Uteroglobin and FLRG concentrations in aqueous humor are associated with age in primary open angle glaucoma patients

Briggs, Esther L. Ashworth; Toh, Tze’Yo; Eri, Rajaraman; Hewitt, Alex W.; Cook, Anthony

doi:10.1186/s12886-018-0723-4

Cited by 5 publications

(5 citation statements)

References 44 publications

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“…To date, uteroglobin has received little attention with respect to cardiac function and/or cardiovascular disease; however, loss of uteroglobin has been implicated in pulmonary inflammation and renal failure 87,88 . Further, uteroglobin is known to play an important role in combatting oxidative stress, which is known to be highly important with respect to heart failure 89,90 . Although this provides insight as to how ACVR2B/Fc may preserve cardiac function in more advanced metastatic CRC, we did not interrogate specific mechanisms of action, and thus, future studies should investigate specifically how ACVR2B/Fc administration may benefit cardiac function in models of cancer‐induced cardiac cachexia.…”

Section: Discussionmentioning

confidence: 94%

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

Huot

Narasimhan

et al. 2020

J cachexia sarcopenia muscle

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Background Advanced colorectal cancer (CRC) is often accompanied by the development of liver metastases, as well as cachexia, a multi-organ co-morbidity primarily affecting skeletal (SKM) and cardiac muscles. Activin receptor type 2B (ACVR2B) signalling is known to cause SKM wasting, and its inhibition restores SKM mass and prolongs survival in cancer. Using a recently generated mouse model, here we tested whether ACVR2B blockade could preserve multiple organs, including skeletal and cardiac muscle, in the presence of metastatic CRC. Methods NSG male mice (8 weeks old) were injected intrasplenically with HCT116 human CRC cells (mHCT116), while sham-operated animals received saline (n = 5-10 per group). Sham and tumour-bearing mice received weekly injections of ACVR2B/Fc, a synthetic peptide inhibitor of ACVR2B. Results mHCT116 hosts displayed losses in fat mass (À 79%, P < 0.0001), bone mass (À 39%, P < 0.05), and SKM mass (quadriceps: À 22%, P < 0.001), in line with reduced muscle cross-sectional area (À 24%, P < 0.01) and plantarflexion force (À 28%, P < 0.05). Further, despite only moderately affected heart size, cardiac function was significantly impaired (ejection fraction %: À 16%, P < 0.0001; fractional shortening %: À 25%, P < 0.0001) in the mHCT116 hosts. Conversely, ACVR2B/Fc preserved fat mass (+ 238%, P < 0.001), bone mass (+ 124%, P < 0.0001), SKM mass (quadriceps: + 31%, P < 0.0001), size (cross-sectional area: + 43%, P < 0.0001) and plantarflexion force (+ 28%, P < 0.05) in tumour hosts. Cardiac function was also completely preserved in tumour hosts receiving ACVR2B/Fc (ejection fraction %: + 19%, P < 0.0001), despite no effect on heart size. RNA sequencing analysis of heart muscle revealed rescue of genes related to cardiac development and contraction in tumour hosts treated with ACVR2B/Fc. Conclusions Our metastatic CRC model recapitulates the multi-systemic derangements of cachexia by displaying loss of fat, bone, and SKM along with decreased muscle strength in mHCT116 hosts. Additionally, with evidence of severe cardiac dysfunction, our data support the development of cardiac cachexia in the occurrence of metastatic CRC. Notably, ACVR2B antagonism preserved adipose tissue, bone, and SKM, whereas muscle and cardiac functions were completely maintained upon treatment. Altogether, our observations implicate ACVR2B signalling in the development of multi-organ perturbations in metastatic CRC and further dictate that ACVR2B represents a promising therapeutic target to preserve body composition and functionality in cancer cachexia.

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Section: Discussionmentioning

confidence: 94%

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

Huot

Narasimhan

et al. 2020

J cachexia sarcopenia muscle

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“…Inappropriate activation of the complement system is known to play a crucial role in many neurodegenerative diseases, such as multiple sclerosis [ 23 ] and Alzheimer’s disease [ 24 , 25 ]. Upregulated levels of complement proteins were also found in aqueous humour, sera, and retinas of patients with primary open-angle glaucoma [ 13 , 17 , 18 , 26 , 27 ]. Even if previous studies examined the role of the complement system in retinal diseases, the exact role is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Hypoxic Processes Induce Complement Activation via Classical Pathway in Porcine Neuroretinas

Mueller‐Buehl

Buehner

Pfarrer

et al. 2021

Cells

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Considering the fact that many retinal diseases are yet to be cured, the pathomechanisms of these multifactorial diseases need to be investigated in more detail. Among others, oxidative stress and hypoxia are pathomechanisms that take place in retinal diseases, such as glaucoma, age-related macular degeneration, or diabetic retinopathy. In consideration of these diseases, it is also evidenced that the immune system, including the complement system and its activation, plays an important role. Suitable models to investigate neuroretinal diseases are organ cultures of porcine retina. Based on an established model, the role of the complement system was studied after the induction of oxidative stress or hypoxia. Both stressors led to a loss of retinal ganglion cells (RGCs) accompanied by apoptosis. Hypoxia activated the complement system as noted by higher C3+ and MAC+ cell numbers. In this model, activation of the complement cascade occurred via the classical pathway and the number of C1q+ microglia was increased. In oxidative stressed retinas, the complement system had no consideration, but strong inflammation took place, with elevated TNF, IL6, and IL8 mRNA expression levels. Together, this study shows that hypoxia and oxidative stress induce different mechanisms in the porcine retina inducing either the immune response or an inflammation. Our findings support the thesis that the immune system is involved in the development of retinal diseases. Furthermore, this study is evidence that both approaches seem suitable models to investigate undergoing pathomechanisms of several neuroretinal diseases.

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“…However, the in vivo release confirms hydrolytic degradation as a main mechanism in alignment with a previous study [40,41] because collagenases might not exist sufficiently in the intraocular fluid. [42] Several biocompatible properties of SMP materials have been reported, even though these properties have not been fully investigated in glaucoma drainage devices: i) the SMP material was found to be safe in terms of excellent performance, with no evidence of toxic and immune-rejection upon implantation in rabbits, pigs, dogs, and rodents as reported previously. [34,[43][44][45] ii) The Korean Ministry of Food and Drug safety approved the use of SMP material for an eye device (i.e., nasolacrimal duct stent), c) The SMP+PCL ring was developed to address this issue as argon laser shots induced shape recovery of the ring by squeezing the silicone tube, while it was externally wrapped around the tube.…”

Section: Rescue Of Glaucomatous Rabbit Eyes By Smp Tubementioning

confidence: 85%

Laser‐Responsive Shape Memory Device to Program the Stepwise Control of Intraocular Pressure in Glaucoma

Lee

Choi

Kim

et al. 2023

Adv Funct Materials

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There is an unmet need in the glaucoma clinic to control changes in the intraocular pressure (IOP), i.e., patient‐specific hypotony and tissue fibrosis‐mediated ocular hypertension, owing to the fixed tube diameter of the glaucoma drainage device. As a potential solution, the tube diameter can be adjusted, depending on the IOP, by shape memory polymer (SMP) and clinical laser systems, which can control the energy level, focus, and frequency by minimizing untargeted influences. To develop a translatable device, a laser‐responsive SMP with two additional elements: i) a tube with an intimal gel coating to release 5‐fluorouracil as an anti‐fibrotic drug and ii) a safety lock ring to block late hypotony in special cases is employed. When the SMP tube is inserted into a silicone tube and wrapped externally by the ring, intimal gel degradation and argon laser‐triggered diameter increase enable a three‐step IOP control. Sustained drug release of the intimal gel suppresses tissue fibrosis, and the ring prevents late hypotony by externally squeezing the silicone tube. The advanced design and functions are validated using computational in vitro and rabbit glaucoma models by determining clinic‐friendly argon laser parameters.

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Uteroglobin and FLRG concentrations in aqueous humor are associated with age in primary open angle glaucoma patients

Cited by 5 publications

References 44 publications

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

Hypoxic Processes Induce Complement Activation via Classical Pathway in Porcine Neuroretinas

Laser‐Responsive Shape Memory Device to Program the Stepwise Control of Intraocular Pressure in Glaucoma

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