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Article ; Online: TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties.

Day, Anthony J / Milner, Caroline M

Matrix biology : journal of the International Society for Matrix Biology

2018 Volume 78-79, Page(s) 60–83

Abstract: Tumor necrosis factor- (TNF) stimulated gene-6 (TSG-6) is an inflammation-associated secreted protein that has been implicated as having important and diverse tissue protective and anti-inflammatory properties, e.g. mediating many of the immunomodulatory ...

Abstract	Tumor necrosis factor- (TNF) stimulated gene-6 (TSG-6) is an inflammation-associated secreted protein that has been implicated as having important and diverse tissue protective and anti-inflammatory properties, e.g. mediating many of the immunomodulatory and beneficial activities of mesenchymal stem/stromal cells. TSG-6 is constitutively expressed in some tissues, which are either highly metabolically active or subject to challenges from the environment, perhaps providing protection in these contexts. The diversity of its functions are dependent on the binding of TSG-6 to numerous ligands, including matrix molecules such as glycosaminoglycans, as well as immune regulators and growth factors that themselves interact with these linear polysaccharides. It is becoming apparent that TSG-6 can directly affect matrix structure and modulate the way extracellular signalling molecules interact with matrix. In this review, we focus mainly on the literature for TSG-6 over the last 10 years, summarizing its expression, structure, ligand-binding properties, biological functions and highlighting TSG-6's potential as a therapeutic for a broad range of disease indications.
MeSH term(s)	Animals ; Cell Adhesion Molecules/chemistry ; Cell Adhesion Molecules/metabolism ; Extracellular Matrix/metabolism ; Glycosaminoglycans/metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Mesenchymal Stem Cells/immunology ; Models, Molecular ; Protein Binding ; Protein Conformation ; Signal Transduction
Chemical Substances	Cell Adhesion Molecules ; Glycosaminoglycans ; Intercellular Signaling Peptides and Proteins ; TNFAIP6 protein, human
Language	English
Publishing date	2018-01-31
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2018.01.011
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Zs.A 1694: Show issues

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Article ; Online: Inter-alpha-trypsin inhibitor (IαI) and hyaluronan modifications enhance the innate immune response to influenza virus in the lung.

Tang, Fengying / Reeves, Stephen R / Brune, Jourdan E / Chang, Mary Y / Chan, Christina K / Waldron, Peter / Drummond, Sheona P / Milner, Caroline M / Alonge, Kimberly M / Garantziotis, Stavros / Day, Anthony J / Altemeier, William A / Frevert, Charles W

Matrix biology : journal of the International Society for Matrix Biology

2024 Volume 126, Page(s) 25–42

Abstract: The inter-alpha-trypsin inhibitor (IαI) complex is composed of the bikunin core protein with a single chondroitin sulfate (CS) attached and one or two heavy chains (HCs) covalently linked to the CS chain. The HCs from IαI can be transferred to hyaluronan ...

Abstract	The inter-alpha-trypsin inhibitor (IαI) complex is composed of the bikunin core protein with a single chondroitin sulfate (CS) attached and one or two heavy chains (HCs) covalently linked to the CS chain. The HCs from IαI can be transferred to hyaluronan (HA) through a TNFα-stimulated gene-6 (TSG-6) dependent process to form an HC•HA matrix. Previous studies reported increased IαI, HA, and HC•HA complexes in mouse bronchoalveolar lavage fluid (BALF) post-influenza infection. However, the expression and incorporation of HCs into the HA matrix of the lungs during the clinical course of influenza A virus (IAV) infection and the biological significance of the HC•HA matrix are poorly understood. The present study aimed to better understand the composition of HC•HA matrices in mice infected with IAV and how these matrices regulate the host pulmonary immune response. In IAV infected mice bikunin, HC1-3, TSG-6, and HAS1-3 all show increased gene expression at various times during a 12-day clinical course. The increased accumulation of IαI and HA was confirmed in the lungs of infected mice using immunohistochemistry and quantitative digital pathology. Western blots confirmed increases in the IαI components in BALF and lung tissue at 6 days post-infection (dpi). Interestingly, HCs and bikunin recovered from BALF and plasma from mice 6 dpi with IAV, displayed differences in the HC composition by Western blot analysis and differences in bikunin's CS chain sulfation patterns by mass spectrometry analysis. This strongly suggests that the IαI components were synthesized in the lungs rather than translocated from the vascular compartment. HA was significantly increased in BALF at 6 dpi, and the HA recovered in BALF and lung tissues were modified with HCs indicating the presence of an HC•HA matrix. In vitro experiments using polyinosinic-polycytidylic acid (poly(I:C)) treated mouse lung fibroblasts (MLF) showed that modification of HA with HCs increased cell-associated HA, and that this increase was due to the retention of HA in the MLF glycocalyx. In vitro studies of leukocyte adhesion showed differential binding of lymphoid (Hut78), monocyte (U937), and neutrophil (dHL60) cell lines to HA and HC•HA matrices. Hut78 cells adhered to immobilized HA in a size and concentration-dependent manner. In contrast, the binding of dHL60 and U937 cells depended on generating a HC•HA matrix by MLF. Our in vivo findings, using multiple bronchoalveolar lavages, correlated with our in vitro findings in that lymphoid cells bound more tightly to the HA-glycocalyx in the lungs of influenza-infected mice than neutrophils and mononuclear phagocytes (MNPs). The neutrophils and MNPs were associated with a HC•HA matrix and were more readily lavaged from the lungs. In conclusion, this work shows increased IαI and HA accumulation and the formation of a HC•HA matrix in mouse lungs post-IAV infection. The formation of HA and HC•HA matrices could potentially create specific microenvironments in the lungs for immune cell recruitment and activation during IAV infection.
MeSH term(s)	Mice ; Animals ; Humans ; Hyaluronic Acid/metabolism ; Influenza, Human ; Chondroitin Sulfates/metabolism ; Lung/metabolism ; Orthomyxoviridae/metabolism ; Immunity, Innate ; Disease Progression ; Alpha-Globulins
Chemical Substances	inter-alpha-inhibitor (39346-44-6) ; Hyaluronic Acid (9004-61-9) ; Chondroitin Sulfates (9007-28-7) ; Alpha-Globulins
Language	English
Publishing date	2024-01-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2024.01.004
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Zs.A 1694: Show issues

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Article ; Online: The recombinant Link module of human TSG-6 suppresses cartilage damage in models of osteoarthritis: A potential disease-modifying OA drug.

Drummond, Sheona P / Bartnik, Eckart / Kouvatsos, Nikolaos / Scott, Jenny L / Dyer, Douglas P / Thomson, Jennifer M / Price, Andrew J / Anand, Sanjay / Biant, Leela C / Leeuw, Thomas / Herrmann, Matthias / Milner, Caroline M / Day, Anthony J

Osteoarthritis and cartilage

2023 Volume 31, Issue 10, Page(s) 1353–1364

Abstract: Objective: To investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA.: Design: Knee articular cartilages from OA ... ...

Abstract	Objective: To investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA. Design: Knee articular cartilages from OA patients were analyzed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module (Link_TSG6) on cytokine-induced degradation of OA cartilage explants were compared. Human mesenchymal stem/stromal cell-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β-, or TNF-stimulated ADAMTS4, ADAMTS5, and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model; cartilage damage and tactile allodynia were assessed. Results: TSG-6 is predominantly associated with chondrocytes in regions of cartilage damage where high TSG-6 expression aligns with low MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants;>50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Link_TSG6 also displayed more potent effects in 3D pellet cultures, suppressing ADAMTS4, ADAMTS5, and MMP13 gene expression, which was consistent with reduced aggrecanase and collagenase activities in explant cultures. Link_TSG6 treatment reduced touch-evoked pain behavior and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA. Conclusions: Link_TSG6 has enhanced chondroprotective activity compared to the full-length TSG-6 protein and shows potential as a disease modifying OA drug via its inhibition of aggrecanase and collagenase activity.
MeSH term(s)	Humans ; Rats ; Animals ; Matrix Metalloproteinase 13/genetics ; Matrix Metalloproteinase 13/metabolism ; Osteoarthritis/drug therapy ; Osteoarthritis/metabolism ; Chondrocytes/metabolism ; Cartilage, Articular/metabolism ; RNA, Messenger/metabolism
Chemical Substances	Matrix Metalloproteinase 13 (EC 3.4.24.-) ; RNA, Messenger
Language	English
Publishing date	2023-05-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1167809-4
ISSN	1522-9653 ; 1063-4584
ISSN (online)	1522-9653
ISSN	1063-4584
DOI	10.1016/j.joca.2023.05.013
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Zs.A 3828: Show issues

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Article ; Online: A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.

Weemering, Daphne N / Midei, Mark / Milner, Peter / Gopalakrishnan, Vidhya / Kumar, Anil / Dannenberg, Andrew J / Bunte, Tommy M / Foucher, Juliette / Ingre, Caroline / Ķēniņa, Viktorija / Rallmann, Karin / van den Berg, Leonard H / van Eijk, Ruben P A

European journal of neurology

2023 Volume 30, Issue 12, Page(s) 3722–3731

Abstract: Background and purpose: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS).! ...

Abstract	Background and purpose: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Methods: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration. Results: In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed. Conclusions: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/diagnosis ; Linoleic Acids/therapeutic use ; Double-Blind Method ; Treatment Outcome
Chemical Substances	RT001 ; Linoleic Acids
Language	English
Publishing date	2023-08-21
Publishing country	England
Document type	Randomized Controlled Trial ; Multicenter Study ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	1280785-0
ISSN	1468-1331 ; 1351-5101 ; 1471-0552
ISSN (online)	1468-1331
ISSN	1351-5101 ; 1471-0552
DOI	10.1111/ene.16020
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Zs.A 4738: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The Link module of human TSG-6 (Link_TSG6) promotes wound healing, suppresses inflammation and improves glandular function in mouse models of Dry Eye Disease.

Oh, Joo Youn / Ryu, Jin Suk / Kim, Hyeon Ji / Kouvatsos, Nikolaos / Dodd, Rebecca J / Choi, Se Hyun / Kim, Yu Jeong / Milner, Caroline M / Day, Anthony J

The ocular surface

2021 Volume 24, Page(s) 40–50

Abstract: Purpose: To investigate the potential of the Link_TSG6 polypeptide comprising the Link module of human TSG-6 (TNF-stimulated gene/protein-6) as a novel treatment for dry eye disease (DED).: Methods: We analyzed the therapeutic effects of topical ... ...

Abstract	Purpose: To investigate the potential of the Link_TSG6 polypeptide comprising the Link module of human TSG-6 (TNF-stimulated gene/protein-6) as a novel treatment for dry eye disease (DED). Methods: We analyzed the therapeutic effects of topical application of Link_TSG6 in two murine models of DED, the NOD.B10.H2 Results: Topical Link_TSG6 administration dose-dependently reduced corneal epithelial defects in DED mice while increasing tear production and conjunctival goblet cell density. At the highest dose, no corneal lesions remained in ∼50% of eyes treated. Also, Link_TSG6 significantly suppressed the levels of inflammatory cytokines at the ocular surface and inhibited the infiltration of T cells in the lacrimal glands and draining lymph nodes. Link_TSG6 was more effective in decreasing corneal epithelial defects than an equimolar concentration of FL_TSG6. Link_TSG6 was significantly more potent than Restasis® at ameliorating clinical signs and reducing inflammation. Link_TSG6 markedly and rapidly facilitated epithelial healing in mice with corneal epithelial debridement wounds. Conclusion: Link_TSG6 holds promise as a novel therapeutic agent for DED through its effects on the promotion of corneal epithelial healing and tear secretion, the preservation of conjunctival goblet cells and the suppression of inflammation.
MeSH term(s)	Animals ; Cell Adhesion Molecules ; Cyclosporine ; Disease Models, Animal ; Dry Eye Syndromes/drug therapy ; Dry Eye Syndromes/pathology ; Humans ; Inflammation/drug therapy ; Mice ; Mice, Inbred NOD ; Tears ; Wound Healing
Chemical Substances	Cell Adhesion Molecules ; Tnfaip6 protein, mouse ; Cyclosporine (83HN0GTJ6D)
Language	English
Publishing date	2021-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2208578-6
ISSN	1937-5913 ; 1542-0124
ISSN (online)	1937-5913
ISSN	1542-0124
DOI	10.1016/j.jtos.2021.12.012
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Zs.A 6458: Show issues

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Article: Oocyte-specific ablation of N- and O-glycans alters cumulus cell signalling and extracellular matrix composition.

Lo, Belinda K M / Archibong-Omon, Agnes / Ploutarchou, Panayiota / Day, Anthony J / Milner, Caroline M / Williams, Suzannah A

Reproduction, fertility, and development

2018 Volume 31, Issue 3, Page(s) 529–537

Abstract: Cumulus-oocyte complex (COC) expansion is essential for ovulation and fertilisation and is linked to oocyte quality. Hyaluronan (HA), the major matrix constituent, is cross-linked via inter-α-inhibitor heavy chains (HCs), pentraxin 3 (PTX3) and tumour ... ...

Abstract	Cumulus-oocyte complex (COC) expansion is essential for ovulation and fertilisation and is linked to oocyte quality. Hyaluronan (HA), the major matrix constituent, is cross-linked via inter-α-inhibitor heavy chains (HCs), pentraxin 3 (PTX3) and tumour necrosis factor-stimulated gene 6 (TSG-6). All except HCs are secreted by cumulus cells in response to oocyte-secreted factors, which signal via SMAD pathways. The double mutant (DM) mouse generates oocytes lacking complex N- and O-glycans due to oocyte-specific deletion of core 1 β1,3-galactosyltransferase (C1galt1) and N-acetylglucosaminyltransferase I (Mgat1) and has modified cumulus expansion. We compared COCs before expansion (48 h-post-pregnant mare serum gonadotrophin (PMSG)) and at late-stage expansion (9 h-post-human chorionic gonadotrophin (hCG); control n=3 mice, DM n=3 per group). Using histochemistry the levels of HA, HCs, PTX3, TSG-6 and phosphorylated-SMAD1/5/8 and -SMAD2 (12-25 COCs per group) were assessed. DM COCs did not differ from Controls in cumulus size or cell density at 9 h-post-hCG; however, HA and HC levels and phosphorylated-SMAD1/5/8 were reduced. Furthermore, no correlations were found between the levels of matrix molecules and cumulus area in DM or Control samples. These data suggest that HA and HCs can support cumulus expansion provided that they are present above minimum threshold levels. We propose that oocyte-specific ablation of C1galt1 and Mgat1 may affect bone morphogenetic protein 15 synthesis or bioactivity, thereby reducing SMAD1/5/8 phosphorylation and HA production.
MeSH term(s)	Animals ; Cumulus Cells/metabolism ; Extracellular Matrix/metabolism ; Female ; Mice ; Oocytes/metabolism ; Ovarian Follicle/metabolism ; Ovulation/metabolism ; Phosphorylation ; Polysaccharides/genetics ; Polysaccharides/metabolism ; Signal Transduction/physiology
Chemical Substances	Polysaccharides
Language	English
Publishing date	2018-10-29
Publishing country	Australia
Document type	Journal Article
ZDB-ID	1019913-5
ISSN	1448-5990 ; 1031-3613
ISSN (online)	1448-5990
ISSN	1031-3613
DOI	10.1071/RD18209
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Zs.A 2756: Show issues

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Article ; Online: Inter-α-inhibitor heavy chain-1 has an integrin-like 3D structure mediating immune regulatory activities and matrix stabilization during ovulation.

Briggs, David C / Langford-Smith, Alexander W W / Birchenough, Holly L / Jowitt, Thomas A / Kielty, Cay M / Enghild, Jan J / Baldock, Clair / Milner, Caroline M / Day, Anthony J

The Journal of biological chemistry

2020 Volume 295, Issue 16, Page(s) 5278–5291

Abstract: Inter-α-inhibitor is a proteoglycan essential for mammalian reproduction and also plays a less well-characterized role in inflammation. It comprises two homologous "heavy chains" (HC1 and HC2) covalently attached to chondroitin sulfate on the bikunin ... ...

Abstract	Inter-α-inhibitor is a proteoglycan essential for mammalian reproduction and also plays a less well-characterized role in inflammation. It comprises two homologous "heavy chains" (HC1 and HC2) covalently attached to chondroitin sulfate on the bikunin core protein. Before ovulation, HCs are transferred onto the polysaccharide hyaluronan (HA) to form covalent HC·HA complexes, thereby stabilizing an extracellular matrix around the oocyte required for fertilization. Additionally, such complexes form during inflammatory processes and mediate leukocyte adhesion in the synovial fluids of arthritis patients and protect against sepsis. Here using X-ray crystallography, we show that human HC1 has a structure similar to integrin β-chains, with a von Willebrand factor A domain containing a functional metal ion-dependent adhesion site (MIDAS) and an associated hybrid domain. A comparison of the WT protein and a variant with an impaired MIDAS (but otherwise structurally identical) by small-angle X-ray scattering and analytical ultracentrifugation revealed that HC1 self-associates in a cation-dependent manner, providing a mechanism for HC·HA cross-linking and matrix stabilization. Surprisingly, unlike integrins, HC1 interacted with RGD-containing ligands, such as fibronectin, vitronectin, and the latency-associated peptides of transforming growth factor β, in a MIDAS/cation-independent manner. However, HC1 utilizes its MIDAS motif to bind to and inhibit the cleavage of complement C3, and small-angle X-ray scattering-based modeling indicates that this occurs through the inhibition of the alternative pathway C3 convertase. These findings provide detailed structural and functional insights into HC1 as a regulator of innate immunity and further elucidate the role of HC·HA complexes in inflammation and ovulation.
MeSH term(s)	Alpha-Globulins/chemistry ; Extracellular Matrix/metabolism ; Humans ; Immunity, Innate ; Integrin beta Chains/chemistry ; Molecular Dynamics Simulation ; Ovulation ; Protein Domains ; von Willebrand Factor/chemistry
Chemical Substances	Alpha-Globulins ; Integrin beta Chains ; von Willebrand Factor ; inter-alpha-inhibitor (39346-44-6)
Language	English
Publishing date	2020-03-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.011916
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Uc I Zs.108: Show issues

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Article ; Online: Cost-Utility Analysis of Total Ankle Replacement Compared with Ankle Arthrodesis for Patients Aged 50-85 Years with End-Stage Ankle Osteoarthritis: The TARVA Study.

PharmacoEconomics - open

2024 Volume 8, Issue 2, Page(s) 235–249

Abstract: Background: Patients with end-stage ankle osteoarthritis suffer from reduced mobility and quality of life and the main surgical treatments are total ankle replacement (TAR) and ankle fusion (AF).: Objectives: Our aim was to calculate the mean ... ...

Abstract	Background: Patients with end-stage ankle osteoarthritis suffer from reduced mobility and quality of life and the main surgical treatments are total ankle replacement (TAR) and ankle fusion (AF). Objectives: Our aim was to calculate the mean incremental cost per quality-adjusted life-year (QALY) of TAR compared with AF in patients with end-stage ankle osteoarthritis, over 52 weeks and over the patients' lifetime. Method: We conducted a cost-utility analysis of 282 participants from 17 UK centres recruited to a randomised controlled trial (TARVA). QALYs were calculated using index values from EQ-5D-5L. Resource use information was collected from case report forms and self-completed questionnaires. Primary analysis was within-trial analysis from the National Health Service (NHS) and Personal Social Services (PSS) perspective, while secondary analyses were within-trial analysis from wider perspective and long-term economic modelling. Adjustments were made for baseline resource use and index values. Results: Total cost at 52 weeks was higher in the TAR group compared with the AF group, from the NHS and PSS perspective (mean adjusted difference £2539, 95% confidence interval [CI] £1142, £3897). The difference became very small from the wider perspective (£155, 95% CI - £1947, £2331). There was no significant difference between TAR and AF in terms of QALYs (mean adjusted difference 0.02, 95% CI - 0.015, 0.05) at 52 weeks post-operation. The incremental cost-effectiveness ratio (ICER) was £131,999 per QALY gained 52 weeks post-operation. Long-term economic modelling resulted in an ICER of £4200 per QALY gained, and there is a 69% probability of TAR being cost effective at a cost-effectiveness threshold of £20,000 per QALY gained. Conclusion: TAR does not appear to be cost effective over AF 52 weeks post-operation. A decision model suggests that TAR can be cost effective over the patients' lifetime but there is a need for longer-term prospectively collected data. Clinical trial registration ISRCTN60672307 and ClinicalTrials.gov NCT02128555.
Language	English
Publishing date	2024-01-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2874287-4
ISSN	2509-4254 ; 2509-4262
ISSN (online)	2509-4254
ISSN	2509-4262
DOI	10.1007/s41669-023-00449-4
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Article ; Online: Molecular analysis of the cumulus matrix: insights from mice with O-glycan-deficient oocytes.

Ploutarchou, Panayiota / Melo, Pedro / Day, Anthony J / Milner, Caroline M / Williams, Suzannah A

Reproduction (Cambridge, England)

2015 Volume 149, Issue 5, Page(s) 533–543

Abstract: During follicle development, oocytes secrete factors that influence the development of granulosa and cumulus cells (CCs). In response to oocyte and somatic cell signals, CCs produce extracellular matrix (ECM) molecules resulting in cumulus expansion, ... ...

Abstract	During follicle development, oocytes secrete factors that influence the development of granulosa and cumulus cells (CCs). In response to oocyte and somatic cell signals, CCs produce extracellular matrix (ECM) molecules resulting in cumulus expansion, which is essential for ovulation, fertilisation, and is predictive of oocyte quality. The cumulus ECM is largely made up of hyaluronan (HA), TNF-stimulated gene-6 (TSG-6, also known as TNFAIP6), pentraxin-3 (PTX3), and the heavy chains (HCs) of serum-derived inter-α-inhibitor proteins. In contrast to other in vivo models where modified expansion impairs fertility, the cumulus mass of C1galt1 Mutants, which have oocyte-specific deletion of core 1-derived O-glycans, is modified without impairing fertility. In this report, we used C1galt1 Mutant (C1galt1(FF):ZP3Cre) and Control (C1galt1(FF)) mice to investigate how cumulus expansion is affected by oocyte-specific deletion of core 1-derived O-glycans without adversely affecting oocyte quality. Mutant cumulus-oocyte complexes (COCs) are smaller than Controls, with fewer CCs. Interestingly, the CCs in Mutant mice are functionally normal as each cell produced normal levels of the ECM molecules HA, TSG-6, and PTX3. However, HC levels were elevated in Mutant COCs. These data reveal that oocyte glycoproteins carrying core 1-derived O-glycans have a regulatory role in COC development. In addition, our study of Controls indicates that a functional COC can form provided all essential components are present above a minimum threshold level, and thus some variation in ECM composition does not adversely affect oocyte development, ovulation or fertilisation. These data have important implications for IVF and the use of cumulus expansion as a criterion for oocyte assessment.
MeSH term(s)	Animals ; Cells, Cultured ; Cumulus Cells/cytology ; Cumulus Cells/metabolism ; Extracellular Matrix/metabolism ; Female ; Fertilization ; Galactosyltransferases/physiology ; Immunoenzyme Techniques ; Mice ; Mice, Knockout ; Oocytes/cytology ; Oocytes/metabolism ; Ovarian Follicle/cytology ; Ovarian Follicle/metabolism ; Ovulation/physiology ; Polysaccharides/deficiency ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction
Chemical Substances	Polysaccharides ; RNA, Messenger ; C1galt1 protein, mouse (EC 2.4.1.-) ; Galactosyltransferases (EC 2.4.1.-)
Language	English
Publishing date	2015-03-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2034501-X
ISSN	1741-7899 ; 1470-1626 ; 1476-3990
ISSN (online)	1741-7899
ISSN	1470-1626 ; 1476-3990
DOI	10.1530/REP-14-0503
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Collision-induced dissociation of halide ion-arginine complexes: evidence for anion-induced zwitterion formation in gas-phase arginine.

Milner, Edward M / Nix, Michael G D / Dessent, Caroline E H

The journal of physical chemistry. A

2012 Volume 116, Issue 2, Page(s) 801–809

Abstract: We report the first low-energy collisional-induced dissociation studies of the X(-)·arginine (X(-) = F(-), Cl(-), Br(-), I(-), NO(3)(-), ClO(3)(-)) series of clusters to investigate the novel phenomenom of anion-induced zwitterion formation in a gas- ... ...

Abstract	We report the first low-energy collisional-induced dissociation studies of the X(-)·arginine (X(-) = F(-), Cl(-), Br(-), I(-), NO(3)(-), ClO(3)(-)) series of clusters to investigate the novel phenomenom of anion-induced zwitterion formation in a gas-phase amino acid. Fragmentation of the small halide ion clusters (F(-)·arginine and Cl(-)·arginine) is dominated by deprotonation of the arginine, whereas the major fragmentation channel for the largest ion clusters (I(-)·arginine and ClO(3)(-)·arginine) corresponds to simple cluster fission into the ion and neutral molecule. However, the fragmentation profiles of Br(-)·arginine and NO(3)(-)·arginine, display distinctive features that are consistent with the presence of the zwitterionic form of the amino acid in these clusters. The various dissociation pathways have been studied as a function of % collision energy and are discussed in comparison to the fragmentation profiles of protonated and deprotonated arginine. Electronic structure calculations are presented for Br(-)·arginine to support the presence of the zwitterionic amino acid in this complex. The results obtained in this work provide important information on the low-energy potential energy surfaces of these anion-amino acid clusters and reveal the presence of several overlapping surfaces in the low-energy region for the Br(-)·arginine and NO(3)(-)·arginine systems.
MeSH term(s)	Anions/chemistry ; Arginine/chemistry ; Gases/chemistry ; Halogens/chemistry ; Nitrates/chemistry ; Quantum Theory
Chemical Substances	Anions ; Gases ; Halogens ; Nitrates ; Arginine (94ZLA3W45F)
Language	English
Publishing date	2012-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5215
ISSN (online)	1520-5215
DOI	10.1021/jp208183p
Database	MEDical Literature Analysis and Retrieval System OnLINE

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