Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma

Sahay, Prity; Rao, Aparna; Padhy, Debananda; Sarangi, Sarada; Das, Gopinath; Reddy, Mamatha M.; Modak, Rahul

doi:10.1167/iovs.17-21723

Cited by 50 publications

(56 citation statements)

References 16 publications

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“…The posterior particles gelling would hinder the drug diffusion from its inner core to the release media leading to a low release fashion extended for three additional days [76,77]. In vitro release studies were also performed in media containing protease or MMP-2 at the equivalent concentrations observed on the ocular surface in glaucomatous patients suffering inflammation events [53][54][55]. According to our data, these nanoparticles were resistant to these media, being able to protect the active compound and to progressively release it even at these conditions, probably due to the high density of the crosslinked gelatin matrix [78].…”

Section: Discussionmentioning

confidence: 99%

“…Formulations were physicochemically characterized. In order to mimic ocular surface conditions, the in vitro release tests were performed with proteases or metalloproteinase-2 (MMP-2) in the release media, which are enzymes typically present in the eye of glaucomatous patients [53][54][55]. These results were compared with conventional release studies performed with plain PBS solutions.…”

Section: Introductionmentioning

confidence: 99%

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Gelatin Nanoparticles-HPMC Hybrid System for Effective Ocular Topical Administration of Antihypertensive Agents

et al. 2020

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The increment in ocular drug bioavailability after topical administration is one of the main challenges in pharmaceutical technology. For several years, different strategies based on nanotechnology, hydrogels or implants have been evaluated. Nowadays, the tolerance of ophthalmic preparations has become a critical issue and it is essential to the use of well tolerated excipients. In the present work, we have explored the potential of gelatin nanoparticles (GNPs) loaded with timolol maleate (TM), a beta-adrenergic blocker widely used in the clinic for glaucoma treatment and a hybrid system of TM-GNPs included in a hydroxypropyl methylcellulose (HPMC) viscous solution. The TM- loaded nanoparticles (mean particle size of 193 ± 20 nm and drug loading of 0.291 ± 0.019 mg TM/mg GNPs) were well tolerated both in vitro (human corneal cells) and in vivo. The in vivo efficacy studies performed in normotensive rabbits demonstrated that these gelatin nanoparticles were able to achieve the same hypotensive effect as a marketed formulation (0.5% TM) containing a 5-fold lower concentration of the drug. When comparing commercial and TM-GNPs formulations with the same TM dose, nanoparticles generated an increased efficacy with a significant (p < 0.05) reduction of intraocular pressure (IOP) (from 21% to 30%) and an augmentation of 1.7-fold in the area under the curve (AUC)(0–12h). On the other hand, the combination of timolol-loaded nanoparticles (TM 0.1%) and the viscous polymer HPMC 0.3%, statistically improved the IOP reduction up to 30% (4.65 mmHg) accompanied by a faster time of maximum effect (tmax = 1 h). Furthermore, the hypotensive effect was extended for four additional hours, reaching a pharmacological activity that lasted 12 h after a single instillation of this combination, and leading to an AUC(0–12h) 2.5-fold higher than the one observed for the marketed formulation. According to the data presented in this work, the use of hybrid systems that combine well tolerated gelatin nanoparticles and a viscous agent could be a promising alternative in the management of high intraocular pressure in glaucoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gelatin Nanoparticles-HPMC Hybrid System for Effective Ocular Topical Administration of Antihypertensive Agents

et al. 2020

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“… A number of studies have found that MMP‐9 in biologic fluids, such as blood, urine, synovial fluid, and gingival crevicular fluid, are a diagnostic marker of local and systemic diseases including cardiovascular diseases; pulmonary disease; rheumatoid arthritis; and osteoarthritis; ophthalmologic diseases such as cataracts and glaucoma; sepsis and mortality; and periodontitis …”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have found that MMP-9 in biologic fluids, such as blood, urine, synovial fluid, and gingival crevicular fluid, are a diagnostic marker of local and systemic diseases including cardiovascular diseases 2,3,19,20 ; pulmonary disease 18,21 ; rheumatoid arthritis; and osteoarthritis [22][23][24] ; ophthalmologic diseases such as cataracts and glaucoma 25,26 ; sepsis and mortality 27 ; and periodontitis. 28 MMP-9 is now known to have multiple biological effects beyond its originally recognized ability to degrade denatured collagen fragments (gelatin) and basement membrane (type IV) collagen.…”

Section: Discussionmentioning

confidence: 99%

Loss of alveolar bone density in postmenopausal, osteopenic women is associated with circulating levels of gelatinases

Thompson

Lee

Stoner

et al. 2019

J of Periodontal Research

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Objective To determine whether circulating levels of two matrix metalloproteinases, MMP‐2 and MMP‐9, are associated with loss of alveolar bone density (ABD) or height (ABH), or with progression of periodontitis (relative clinical attachment level [RCAL]), among postmenopausal women with local and systemic bone loss. Background This study was planned as part of a 2‐year randomized, double‐blind, placebo‐controlled, clinical trial examining efficacy/safety of subantimicrobial dose doxycycline (20 mg bid) in postmenopausal osteopenic women. This study examines whether serum levels of gelatinases are associated with local changes in the periodontium. Methods A sample of 113 women received periodontal maintenance for moderate to advanced chronic periodontitis and consented to analysis of stored serum biomarkers. Posterior vertical bitewings were taken, and serum collected, at baseline, one, and 2 years. ABD was determined by computer‐assisted densitometric image analysis (CADIA), ABH by the Hausmann et al (1992, J Periodontol 63, 657) method, and RCAL by Florida Probe (every 6 months). MMPs were measured densitometrically on gelatin zymograms using denatured type I collagen as substrate and purified MMP‐2 (72 kDa) and MMP‐9 (92 kDa) as standards. Evidence of worsening in the periodontium at a tooth site was defined as a change from baseline of, for ABD, at least 14 densitometric units (for subcrestal locations) or 17 units (for crestal locations); of at least 0.4 mm for ABH; and of at least 1.5 mm for RCAL. Logistic regression models, while accounting for clustering, compared the odds of worsening in ABD, ABH, or RCAL, after 2 years of observation, between groups defined by baseline and concurrent levels of serum gelatinases. Results Changes in ABH and RCAL were not associated with circulating levels of MMP‐2 or MMP‐9. However, elevated odds of ABD loss over 24 months were associated, among smokers, with both baseline and concurrent levels of MMP‐9 in the middle and highest tertile, and with concurrent levels of MMP‐2 in the middle (but not the highest) tertile. Elevated odds of ABD loss were also associated, among women within 5 years of menopause, with baseline levels of MMP‐2 in the highest tertile. Conclusion Among postmenopausal osteopenic women, loss of ABD was associated, in smokers, with elevated circulating levels of MMP‐9 and MMP‐2. In those within 5 years of menopause, ABD loss was associated with elevated circulating levels of MMP‐2.

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“…Our earlier study on HTM cell lines showed de nite morphological differences apart from differential MMP expressions with varying time period of exposure to oxidative stress re ecting that cell death mechanisms may be different with different severity of the insult. 23 Yet, the exact molecular mechanisms in-vivo regulating cell death/functioning in the TM tissue at different stages of glaucoma is not yet elucidated.This study explores the differential role of cell death process in the TM in different stages of glaucoma.…”

Section: Introductionmentioning

confidence: 99%

Switch to autophagy the key mechanism for trabecular meshwork death in severe glaucoma.

Rao¹,

Sahay

Chakraborty³

et al. 2020

Preprint

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Background The key differences in cell deathmechanisms in the trabecular meshwork (TM) in adult moderate and severe primary glaucoma remain still unanswered. This studyexplored key differences in cell deathmechanisms in the trabecular meshwork (TM) in adult moderate and severe primary glaucoma. Methods Select cell death related proteins differentially expressed on mass spectrometric analysis in ex-vivo dissected TM specimens patients with severe adult primary open angle (POAG) or angle closure glaucoma (PACG) compared to controls (cadaver donor cornea), were validated for temporal changes in cell death related gene expression on in-vitro primary human TM cell culture after 48 hours (moderate) or 72 hours (severe) oxidative stress with H2O2 (400-1000uM concentration). These were compared with histone modifications after oxidative stress in HTM culture and peripheral blood of patients with moderate and severe glaucoma. Results Autophagy related proteins seemed to be the predominant cell death mechanism over apoptosis in ex-vivo dissected TM specimens in severe glaucoma. Analyzing HTM cell gene expression at 48 hrs and 72 hours of oxidative stress, autophagy genes were up-regulated at 48 hours of exposure > 72 hours which was in contrast to apoptosis related genes showing down-regulation at 72 hours. There was corresponding preferential abrupt upregulation of autophagy genes in the peripheral blood of the patients with severe glaucoma with associated increased expression of H3K14ac in HTM after 72 hrs of oxidative stress and in peripheral blood of severe POAG and PACG patients. Necrosis seemed to play a minimal role in cell death in moderate or severe stress in cell lines or peripheral blood. Conclusion A preference of autophagy over apoptosis may be underlie the mechanism of stage transition from moderate to severe glaucoma in the trabecular meshwork or peripheral blood which may be tightly regulated by epigenetic modulators. Associated epigenetic control mediating the unidirectional upregulation of autophagy in severe glaucoma requires to be explored.

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Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma

Cited by 50 publications

References 16 publications

Gelatin Nanoparticles-HPMC Hybrid System for Effective Ocular Topical Administration of Antihypertensive Agents

Gelatin Nanoparticles-HPMC Hybrid System for Effective Ocular Topical Administration of Antihypertensive Agents

Loss of alveolar bone density in postmenopausal, osteopenic women is associated with circulating levels of gelatinases

Switch to autophagy the key mechanism for trabecular meshwork death in severe glaucoma.

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