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Keywords = cathepsin D (CTSD)

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14 pages, 3146 KiB  
Article
A High Performing Biomarker Signature for Detecting Early-Stage Pancreatic Ductal Adenocarcinoma in High-Risk Individuals
by Norma A. Palma, Aimee L. Lucas, Bryson W. Katona, Alcibiade Athanasiou, Natasha M. Kureshi, Lisa Ford, Thomas Keller, Stephen Weber, Ralph Schiess, Thomas King, Diane M. Simeone and Randall Brand
Cancers 2025, 17(11), 1866; https://doi.org/10.3390/cancers17111866 - 2 Jun 2025
Viewed by 1321
Abstract
Background/Objectives: Early detection of pancreatic cancer can improve patient survival, and blood-based biomarkers to aid in this are a significant need. The goal of this study was to develop and evaluate the performance of a 4- to 6-plex biomarker signature for detection of [...] Read more.
Background/Objectives: Early detection of pancreatic cancer can improve patient survival, and blood-based biomarkers to aid in this are a significant need. The goal of this study was to develop and evaluate the performance of a 4- to 6-plex biomarker signature for detection of early-stage pancreatic ductal adenocarcinoma (PDAC) that performs well in high-risk controls. Methods: Enzyme-linked immunosorbent assays were used to measure 10 previously identified serum protein biomarker candidates in Stage I and II PDAC cases (n = 128), high-risk controls (n = 465), and normal-risk controls (n = 30). Various combinations of biomarker candidates (models) were trained using machine learning and tested for robustness in differentiating cases from controls on the full cohort and in clinically relevant sub-types including those with diabetes, those ≥65 years of age, and low producers of carbohydrate antigen 19-9 (CA 19-9). Results: At 98% specificity, the top performing model, which was comprised of tissue inhibitor of metalloproteinase 1 (TIMP1), intracellular adhesion molecule 1 (ICAM1), thrombospondin 1 (THBS1), cathepsin D (CTSD), and CA 19-9, achieved 85% sensitivity in the full cohort and sensitivities of 91% in diabetics, 90% in ≥65 years of age, and 60% in low CA 19-9 producers. This model demonstrated significantly higher sensitivity in detecting PDAC in the full cohort and all sub-populations compared to CA 19-9 alone (p < 0.001). Conclusions: Our findings demonstrate the feasibility of a blood-based assay for detecting early-stage PDAC in high-risk individuals and key sub-populations, representing an important step towards improving diagnostic success for early-stage disease. Full article
(This article belongs to the Section Cancer Biomarkers)
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19 pages, 15026 KiB  
Article
Proteomics-Based Exploration of the Hepatoprotective Mechanism of α-Lipoic Acid in Rats with Iron Overload-Induced Liver Injury
by Shuxia Jiang, Yujia Shu, Shihui Guo, Yingdong Ni, Ruqian Zhao, Hongli Shan and Wenqiang Ma
Int. J. Mol. Sci. 2025, 26(10), 4774; https://doi.org/10.3390/ijms26104774 - 16 May 2025
Viewed by 581
Abstract
Excessive iron accumulation poses a significant threat to liver health, primarily through oxidative stress and autophagy dysregulation. α-Lipoic acid (ALA), a natural antioxidant with hepatoprotective properties, may alleviate iron-induced liver damage, but its underlying mechanisms are not fully understood. This study utilized male [...] Read more.
Excessive iron accumulation poses a significant threat to liver health, primarily through oxidative stress and autophagy dysregulation. α-Lipoic acid (ALA), a natural antioxidant with hepatoprotective properties, may alleviate iron-induced liver damage, but its underlying mechanisms are not fully understood. This study utilized male Sprague Dawley rats and BRL-3A cells to explore the protective effects of ALA against iron overload in vivo and in vitro, respectively. ALA treatment significantly reduced hepatic iron accumulation, improved liver morphology, and alleviated iron-induced ultrastructural damage in rats. ALA also improved liver function markers in plasma, including alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), total bilirubin (TBIL), and the AST/ALT ratio. Furthermore, ALA mitigated iron-induced oxidative stress by lowering hepatic reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing the antioxidant enzyme activities of glutathione peroxidase (GSH-Px) and catalase (CAT). In BRL-3A cells, ALA improved cell viability, decreased intracellular ROS, and reduced iron levels. Proteomics analysis indicates that NAD(P)H: quinone oxidoreductase 1 (NQO1) may play a critical role in the protective effects of ALA against iron overload-induced hepatic damage in rats. Mechanistically, ALA upregulated NQO1 expression while downregulating autophagy-related proteins, including light chain 3B (LC3B), lysosomal-associated membrane protein 1 (LAMP1), and cathepsin D (CTSD). Inhibition or knockdown of NQO1 abolished ALA’s protective effects, confirming its role in reducing oxidative stress and excessive autophagy. These findings highlight the potential of ALA as a therapeutic agent for managing hepatic iron toxicity through iron chelation and activation of NQO1. Full article
(This article belongs to the Special Issue New Advances in Proteomics in Disease)
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16 pages, 270 KiB  
Article
Effects of Dietary Copper Sources and Levels on Liver Copper Metabolism and the Expression of Transporters in Growing Pigs
by Rui Sun, Meng Li, Tianrui Zhang, Wenyan Yang and Lianyu Yang
Animals 2025, 15(4), 526; https://doi.org/10.3390/ani15040526 - 12 Feb 2025
Viewed by 930
Abstract
Research on the effects of organic and inorganic Cu sources on metabolic processes and mechanisms in pigs is lacking. This study investigated the effects of different copper (Cu) sources and levels on hepatic Cu metabolism and transporter factors in growing pigs. Sixty healthy [...] Read more.
Research on the effects of organic and inorganic Cu sources on metabolic processes and mechanisms in pigs is lacking. This study investigated the effects of different copper (Cu) sources and levels on hepatic Cu metabolism and transporter factors in growing pigs. Sixty healthy piglets (initial body weight 14.00 ± 0.30 kg) were randomly divided into four groups with five replicates of three pigs each. Four diets (AM, AH, BM, and BH) had different Cu sources [Cu sulphate (CuSO4): A and Cu amino acids (Cu-AA): B] and levels [supplemented (120 mg/kg DM): M, supplemented (240 mg/kg DM): H]. The pre-feeding period was 7 days, followed by a 45-day feeding period. Slaughter and sample collection were carried out on the 46th day of the formal feeding period. Significant differences were considered at p < 0.05. The final weight and average daily gain (ADG) of growing pigs in the Cu-AA groups were significantly higher than those in the CuSO4 groups. Serum Cu increased with increasing Cu supplementation on days 20 and 40. Cu concentrations in muscle, liver, and liver subcellular organelles were higher in Cu-AA groups. In the CuSO4 groups, Cu concentrations were higher in kidneys and faeces. In Cu-AA groups, both the Cu concentrations in lysosomes and cytosol were higher, and the activities of cathepsin D (CTSD), β-glucosidase (BGL), and acid phosphatase (ACP) in lysosomes and cytoplasm were higher. Comparisons between groups showed that liver mRNA of copper transporter protein 1 (CTR1), ATPase copper-transporting beta (ATP7B), ceruloplasmin (CP), antioxidant protein 1 (ATOX1), and metallothionein (MT) was lower in the CuSO4 group than in the Cu-AA group, with the best performance at 120 mg/kg Cu. mRNAs for ATPase copper-transporting alpha (ATP7A), cytochrome c oxidase copper chaperone 17 (COX17), and copper chaperone for superoxide dismutase (CCS) showed a decreasing trend in the Cu-AA groups. Cu-AA is better for Cu deposition, enhances the utilisation of Cu, reduces Cu excretion, and promotes the expression of relevant enzymes and transporters in the liver. Full article
(This article belongs to the Special Issue Exploration of Sustainable Feed Resources and Pig Dietary Strategies)
16 pages, 1633 KiB  
Article
The Expression of Proteases and the Oligopeptide Transporter PepT1 in the Yolk Sac Membrane, Proventriculus, and Small Intestine During the Development of Anas platyrhynchos domestica Embryo
by Seba Jamal Shbailat and Ibtisam Omar Aslan
Biology 2024, 13(12), 989; https://doi.org/10.3390/biology13120989 - 29 Nov 2024
Viewed by 1087
Abstract
The role of the yolk sac membrane (YSM) and digestive tract in the processing of egg yolk proteins during embryogenesis is unexplored in the duck Anas platyrhynchos domestica. Here, we investigated in the duck embryo the function of the YSM, proventriculus, and [...] Read more.
The role of the yolk sac membrane (YSM) and digestive tract in the processing of egg yolk proteins during embryogenesis is unexplored in the duck Anas platyrhynchos domestica. Here, we investigated in the duck embryo the function of the YSM, proventriculus, and small intestine in protein digestion and uptake. We tested the expression of aminopeptidase N (APN) and the oligopeptide transporter PepT1 as well as the expression of cathepsin B (CTSB) and cathepsin D (CTSD) lysosomal genes in the YSM during incubation days 12, 14, 16–18, 20, 22, 24, 26, and 28 (the day of hatch). Also, we examined embryonic duck pepsinogen (EDPg) expression in the proventriculus and APN and PepT1 expression in the small intestine. In the YSM, CTSD expression was weak compared to that of CTSB, and the expression of CTSB, APN, and PepT1 reached its maximum on day 24 and decreased afterwards. In the proventriculus, EDPg expression peaked on days 17 to 20 and decreased thereafter. The APN and PepT1 expression levels were highest in the jejunum and ileum and reached their maximum on day 28. Our results suggest that the YSM plays a role in the degradation and uptake of the peptides that are digested by the activated yolk proteases, and it also functions in the lysosomal digestion of yolk lipoproteins. Furthermore, the proventriculus is possibly involved in the digestion of yolk proteins. Finally, the jejunum and ileum appear to be the primary sites for peptide digestion and absorption at the end of the incubation. Full article
(This article belongs to the Section Biochemistry and Molecular Biology)
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17 pages, 3180 KiB  
Article
Transcriptome Analysis Reveals the Early Development in Subcutaneous Adipose Tissue of Laiwu Piglets
by Liwen Bian, Zhaoyang Di, Mengya Xu, Yuhan Tao, Fangyuan Yu, Qingyan Jiang, Yulong Yin and Lin Zhang
Animals 2024, 14(20), 2955; https://doi.org/10.3390/ani14202955 - 14 Oct 2024
Viewed by 1487
Abstract
Adipose tissue plays an important role in pig production efficiency. Studies have shown that postnatal development has a vital impact on adipose tissue; however, the mechanisms behind pig adipose tissue early-life programming remain unknown. In this study, we analyzed the transcriptomes of the [...] Read more.
Adipose tissue plays an important role in pig production efficiency. Studies have shown that postnatal development has a vital impact on adipose tissue; however, the mechanisms behind pig adipose tissue early-life programming remain unknown. In this study, we analyzed the transcriptomes of the subcutaneous adipose tissue (SAT) of 1-day and 21-day old Laiwu piglets. The results showed that the SAT of Laiwu piglets significantly increased from 1-day to 21-day, and transcriptome analysis showed that there were 2352 and 2596 differentially expressed genes (DEGs) between 1-day and 21-day SAT in male and female piglets, respectively. Expression of genes in glycolysis, gluconeogenesis, and glycogen metabolism such as pyruvate kinase M1/2 (PKM), phosphoenolpyruvate carboxy kinase 1 (PCK1) and amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) were significantly different between 1-day and 21-day SAT. Genes in lipid uptake, synthesis and lipolysis such as lipase E (LIPE), acetyl-CoA carboxylase alpha (ACACA), Stearoyl-CoA desaturase (SCD), and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were also differentially expressed. Functional analysis showed enrichment of DEGs in transcriptional regulation, protein metabolism and cellular signal transduction. The protein–protein interaction (PPI) networks of these DEGs were analyzed and potential hub genes in these pathways were identified, such as transcriptional factors forkhead box O4 (FOXO4), CCAAT enhancer binding protein beta (CEBPB) and CCAAT enhancer binding protein delta (CEBPD), signal kinases BUB1 mitotic checkpoint serine/threonine kinase (BUB1) and cyclin-dependent kinase 1 (CDK1), and proteostasis-related factors ubiquitin conjugating enzyme E2 C (UBE2C) and cathepsin D (CTSD). Moreover, we further analyzed the transcriptomes of SAT between genders and the results showed that there were 54 and 72 DEGs in 1-day and 21-day old SAT, respectively. Genes such as KDM5D and KDM6C showed gender-specific expression in 1-day and 21-day SAT. These results showed the significant changes in SAT between 1-day and 21-day in male and female Laiwu pigs, which would provide information to comprehensively understand the programming of adipose tissue early development and to regulate adipose tissue function. Full article
(This article belongs to the Section Pigs)
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20 pages, 6013 KiB  
Article
Investigating and Annotating the Human Peptidome Profile from Urine under Normal Physiological Conditions
by Amr Elguoshy, Keiko Yamamoto, Yoshitoshi Hirao, Tomohiro Uchimoto, Kengo Yanagita and Tadashi Yamamoto
Proteomes 2024, 12(3), 18; https://doi.org/10.3390/proteomes12030018 - 25 Jun 2024
Cited by 1 | Viewed by 1807
Abstract
Examining the composition of the typical urinary peptidome and identifying the enzymes responsible for its formation holds significant importance, as it mirrors the normal physiological state of the human body. Any deviation from this normal profile could serve as an indicator of pathological [...] Read more.
Examining the composition of the typical urinary peptidome and identifying the enzymes responsible for its formation holds significant importance, as it mirrors the normal physiological state of the human body. Any deviation from this normal profile could serve as an indicator of pathological processes occurring in vivo. Consequently, this study focuses on characterizing the normal urinary peptidome and investigating the various catalytic enzymes that are involved in generating these native peptides in urine. Our findings reveal that 1503 endogenous peptides, corresponding to 436 precursor proteins, were consistently identified robustly in at least 10 samples out of a total of 19 samples. Notably, the liver and kidneys exhibited the highest number of tissue-enriched or enhanced genes in the analyzed urinary peptidome. Furthermore, among the catalytic types, CTSD (cathepsin D) and MMP2 (matrix metalloproteinase-2) emerged as the most prominent peptidases in the aspartic and metallopeptidases categories, respectively. A comparison of our dataset with two of the most comprehensive urine peptidome datasets to date indicates a consistent relative abundance of core endogenous peptides for different proteins across all three datasets. These findings can serve as a foundational reference for the discovery of biomarkers in various human diseases. Full article
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15 pages, 5072 KiB  
Article
Enhanced Osteocyte Differentiation: Cathepsin D and L Secretion by Human Adipose-Derived Mesenchymal Stem Cells
by Jung-Won Choi, Soyeon Lim, Seung Eun Jung, Seongtae Jeong, Hanbyeol Moon, Byeong-Wook Song, Il-Kwon Kim, Seahyoung Lee, Ki-Chul Hwang and Sang Woo Kim
Cells 2023, 12(24), 2852; https://doi.org/10.3390/cells12242852 - 17 Dec 2023
Cited by 3 | Viewed by 2484
Abstract
Adipose-derived mesenchymal stem cells (ASCs) have the potential to differentiate into bone, cartilage, fat, and neural cells and promote tissue regeneration and healing. It is known that they can have variable responses to hypoxic conditions. In the present study, we aimed to explore [...] Read more.
Adipose-derived mesenchymal stem cells (ASCs) have the potential to differentiate into bone, cartilage, fat, and neural cells and promote tissue regeneration and healing. It is known that they can have variable responses to hypoxic conditions. In the present study, we aimed to explore diverse changes in the cells and secretome of ASCs under a hypoxic environment over time and to present the possibility of ASCs as therapeutic agents from a different perspective. The expression differences of proteins between normoxic and hypoxic conditions (6, 12, or 24 h) were specifically investigated in human ASCs using 2-DE combined with MALDI-TOF MS analysis, and secreted proteins in ASC-derived conditioned media (ASC-derived CM) were examined by an adipokine array. In addition, genetic and/or proteomic interactions were assessed using a DAVID and miRNet functional annotation bioinformatics analysis. We found that 64 and 5 proteins were differentially expressed in hypoxic ASCs and in hypoxic ASC-derived CM, respectively. Moreover, 7 proteins among the 64 markedly changed spots in hypoxic ASCs were associated with bone-related diseases. We found that two proteins, cathepsin D (CTSD) and cathepsin L (CTSL), identified through an adipokine array independently exhibited significant efficacy in promoting osteocyte differentiation in bone-marrow-derived mesenchymal stem cells (BM-MSCs). This finding introduces a promising avenue for utilizing hypoxia-preconditioned ASC-derived CM as a potential therapeutic approach for bone-related diseases. Full article
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18 pages, 2472 KiB  
Article
Structural Congeners of Izenamides Responsible for Cathepsin D Inhibition: Insights from Synthesis-Derived Elucidation
by Hyun Su Kim, Hyejin Kong, Taewoo Kim, Changjin Lim, Seungbeom Lee, Seok-Ho Kim and Young-Ger Suh
Mar. Drugs 2023, 21(5), 281; https://doi.org/10.3390/md21050281 - 28 Apr 2023
Cited by 1 | Viewed by 1781
Abstract
This study aimed to elucidate the structural congeners of natural izenamides A, B, and C (13) responsible for cathepsin D (CTSD) inhibition. Structurally modified izenamides were synthesized and biologically evaluated, and their biologically important core structures were identified. We [...] Read more.
This study aimed to elucidate the structural congeners of natural izenamides A, B, and C (13) responsible for cathepsin D (CTSD) inhibition. Structurally modified izenamides were synthesized and biologically evaluated, and their biologically important core structures were identified. We confirmed that the natural statine (Sta) unit (3S,4S)-γ-amino-β-hydroxy acid is a requisite core structure of izenamides for inhibition of CTSD, which is closely related to the pathophysiological roles in numerous human diseases. Interestingly, the statine-incorporated izenamide C variant (7) and 18-epi-izenamide B variant (8) exhibited more potent CTSD-inhibitory activities than natural izenamides. Full article
(This article belongs to the Section Synthesis and Medicinal Chemistry of Marine Natural Products)
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14 pages, 1652 KiB  
Article
A Dual-Function “TRE-Lox” System for Genetic Deletion or Reversible, Titratable, and Near-Complete Downregulation of Cathepsin D
by Heather M. Terron, Derek S. Maranan, Luke A. Burgard, Frank M. LaFerla, Shelley Lane and Malcolm A. Leissring
Int. J. Mol. Sci. 2023, 24(7), 6745; https://doi.org/10.3390/ijms24076745 - 4 Apr 2023
Cited by 4 | Viewed by 2619
Abstract
Commonly employed methods for reversibly disrupting gene expression, such as those based on RNAi or CRISPRi, are rarely capable of achieving >80–90% downregulation, making them unsuitable for targeting genes that require more complete disruption to elicit a phenotype. Genetic deletion, on the other [...] Read more.
Commonly employed methods for reversibly disrupting gene expression, such as those based on RNAi or CRISPRi, are rarely capable of achieving >80–90% downregulation, making them unsuitable for targeting genes that require more complete disruption to elicit a phenotype. Genetic deletion, on the other hand, while enabling complete disruption of target genes, often produces undesirable irreversible consequences such as cytotoxicity or cell death. Here we describe the design, development, and detailed characterization of a dual-function “TRE-Lox” system for effecting either (a) doxycycline (Dox)-mediated downregulation or (b) genetic deletion of a target gene—the lysosomal aspartyl protease cathepsin D (CatD)—based on targeted insertion of a tetracycline-response element (TRE) and two LoxP sites into the 5′ end of the endogenous CatD gene (CTSD). Using an optimized reverse-tetracycline transrepressor (rtTR) variant fused with the Krüppel-associated box (KRAB) domain, we show that CatD expression can be disrupted by as much as 98% in mouse embryonic fibroblasts (MEFs). This system is highly sensitive to Dox (IC50 = 1.46 ng/mL) and results in rapid (t1/2 = 0.57 d) and titratable downregulation of CatD. Notably, even near-total disruption of CatD expression was completely reversed by withdrawal of Dox. As expected, transient expression of Cre recombinase results in complete deletion of the CTSD gene. The dual functionality of this novel system will facilitate future studies of the involvement of CatD in various diseases, particularly those attributable to partial loss of CatD function. In addition, the TRE-Lox approach should be applicable to the regulation of other target genes requiring more complete disruption than can be achieved by traditional methods. Full article
(This article belongs to the Section Molecular Biology)
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12 pages, 5832 KiB  
Article
The Iridoid Glycoside Loganin Modulates Autophagic Flux Following Chronic Constriction Injury-Induced Neuropathic Pain
by Kuang-I Cheng, Yu-Chin Chang, Li-Wen Chu, Su-Ling Hsieh, Li-Mei An, Zen-Kong Dai and Bin-Nan Wu
Int. J. Mol. Sci. 2022, 23(24), 15873; https://doi.org/10.3390/ijms232415873 - 14 Dec 2022
Cited by 7 | Viewed by 2634
Abstract
Autophagy facilitates the degradation of organelles and cytoplasmic proteins in a lysosome-dependent manner. It also plays a crucial role in cell damage. Whether loganin affects autophagy in chronic constriction injury (CCI)-induced neuropathic pain remains unclear. We investigated the neuroprotective effect of loganin on [...] Read more.
Autophagy facilitates the degradation of organelles and cytoplasmic proteins in a lysosome-dependent manner. It also plays a crucial role in cell damage. Whether loganin affects autophagy in chronic constriction injury (CCI)-induced neuropathic pain remains unclear. We investigated the neuroprotective effect of loganin on the autophagic–lysosomal pathway in the rat CCI model. Sprague–Dawley rats were divided into sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was intraperitoneally injected once daily, and rats were sacrificed on day 7 after CCI. This study focused on the mechanism by which loganin modulates autophagic flux after CCI. CCI enhanced the autophagic marker LC3B-II in the ipsilateral spinal cord. The ubiquitin-binding protein p62 binds to LC3B-II and integrates into autophagosomes, which are degraded by autophagy. CCI caused the accumulation of p62, indicating the interruption of autophagosome turnover. Loganin significantly attenuated the expression of Beclin-1, LC3B-II, and p62. Double immunofluorescence staining was used to confirm that LC3B-II and p62 were reduced by loganin in the spinal microglia and astrocytes. Loganin also lessened the CCI-increased colocalization of both proteins. Enhanced lysosome-associated membrane protein 2 (LAMP2) and pro-cathepsin D (pro-CTSD) in CCI rats were also attenuated by loganin, suggesting that loganin improves impaired lysosomal function and autophagic flux. Loganin also attenuated the CCI-increased apoptosis protein Bax and cleaved caspase-3. Loganin prevents CCI-induced neuropathic pain, which could be attributed to the regulation of neuroinflammation, neuronal autophagy, and associated cell death. These data suggest autophagy could be a potential target for preventing neuropathic pain. Full article
(This article belongs to the Special Issue Roles of the Immune System in Neuropathic Pain)
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15 pages, 3551 KiB  
Article
Moderate Treadmill Exercise Alleviates NAFLD by Regulating the Biogenesis and Autophagy of Lipid Droplet
by Yangjun Yang, Xi Li, Zonghan Liu, Xinyu Ruan, Huihui Wang, Qiang Zhang, Lu Cao, Luchen Song, Yinghong Chen and Yi Sun
Nutrients 2022, 14(22), 4910; https://doi.org/10.3390/nu14224910 - 20 Nov 2022
Cited by 27 | Viewed by 5179
Abstract
Lipid droplet is a dynamic organelle that undergoes periods of biogenesis and degradation under environmental stimuli. The excessive accumulation of lipid droplets is the major characteristic of non-alcoholic fatty liver disease (NAFLD). Moderate aerobic exercise is a powerful intervention protecting against the progress [...] Read more.
Lipid droplet is a dynamic organelle that undergoes periods of biogenesis and degradation under environmental stimuli. The excessive accumulation of lipid droplets is the major characteristic of non-alcoholic fatty liver disease (NAFLD). Moderate aerobic exercise is a powerful intervention protecting against the progress of NAFLD. However, its impact on lipid droplet dynamics remains ambiguous. Mice were fed with 15 weeks of high-fat diet in order to induce NAFLD. Meanwhile, the mice performed 15 weeks of treadmill exercise. Our results showed that 15 weeks of regular moderate treadmill exercise alleviated obesity, insulin intolerance, hyperlipidemia, and hyperglycemia induced by HFD. Importantly, exercise improved histological phenotypes of NAFLD, including hepatic steatosis, inflammation, and locular ballooning, as well as prevented liver fat deposition and liver injury induced by HFD. Exercise reduced hepatic lipid droplet size, and moreover, it reduced PLIN2 protein level and increased PLIN3 protein level in the liver of HFD mice. Interestingly, our results showed that exercise did not significantly affect the gene expressions of DGAT1, DGAT2, or SEIPIN, which were involved in TG synthesis. However, it did reduce the expressions of FITM2, CIDEA, and FSP27, which were major involved in lipid droplet growth and budding, and lipid droplet expansion. In addition, exercise reduced ATGL protein level in HFD mice, and regulated lipophagy-related markers, including increasing ATG5, LAMP1, LAMP2, LAL, and CTSD, decreasing LC3II/I and p62, and promoting colocalization of LAMP1 with LDs. In summary, our data suggested that 15 weeks of moderate treadmill exercise was beneficial for regulating liver lipid droplet dynamics in HFD mice by inhibiting abnormal lipid droplets expansion and enhancing clearance of lipid droplets by lysosomes during the lipophagic process, which might provide highly flexible turnover for lipid mobilization and metabolism. Abbreviations: β-actin: actin beta; ATG5: autophagy related 5; LAMP2: lysosomal-associated membrane protein 2; LAMP1: lysosomal-associated membrane protein 1; SQSTM1/p62: sequestosome 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ATGL: adipose triglyceride lipase; CSTD: cathepsin D; LAL: lysosomal acid lipase; DGAT1: diacylglycerol-o-acyltransferase 1; DGAT2: diacylglycerol-o-acyltransferase 2; CIDEA: cell death inducing dffa-like effector a; CIDEC/FSP27: cell death inducing dffa-like effector c; FITM2: fat storage-inducing transmembrane protein 2; PLIN2: adipose differentiation related protein; PLN3: tail-interacting protein 47; HSP90: heat shock protein 90; SREBP1c: sterol regulatory element binding protein-1c; chREBP: carbohydrate response element binding protein. Full article
(This article belongs to the Section Nutrition and Obesity)
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13 pages, 1139 KiB  
Article
Saposin C, Key Regulator in the Alpha-Synuclein Degradation Mediated by Lysosome
by Clara Ruz, Francisco J. Barrero, Javier Pelegrina, Sara Bandrés-Ciga, Francisco Vives and Raquel Duran
Int. J. Mol. Sci. 2022, 23(19), 12004; https://doi.org/10.3390/ijms231912004 - 9 Oct 2022
Cited by 4 | Viewed by 2820
Abstract
Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme β-glucocerebrosidase (β-GCase), considered the main genetic risk factor for sporadic [...] Read more.
Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme β-glucocerebrosidase (β-GCase), considered the main genetic risk factor for sporadic PD. The loss of β-GCase activity results in the formation of α-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to α-synuclein (α-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the β-GCase, β-galactosidase (β-gal), β-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, β-GAL, β-HEX, CTSD, PSAP, Saposin C and α-Syn protein levels by Western-blot. We found a 20% reduced β-GCase and β-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of α-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of α-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the β-GCase activity, resulting in the accumulation of α-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD. Full article
(This article belongs to the Special Issue Pathogenesis of Diseases of the Central Nervous System)
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13 pages, 3415 KiB  
Article
Cathepsin D Plays a Vital Role in Macrobrachium nipponense of Ovary Maturation: Identification, Characterization, and Function Analysis
by Dan Cheng, Wenyi Zhang, Sufei Jiang, Yiwei Xiong, Shubo Jin, Fangyan Pan, Junpeng Zhu, Yongsheng Gong, Yan Wu, Hui Qiao and Hongtuo Fu
Genes 2022, 13(8), 1495; https://doi.org/10.3390/genes13081495 - 21 Aug 2022
Cited by 7 | Viewed by 2588
Abstract
The oriental river prawn Macrobrachium nipponense is an economically important aquacultural species. However, its aquaculture is negatively impacted by the rapid sexual maturation of female M. nipponense. The fast sexual maturation produces a large number of offspring which leads to a reduction [...] Read more.
The oriental river prawn Macrobrachium nipponense is an economically important aquacultural species. However, its aquaculture is negatively impacted by the rapid sexual maturation of female M. nipponense. The fast sexual maturation produces a large number of offspring which leads to a reduction in resilience, a low survival rate, and an increased risk of hypoxia, this in turn, seriously affects the economic benefits of prawn farming. Cathepsin D is a lysosomal protease involved in the ovarian maturation of M. nipponense. In the current study, the cDNA of the gene encoding cathepsin D (Mn-CTSD) was cloned from M. nipponense. The total length was 2391 bp and consisted of an open reading frame (ORF) of 1158 bp encoding 385 amino acids. Sequence analysis confirmed the presence of conserved N-glycosylation sites and characteristic sequences of nondigestive cathepsin D. The qPCR analysis indicated that Mn-CTSD was highly expressed in all tissues tested, most significantly in the ovaries, whereas in situ hybridization showed that expression occurred mainly in oocyte nuclei. Analysis of its expression during development showed that Mn-CTSD peaked during the O-IV stage of ovarian maturation. For the RNAi interference experiment, female M. nipponense specimens in the ovary stage I were selected. Injection of Mn-CTSD double-stranded (ds)RNA into female M. nipponense decreased the expression of Mn-CTSD in the ovaries, such that the Gonad Somatic Index (GSI) of the experimental group was significantly lower than that of the control group (1.79% versus 4.57%; p < 0.05). Ovary development reached the O-III stage in 80% of the control group, compared with 0% in the experimental group. These results suggest that Mn-CTSD dsRNA inhibits ovarian maturation in M. nipponense, highlighting its important role in ovarian maturation in this species and suggesting an approach to controlling ovarian maturation during M. nipponense aquaculture. Full article
(This article belongs to the Special Issue Genetic Breeding of Aquaculture)
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19 pages, 1697 KiB  
Article
High Expression of the Lysosomal Protease Cathepsin D Confers Better Prognosis in Neuroblastoma Patients by Contrasting EGF-Induced Neuroblastoma Cell Growth
by Eleonora Secomandi, Amreen Salwa, Chiara Vidoni, Alessandra Ferraresi, Carlo Follo and Ciro Isidoro
Int. J. Mol. Sci. 2022, 23(9), 4782; https://doi.org/10.3390/ijms23094782 - 26 Apr 2022
Cited by 7 | Viewed by 2800
Abstract
Neuroblastoma is a malignant extracranial solid tumor arising from the sympathoadrenal lineage of the neural crest and is often associated with N-MYC amplification. Cathepsin D has been associated with chemoresistance in N-MYC-overexpressing neuroblastomas. Increased EGFR expression also has been associated with the aggressive [...] Read more.
Neuroblastoma is a malignant extracranial solid tumor arising from the sympathoadrenal lineage of the neural crest and is often associated with N-MYC amplification. Cathepsin D has been associated with chemoresistance in N-MYC-overexpressing neuroblastomas. Increased EGFR expression also has been associated with the aggressive behavior of neuroblastomas. This work aimed to understand the mechanisms linking EGFR stimulation and cathepsin D expression with neuroblastoma progression and prognosis. Gene correlation analysis in pediatric neuroblastoma patients revealed that individuals bearing a high EGFR transcript level have a good prognosis only when CTSD (the gene coding for the lysosomal protease Cathepsin D, CD) is highly expressed. Low CTSD expression was associated with poor clinical outcome. CTSD expression was negatively correlated with CCNB2, CCNA2, CDK1 and CDK6 genes involved in cell cycle division. We investigated the biochemical pathways downstream to EGFR stimulation in human SH-SY5Y neuroblastoma cells engineered for overexpressing or silencing of CD expression. Cathepsin D overexpression decreased the proliferative potential of neuroblastoma cells through downregulation of the pro-oncogenic MAPK signaling pathway. EGFR stimulation downregulated cathepsin D expression, thus favoring cell cycle division. Our data suggest that chemotherapeutics that inhibit the EGFR pathway, along with stimulators of cathepsin D synthesis and activity, could benefit neuroblastoma prognosis. Full article
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16 pages, 3811 KiB  
Article
The Different Effect of Decellularized Myocardial Matrix Hydrogel and Decellularized Small Intestinal Submucosa Matrix Hydrogel on Cardiomyocytes and Ischemic Heart
by Xifeng Yang, Shihao Chen, Jiaxin Chen, Yunqi Liu, Ying Bai, Shengli Yin and Daping Quan
Appl. Sci. 2021, 11(17), 7768; https://doi.org/10.3390/app11177768 - 24 Aug 2021
Cited by 8 | Viewed by 2694
Abstract
Injectable decellularized matrix hydrogels derived from either myocardium or small intestinal submucosa (pDMYO-gel, pDSIS-gel) have been successfully used for myocardial injury repair. However, the relationship between tissue-specific biological functions and protein composition in these two materials is not clear yet. In this study, [...] Read more.
Injectable decellularized matrix hydrogels derived from either myocardium or small intestinal submucosa (pDMYO-gel, pDSIS-gel) have been successfully used for myocardial injury repair. However, the relationship between tissue-specific biological functions and protein composition in these two materials is not clear yet. In this study, the protein composition, mechanical properties, and morphology of these two hydrogels and their effects on the behavior of neonatal rat cardiomyocytes (NRCMs) and human umbilical vein endothelial cells (HUVECs), are investigated. The results show that pDMYO-gel is more conducive to growth, adhesion, spreading, and maintenance of normal NRCM beating, due to its higher proportion of extracellular matrix (ECM) glycoproteins (49.55%) and some unique functional proteins such as annexin-6 (ANXA6), agrin (AGRN), cathepsin D (CTSD) and galectin-1 (LGALS1), whereas pDSIS-gel is more conducive to the proliferation of HUVECs. Animal study shows that pDMYO-gel has a better effect on improving cardiac function, inhibiting myocardial fibrosis and maintaining ventricular wall thickness in acute myocardial infarction models in vivo. Therefore, it is proposed that injectable pDMYO-gel hydrogel may be more suitable for functional recovery of myocardial injuries. Full article
(This article belongs to the Section Applied Biosciences and Bioengineering)
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