , *INTESTINES , *ELASTASES - Abstract
SARS-CoV-2 can enter cells after its spike protein is cleaved by either type II transmembrane serine proteases (TTSPs), like TMPRSS2, or cathepsins. It is now widely accepted that the Omicron variant uses TMPRSS2 less efficiently and instead enters cells via cathepsins, but these findings have yet to be verified in more relevant cell models. Although we could confirm efficient cathepsin-mediated entry for Omicron in a monkey kidney cell line, experiments with protease inhibitors showed that Omicron (BA.1 and XBB1.5) did not use cathepsins for entry into human airway organoids and instead utilized TTSPs. Likewise, CRISPR-edited intestinal organoids showed that entry of Omicron BA.1 relied on the expression of the serine protease TMPRSS2 but not cathepsin L or B. Together, these data force us to rethink the concept that Omicron has adapted to cathepsin-mediated entry and indicate that TTSP inhibitors should not be dismissed as prophylactic or therapeutic antiviral strategy against SARS-CoV-2. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
42. Lysosomal hydrolases, from waste-bags effectors to essential multipurpose enzymes in liver fibrosis
- Author
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Paloma Ruiz-Blázquez, Júlia Cacho-Pujol, and Anna Moles
- Subjects
lysosome ,protease ,cathepsin ,liver fibrosis ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Lysosomal hydrolases were once considered effectors of the waste disposal system of the cell, the endo-lysosomal system. However, they are now recognized as highly selective enzymes, which can modulate the function of several substrates, contributing to essential homeostatic and pathological cellular processes. There are more than 50 different lysosomal hydrolases that display optimal activity in the pH present in the acidic cellular compartment but can also be found in other cellular locations. They can work alone or in cooperation with other proteases building signaling pathways or amplification cascades. In the context of liver fibrosis lysosomal hydrolases, especially cysteine cathepsins have been described to participate in several fundamental cellular events contributing to the development, progression, perpetuation, and resolution of liver fibrosis. This paper comprehensively reviews the current knowledge on the contribution of lysosomal hydrolases to liver fibrosis.
- Published
- 2023
- Full Text
- View/download PDF
43. Identification and targeting of metastatic biomarkers for hepatocellular carcinoma therapeutics using small molecules library of curcumin analogues
- Author
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Gupta, Ayushi, Choudhary, Princy, and Singh, Sangeeta
- Published
- 2024
- Full Text
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44. Effect of sodium replacement on the quality characteristics of pastırma (a dry-cured meat product)
- Author
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Barış Yalınkılıç, Güzin Kaban, and Mükerrem Kaya
- Subjects
Pastırma ,Chloride Salts ,Volatile compounds ,Cathepsin ,Lipase ,Nutrition. Foods and food supply ,TX341-641 - Abstract
This study aims to investigate the effect of sodium replacement on the quality characteristics of pastırma. For this purpose, pastırma production with four different salt mixtures (I. 100 % NaCl; II. 50 % NaCl + 50 % KCl; III. 40 % NaCl + 40 % KCl + 20 % CaCl2; IV. 30 % NaCl + 40 % KCl + 20 % CaCl2 + 10 % MgCl2) were carried out using traditional method. The use of different salt mixtures for pastırma had no statistically significant effect on the microbial counts and residual nitrite of the final product. The a* and b* values were affected by this treatment. The salt mixture containing CaCl2 or CaCl2 + MgCl2 significantly decreased the pH values and sensory scores. The eighteen volatile compounds were affected by the salt mixtures. Na+, K+, Ca2+, and Mg2+ had a certain increase depending on their ratio in the salt mixtures. The highest Cathepsin activity in all pastırma samples was observed in Cathepsin B + L. The salt mixture with NaCl + KCl + CaCl2 + MgCl2 increased acid lipase activity. However, this mixture had no significant effect on neutral lipase activity.
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- 2023
- Full Text
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45. Muscle Quality of Sword Prawn (Parapenaeopsis hardwickii) during Cold Storage Based on Changes of Endogenous Enzyme Activity
- Author
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Ting ZHOU, Shanshan SHUI, Zhipeng LI, Yingru WU, Yixuan DING, and Bin ZHANG
- Subjects
cold storage ,parapenaeopsis hardwickii ,quality characteristics ,endogenous enzyme ,trypsin ,cathepsin ,Food processing and manufacture ,TP368-456 - Abstract
Objective: To investigate the changes of endogenous enzyme activity and muscle quality characteristics of Sword prawn (Parapenaeopsis hardwickii) under cold storage. Methods: Sword prawn (Parapenaeopsis hardwickii) was taken as the research object. The muscle texture, TCA-soluble peptide, myofibril protein content and myofibril fragmentation index, as well as the activities of endogenous enzymes in the head and muscle of intact and headless shrimp were compared and analyzed at 0°C for 0, 2, 4 and 6 d. Results: With the extension of cold storage time, the content of TCA-soluble peptide and myofibril fragmentation index in muscle of both groups showed an increasing trend. The myofibril protein content gradually decreased, their content in muscle of whole shrimp group and headless shrimp group reduced by 56.65% and 44.63%, respectively, after 6 d of cold storage. While the hardness and elasticity of shrimp in both groups always decreased. During cold storage, the trypsin activity in the head of whole shrimp group decreased gradually, while the activity in the muscle of whole shrimp group increased continuously. The trypsin activity in the muscle of decapitated shrimp group reduced slowly, and the trypsin activity in the head and muscle of whole shrimp group and the muscle of decapitated shrimp group changed by 16.9%, 68.8%, and 15.2%, respectively. In shrimp muscle, the calpain activity decreased with the extension of cold storage time, and the decrease rate was higher in whole shrimp group. The changes of the activities of cathepsin B, D, H and L were different during cold storage. The cathepsin activities in decapitated shrimp were higher than those in whole shrimp. The activities of cathepsins in each muscle subcellular structure of the two groups decreased gradually during cold storage. And the activities in whole shrimp group were higher than those in decapitated shrimp group. Conclusion: The muscle quality characteristics of the headless shrimp group were better than those of the whole shrimp group, and the endogenous enzyme activities in whole shrimp group were relatively higher than those in decapitated shrimp group during cold storage. Therefore, decapitated shrimp storage is more conducive to protect shrimp meat quality.
- Published
- 2022
- Full Text
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46. The polyphenol EGCG directly targets intracellular amyloid‐β aggregates and promotes their lysosomal degradation.
- Author
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Secker, Christopher, Motzny, Angelika Y., Kostova, Simona, Buntru, Alexander, Helmecke, Lucas, Reus, Laura, Steinfort, Robert, Brusendorf, Lydia, Boeddrich, Annett, Neuendorf, Nancy, Diez, Lisa, Schmieder, Peter, Schulz, Aline, Czekelius, Constantin, and Wanker, Erich E.
- Subjects
- *
ALZHEIMER'S disease , *CATHEPSIN B , *SMALL molecules , *NEURODEGENERATION , *CARRIER proteins - Abstract
The accumulation of amyloidogenic protein aggregates in neurons is a pathogenic hallmark of a large number of neurodegenerative diseases including Alzheimer's disease (AD). Small molecules targeting such structures and promoting their degradation may have therapeutic potential for the treatment of AD. Here, we searched for natural chemical compounds that decrease the abundance of stable, proteotoxic β‐sheet‐rich amyloid‐β (Aβ) aggregates in cells. We found that the polyphenol (−)‐epigallocatechin gallate (EGCG) functions as a potent chemical aggregate degrader in SH‐EP cells. We further demonstrate that a novel, fluorescently labeled EGCG derivative (EGC‐dihydroxybenzoate (DHB)‐Rhodamine) also shows cellular activity. It directly targets intracellular Aβ42 aggregates and competes with EGCG for Aβ42 aggregate binding in vitro. Mechanistic investigations indicated a lysosomal accumulation of Aβ42 aggregates in SH‐EP cells and showed that lysosomal cathepsin activity is critical for efficient EGCG‐mediated aggregate clearance. In fact, EGCG treatment leads to an increased abundance of active cathepsin B isoforms and increased enzymatic activity in our SH‐EP cell model. Our findings suggest that intracellular Aβ42 aggregates are cleared through the endo‐lysosomal system. We show that EGCG directly targets intracellular Aβ42 aggregates and facilitates their lysosomal degradation. Small molecules, which bind to protein aggregates and increase their lysosomal degradation could have therapeutic potential for the treatment of amyloid diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
47. Cystatins from the Human Liver Fluke Opisthorchis viverrini : Molecular Characterization and Functional Analysis.
- Author
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Geadkaew-Krenc, Amornrat, Grams, Rudi, Siricoon, Sinee, Kosa, Nanthawat, Krenc, Dawid, Phadungsil, Wansika, and Martviset, Pongsakorn
- Subjects
OPISTHORCHIS viverrini ,CYSTATINS ,LIVER flukes ,CYSTEINE proteinase inhibitors ,CHOLANGIOCARCINOMA ,SERINE proteinases - Abstract
A high incidence of cholangiocarcinoma (bile duct cancer) has been observed in Thailand. This usually rare cancer has been associated with infection with the human liver fluke, Opisthorchis viverrini. Secretions of the parasite that interact with the host are thought to be a major component of its pathogenicity and proteolysis is a key biological activity of the secreted molecules. In this study, we present a molecular analysis of cysteine proteinase inhibitors (cystatins) of Opisthorchis viverrini. Six cDNA coding sequences of Opisthorchis viverrini cystatins, OvCys1–6, were cloned from the adult stage of the parasite using RT-PCR. Based on their sequences, OvCys1 and OvCys2 are classified as type 1 cystatins, while OvCys3–6 are classified as type 2 cystatins, with each containing a signal peptide and only one C-terminal disulfide bond. Their C-terminal region sequences are diverse compared with other cystatin members. Cystatins OvCys1, 3 and 4 were found in crude worm extracts and excretory-secretory (ES) products from the adult parasite using Western blot detection, while the other isoforms were not. Thus, OvCys1, 3 and 4 were selected for inhibition analysis and immune reactivity with Opisthorchis viverrini-infected hamster sera. OvCys1, 3, and 4 inhibited mammalian cathepsin L more effectively than cathepsin B. The pH range for their full activity was very wide (pH 3–9) and they were heat stable for at least 3 h. Unlike Fasciola gigantica cystatins, they showed no immune reactivity with infected hamster sera based on indirect ELISA. Our findings suggest that Opisthorchis viverrini cystatins are not major antigenic components in the ES product of this parasite and that other effects of Opisthorchis viverrini cystatins should be investigated. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
48. The role of lysosomal peptidases in glioma immune escape: underlying mechanisms and therapeutic strategies.
- Author
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Hao Liu, Jie Peng, Linzhen Huang, Dong Ruan, Yuguang Li, Fan Yuan, Zewei Tu, Kai Huang, and Xingen Zhu
- Subjects
PEPTIDASE ,CENTRAL nervous system tumors ,BRAIN tumors ,GLIOMAS - Abstract
Glioblastoma is the most common primary malignant tumor of the central nervous system, which has the characteristics of strong invasion, frequent recurrence, and rapid progression. These characteristics are inseparable from the evasion of glioma cells from immune killing, which makes immune escape a great obstacle to the treatment of glioma, and studies have confirmed that glioma patients with immune escape tend to have poor prognosis. The lysosomal peptidase lysosome family plays an important role in the immune escape process of glioma, which mainly includes aspartic acid cathepsin, serine cathepsin, asparagine endopeptidases, and cysteine cathepsins. Among them, the cysteine cathepsin family plays a prominent role in the immune escape of glioma. Numerous studies have confirmed that glioma immune escape mediated by lysosomal peptidases has something to do with autophagy, cell signaling pathways, immune cells, cytokines, and other mechanisms, especially lysosome organization. The relationship between protease and autophagy is more complicated, and the current research is neither complete nor in-depth. Therefore, this article reviews how lysosomal peptidases mediate the immune escape of glioma through the above mechanisms and explores the possibility of lysosomal peptidases as a target of glioma immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
49. Cathepsins in oral diseases: mechanisms and therapeutic implications.
- Author
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Hao Jiang, Zuoxiang Dong, Xiaomin Xia, and Xue Li
- Subjects
ORAL diseases ,CATHEPSINS ,CELLULAR therapy ,BONE resorption ,ORAL drug administration - Abstract
Cathepsins are a type of lysosomal globulin hydrolase and are crucial for many physiological processes, including the resorption of bone matrix, innate immunity, apoptosis, proliferation, metastasis, autophagy, and angiogenesis. Findings regarding their functions in human physiological processes and disorders have drawn extensive attention. In this review, we will focus on the relationship between cathepsins and oral diseases. We highlight the structural and functional properties of cathepsins related to oral diseases, as well as the regulatory mechanisms in tissue and cells and their therapeutic uses. Elucidating the associated mechanism between cathepsins and oral diseases is thought to be a promising strategy for the treatment of oral diseases and may be a starting point for further studies at the molecular level. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
50. Microglial P2X4 receptors promote ApoE degradation and contribute to memory deficits in Alzheimer’s disease.
- Author
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Hua, Jennifer, Garcia de Paco, Elvira, Linck, Nathalie, Maurice, Tangui, Desrumaux, Catherine, Manoury, Bénédicte, Rassendren, François, and Ulmann, Lauriane
- Abstract
Numerous evidences support that microglia contributes to the progression of Alzheimer’s disease. P2X4 receptors are ATP-gated channels with high calcium permeability, which are de novo expressed in a subset of reactive microglia associated with various pathological contexts, contributing to microglial functions. P2X4 receptors are mainly localized in lysosomes and trafficking to the plasma membrane is tightly regulated. Here, we investigated the role of P2X4 in the context of Alzheimer’s disease (AD). Using proteomics, we identified Apolipoprotein E (ApoE) as a specific P2X4 interacting protein. We found that P2X4 regulates lysosomal cathepsin B (CatB) activity promoting ApoE degradation; P2rX4 deletion results in higher amounts of intracellular and secreted ApoE in both bone-marrow-derived macrophage (BMDM) and microglia from APPswe/PSEN1dE9 brain. In both human AD brain and APP/PS1 mice, P2X4 and ApoE are almost exclusively expressed in plaque-associated microglia. In 12-month-old APP/PS1 mice, genetic deletion of P2rX4 reverses topographical and spatial memory impairment and reduces amount of soluble small aggregates of Aß1-42 peptide, while no obvious alteration of plaque-associated microglia characteristics is observed. Our results support that microglial P2X4 promotes lysosomal ApoE degradation, indirectly altering Aß peptide clearance, which in turn might promotes synaptic dysfunctions and cognitive deficits. Our findings uncover a specific interplay between purinergic signaling, microglial ApoE, soluble Aß (sAß) species and cognitive deficits associated with AD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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