CTSB
Cathepsin B precursor (EC 3.4.22.1) (APP secretase) (APPS) (Cathepsin B1) [Contains: Cathepsin B light chain; Cathepsin B heavy chain] [CPSB]
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Cathepsins are the major lysosomal proteases that maintain intracellular homeostasis. Herein, we investigated the alterations in myocardial cathepsin expression during aging, cardiac hypertrophy, and sudden cardiac death (SCD). Cardiac tissue and blood were sampled from autopsy cases. Subjects were classified into three groups: SCD with cardiac hypertrophy (SCH), compensated cardiac hypertrophy (CCH), and control. Immunoblotting was performed for the major cardiac cathepsins and their targets: cathepsin B, D, and L (CTSB/D/L), p62, ATP synthase subunit c (ATPSC), and α-synuclein (ASNC). Immunohistochemical analysis and ELISA using serum samples were performed for CTSD. Cardiac CTSB and CTSD were upregulated with age (r = 0.63 and 0.60, respectively), whereas the levels of CTSL, p62, ATPSC, and ASNC remained unchanged. In age-matched groups, cardiac CTSD was significantly downregulated in SCH (p = 0.006) and CTSL was moderately downregulated in CCH (p = 0.021); however, p62, ATPSC, and ASNC were not upregulated in cardiac hypertrophy. Immunohistochemistry also revealed decreased myocardial CTSD levels in SCH, and serum CTSD levels were relatively lower in SCH cases. Overall, these results suggest that upregulation of cardiac CTSB and CTSD with age may compensate for the elevated proteolytic demand, and that downregulation of CTSD is potentially linked to SCH.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cathepsin D
- Death, Sudden, Cardiac
- Down-Regulation
- Female
- Humans
- Male
- Middle Aged
- Myocardium
- Substrate Specificity
Amyloid-β (Aβ), a major component of senile plaques, is generated via the proteolysis of amyloid-β protein precursor (AβPP). This cleavage also produces AβPP fragment-derived oligomers which can be highly neurotoxic. AβPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer's disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AβPP proteolysis (β-secretase activity) and Aβ clearance (Aβ degradative activity). The present work examines the effect of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AβPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AβPP and secreted α-secretase-cleaved soluble AβPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Brain
- Cathepsin B
- Cell Line, Tumor
- Dipeptides
- Free Radicals
- Humans
- Lysosomes
- Neurons
- Oxidative Stress
Keywords
- amyloid-β
- amyloid-β protein precursor
- cathepsin B
- free radicals
- oligomer
- oxidative stress
Melanoma is an aggressive skin cancer that can rapidly metastasize to become fatal, if not diagnosed early. Despite recent therapeutic advances, management of melanoma remains difficult. Therefore, novel molecular targets and strategies are required to manage this neoplasm. This study was undertaken to determine the role of the sirtuin SIRT6 in melanoma. Employing a panel of human melanoma cells and normal human melanocytes, we found significant SIRT6 mRNA and protein upregulation in melanoma cells. Further, using a tissue microarray coupled with quantitative Vectra analysis, we demonstrated significant SIRT6 overexpression in human melanoma tissues. Lentiviral short hairpin RNA-mediated knockdown of SIRT6 in A375 and Hs 294T human melanoma cells significantly decreased cell growth, viability, and colony formation, induced G1-phase arrest and increased senescence-associated beta-galactosidase staining. As autophagy is important in melanoma and is associated with SIRT6, we used a qPCR array to study SIRT6 knockdown in A375 cells. We found significant modulation in several genes and/or proteins (decreases in AKT1, ATG12, ATG3, ATG7, BAK1, BCL2L1, CLN3, CTSB, CTSS, DRAM2, HSP90AA1, IRGM, NPC1, SQSTM1, TNF, and BECN1; increases in GAA, ATG10). Our data suggests that increased SIRT6 expression may contribute to melanoma development and/or progression, potentially via senescence-and autophagy-related pathways.
Keywords
- SIRT6
- autophagy
- melanoma
- senescence
- sirtuins
Whether obesity accelerates or suppresses autophagy in adipose tissue is still debatable. To clarify dysregulation of autophagy and its role in pathologies of obese adipose tissue, we focused on lysosomal function, protease maturation and activity, both in vivo and in vitro. First, we showed that autophagosome formation was accelerated, but autophagic clearance was impaired in obese adipose tissue. We also found protein and activity levels of CTSL (cathepsin L) were suppressed in obese adipose tissue, while the activity of CTSB (cathepsin B) was significantly enhanced. Moreover, cellular senescence and inflammasomes were activated in obese adipose tissue. In 3T3L1 adipocytes, downregulation of CTSL deteriorated autophagic clearance, upregulated expression of CTSB, promoted cellular senescence and activated inflammasomes. Upregulation of CTSB promoted additional activation of inflammasomes. Therefore, we suggest lysosomal dysfunction observed in obese adipose tissue leads to lower autophagic clearance, resulting in autophagosome accumulation. Simultaneously, lysosomal abnormalities, including deteriorated CTSL function and compensatory activation of CTSB, caused cellular senescence and inflammasome activation. Our findings strongly suggest lysosomal dysfunction is involved in early pathologies of obese adipose tissue.
MeSH Terms
- 3T3-L1 Cells
- Adipocytes
- Adipose Tissue, White
- Animals
- Autophagosomes
- Autophagy-Related Proteins
- Cathepsins
- Cellular Senescence
- Diet, High-Fat
- Inflammasomes
- Lysosomes
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Obese
- Obesity
- Up-Regulation
Keywords
- adipose tissue
- autophagy
- cathepsin
- inflammasome
- lysosome
- obesity
- senescence
Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.
MeSH Terms
- Adult
- Affect
- Aging
- Animals
- Behavior, Animal
- Brain-Derived Neurotrophic Factor
- Cathepsin B
- Cognition
- Exercise Test
- Female
- Hippocampus
- Humans
- Macaca mulatta
- Male
- Memory
- Mice, Inbred C57BL
- Mice, Knockout
- Microtubule-Associated Proteins
- Motor Activity
- Neurogenesis
- Neurons
- Neuropeptides
- Physical Conditioning, Animal
- Reproducibility of Results
- Running
- Sedentary Behavior
- Young Adult
Keywords
- cathepsin B
- exercise
- hippocampus
- humans
- memory
- mice
- muscle
Cathepsin B (CTSB) is an important enzyme for many physiological and pathological processes, and its activity increases with age. Here, we explored the association between serum CTSB and aging-related subclinical cardiovascular and renal status in a healthy Chinese population. The study included 369 healthy individuals aged 36-87 years. Cardiovascular structure and function were assessed by the left ventricular ejection fraction, the early-diastolic peak flow velocity to late-diastolic peak flow velocity ratio at the mitral leaflet tips, carotid intima-media thickness (IMT), the diameter of the bilateral common carotid artery (D), and blood systolic peak (SPV) and end diastolic velocities, which were measured by M-mode ultrasonography. Serum CTSB, insulin-like growth factor-1 (IGF-1), 1, 25-dihydroxy vitamin D3, and parathyroid hormone (PTH) were measured by enzyme-linked immunosorbent assay. In men, serum CTSB was significantly related to IMT and IMT/D in the unadjusted model, and these associations were lost after age adjustment. In women, serum CTSB remained significantly associated with serum creatinine (SCr) (p=0.009), estimated glomerular filtration rate (p=0.048) and IMT/D (p=0.017) following full adjustment. PTH was independently associated with SCr. IGF-1 was significantly associated with SPV in women. CTSB was correlated with metabolic and endocrine biomarkers. Serum CTSB was associated with aging-related cardiovascular-renal parameters even in healthy people. Measurement of serum CTSB alone or in combination with metabolic and endocrine biomarkers can provide valuable information for predicting cardiovascular-renal function in healthy people, especially in elderly women.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- Biomarkers
- Blood Flow Velocity
- Carotid Artery, Common
- Carotid Intima-Media Thickness
- Cathepsin B
- China
- Coronary Circulation
- Creatinine
- Cross-Sectional Studies
- Female
- Glomerular Filtration Rate
- Humans
- Male
- Middle Aged
- Stroke Volume
Keywords
- Age
- CTSB
- Cardiovascular
- Renal
- Subclinical-state
Previous studies have suggested that high mobility group box-1 protein (HMGB1) binds to the toll-like receptor 4 (TLR4) signaling mediates the progression of various inflammatory diseases. But the roles of HMGB1 and TLR4 in aging remain poorly unknown. In this study, we aimed to investigate the serum levels of HMGB1 and myeloid differentiation factor 88 (MyD88), which is one of TLR4's intracellular adaptor proteins during human aging process and their relevance with cathepsin B (CTSB). This research was conducted using the blood samples provided by healthy people (n = 90, 63 men and 27 women). Subjects were subdivided into groups with respect to age: young (about 25 years old, n = 30), middle age (about 40 years old, n = 30), and aged (above 65 years old, n = 30). Altered serum levels of HMGB1, MyD88 and CTSB were measured using an enzyme-linked immunosorbent assay. The serum levels of HMGB1 and MyD88 were significantly decreased in the aged group compared with those in the young group. Linear regression analysis showed that HMGB1 and MyD88 positively correlated with CTSB among the whole healthy people. A negative correlation was determined between MyD88 and age. The serum levels of HMGB1 and MyD88 significantly decreased with age. MyD88, but not HMGB1, was negatively correlated with age.
MeSH Terms
- Adult
- Aged
- Aging
- Cathepsin B
- Female
- HMGB1 Protein
- Humans
- Male
- Middle Aged
- Myeloid Differentiation Factor 88
- Regression Analysis
- Signal Transduction
- Toll-Like Receptor 4
Keywords
- Aging
- Cathepsin B
- HMGB1
- MyD88