BACKGROUNDMultiple sclerosis (MS) is characterized as an inflammatory neurodegenerative disease in the central nervous system (CNS), presenting with significant inter- and intra individual heterogeneity. The pathological hallmarks of active MS lesions are blood brain barrier (BBB) disruption, inflammation, and demyelination with axonal damage. Blood-based biomarkers reflecting tissue changes in immunology and/or neurobiology may reflect MS pathology and be easily accessible. The basement membrane (BM) is a specialized form of extracellular matrix (ECM), which is primarily composed of type IV collagen and modulated in inflammatory conditions.OBJECTIVEWe hypothesized that BM biomarkers, quantifying type IV collagen fragments, could be diagnostic blood-based biomarkers in patients with MS.METHODSA monoclonal antibody was raised against the cleavage site of canstatin, the C-terminal of type IV collagen-alpha-2 chain, and employed in an ELISA assay. The assay was developed, technically evaluated, and evaluated in serum from patients diagnosed with MS and compared to healthy donors. The assay was named CAN. To test the role of different blood-based biomarkers of type IV collagen in MS, we evaluated the CAN biomarker together with biomarkers of type IV collagen alpha-1 (C4M), type IV collagen alpha-3 (TUM), and type IV collagen 7S domain (PROC4) in serum from patients with MS and healthy donors.RESULTSThe type IV collagen biomarkers CAN, TUM, and PROC4 had significantly higher levels in MS patients compared to healthy donors (CAN: 7.4 ng/mL vs. 4.9 ng/mL, p = 0.0046; TUM: 2.0 ng/mL vs. 0.7 ng/mL, p < 0.0001; and PROC4: 248.4 ng/mL vs. 160.2 ng/mL, p = 0.0067). No difference were found for C4M. TUM presented the best diagnostic power with an AUC of 0.996.CONCLUSIONThese findings are exploratory and hypothesis generating, indicating type IV collagen plays a role in the basement membrane turnover found in MS lesions, and the different collagen chains have different expression levels. These findings need to be validated in larger cohorts and longitudinal studies.

01 Oct 2024·Biomedicine & Pharmacotherapy

Recombinant canstatin inhibits the progression of hepatocellular carcinoma by repressing the HIF-1α/VEGF signaling pathway

Article

Author: Guo, Zitao ; Xin, Yu ; Yang, Yuliang ; Zhu, Lingyu ; Wang, Zilong ; Ao, Long ; Gu, Zhenghua ; Zhou, Leyuan ; Zhang, Liang

Hepatocellular carcinoma (HCC), a hypervascular tumor, is the most frequent primary malignant tumor of the liver. Angiogenesis inhibitors, such as endogenous angiogenesis inhibitors, are essential for HCC therapy and have generated significant interest owing to their safety, efficacy, and multitargeting attributes. Canstatin is an angiogenesis inhibitor derived from the basement membrane and exerts anti-tumor effects. However, the inhibitory effects and underlying mechanisms of action of canstatin on HCC remain unclear. Therefore, in this study, HepG2 and Huh7 cells were used to investigate the inhibitory effects of recombinant canstatin on HCC cells. Subsequently, the biosafety and inhibitory effects of recombinant canstatin on tumor growth were investigated in a xenograft animal model of liver cancer. Canstatin inhibited the growth of liver cancer cells by regulating their proliferation, apoptosis, and migration. Additionally, it suppressed the occurrence and progression of HCC by modulating the HIF-1α/VEGF signaling pathway. In mice, canstatin exerted no discernible harmful side effects and suppressed the growth of HCC subcutaneous xenograft tumors. Overall, our findings shed light on the molecular pathways underlying canstatin-induced HCC cell death that may help develop novel HCC treatments.

01 Aug 2023·Matrix Biology

Peptide location fingerprinting identifies structural alterations within basement membrane components in ageing kidney

Article

Author: Morais, Mychel Rpt ; Eckersley, Alexander ; Ozols, Matiss ; Lennon, Rachel

During ageing, the glomerular and tubular basement membranes (BM) of the kidney undergo a progressive decline in function that is underpinned by histological changes, including glomerulosclerosis and tubular interstitial fibrosis and atrophy. This BM-specific ageing is thought to result from damage accumulation to long-lived extracellular matrix (ECM) protein structures. Determining which BM proteins are susceptible to these structure-associated changes, and the possible mechanisms and downstream consequences, is critical to understand age-related kidney degeneration and to identify markers for therapeutic intervention. Peptide location fingerprinting (PLF) is an emerging proteomic mass spectrometry analysis technique capable of identifying ECM proteins with structure-associated differences that may occur by damage modifications in ageing. Here, we apply PLF as a bioinformatic screening tool to identify BM proteins with structure-associated differences between young and aged human glomerular and tubulointerstitial compartments. Several functional regions within key BM components displayed alterations in tryptic peptide yield, reflecting potential age-dependent shifts in molecular (e.g. laminin-binding regions in agrin) and cellular (e.g. integrin-binding regions in laminins 521 and 511) interactions, oxidation (e.g. collagen IV) and the fragmentation and release of matrikines (e.g. canstatin and endostatin from collagens IV and XVIII). Furthermore, we found that periostin and the collagen IV α2 chain exhibited structure-associated differences in ageing that were conserved between human kidney and previously analysed mouse lung, revealing BM components that harbour shared susceptibilities across species and organs.

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