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Review Article
*Corresponding Author: Asaad A. Ghanem, Mansoura Ophthalmic Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Citation: Asaad A. Ghanem, Ahmed A. Ghanem and Tharwat H. Mokbel (2022). Biomarkers in Primary Open Angle Glaucoma, Part II: A Review. J. Experimental and Clinical Ophthalmology. 2(1). DOI: 10.31579/eco.2022/007
Copyright: ©2022. Asaad A. Ghanem this is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 05 April 2022 | Accepted: 16 May 2022 | Published: 30 May 2022
Keywords: aqueous humor; biomarker; intraocular pressure; primary open angle glaucoma; trabecular meshwork
Primary open angle glaucoma (POAG) described as a multifactorial neurodegenerative optic neuropathy that is chronic and progressive. It manifests by cupping and atrophy of the optic disc, associated with deterioration of visual field in absence of other known causes of glaucomatous disease.
Glaucoma, is the second most common cause of blindness. Since early diagnosis facilitates timely treatment, it is therefore essential to identify appropriate markers.
In POAG, biomarkers could potentially aid in earlier diagnosis, grading, and/or progression risk. Biomarkers will offer a new clinical tool useful in POAG diagnosis, in prediction of disease prognosis, and in monitoring clinical responses to standard treatment.
In the future, so-called biomarkers could be helpful in early detection and follow-up. In glaucoma, these parameters could be obtained in the aqueous humor, and blood.
This review provides insight into possible changes in the aqueous humor regarding the non-genetic biochemical molecular markers of patients with primary open-angle glaucoma (POAG).
Running title: Biomarkers in primary open angle glaucoma
As part of neurodegenerative disease, glaucoma is defined by changes in the optic nerve and visual field defects, which is characterized by retinal ganglion cells (RGCs) loss. In primary open-angle glaucoma (POAG), intraocular pressure (IOP) is the most crucial risk factor, whereas in normal-tension glaucoma(NTG), both intraocular pressure and hemodynamic factors are considered important. The pathophysiology of neurodegenerative changes in glaucoma is not fully understood [1].
Glaucoma is one of the main causes of irreversible visual field loss and blindness worldwide. The incidence of glaucoma is one in 200 people aged 50 or younger, and one in 10 people aged 80 or older [2].
POAG is a complex heterogeneous disease and by the year 2020 is predicted to affect more than 50 million people worldwide [3]. It is the most common form of glaucoma, with reported prevalence rates ranging from 1.1% [4] to 3.8% [5].
In POAG, the levels of certain proteins, including interleukins and endothelin-1, were elevated. The vasoconstrictor endothelin-1 may play a role in regulating intraocular pressure. By contrast, proteins playing a role in the response to oxidative stress were downregulated. Levels of various cytokines have been found to correlate with the extent of IOP or glaucomatous disc damage in several independent studies[6].
TGFβ1, MMP-2, TIMP-2 levels in aqueous humor have been found to be elevated in PXG eyes as compared to POAG. Yet, the molecular mechanisms regulating clinical findings and those that cause transition from one phenotype to the other remain unclear. In addition, most studies demonstrate the complex changes in aqueous humor in glaucoma [6].
Biomarkers are biological markers defined as an objective and quantifiable characteristic of any biological processes. The National Institutes of Health Biomarkers Definitions Working Group defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [7].
A biochemical marker is a biochemical variable associated with a disorder (directly or indirectly) and might be any biochemical compound (antigen, antibody, enzyme, hormone) that is sufficiently altered to provide diagnostic value. They may be present due to their causative role in glaucoma or as a result of the disease process[7].
This review provides insight into possible changes in the aqueous humor, blood (serum or plasma), tissues, alone or in combination with each other regarding the non-genetic biochemical molecular markers of patients with primary open-angle glaucoma (POAG).
A literature conducted a detailed review using various electronic databases, including PubMed, Science Direct, Google scholar, Scopus, Web of science and Journals of Ophthalmology. For the PubMed search, Medical Subject Headings (MeSH) were used. The principal term used to dictate the MeSH search was “POAG biomarkers”. It was connected to the following terms: glaucoma, intraocular pressure, trabecular meshwork, aqueous humor, biomarkers. Multiple clinical studies were identified and reviewed. Sources from these studies were identified, reviewed.
Biomarkers in POAG
Myocilin
Myocilin is a secreted glycoprotein with a molecular weight of approximately 55-57kDa which forms dimers and multimers. In the eye myocilin is components of the extracellular matrix in the cribriform portion of the TM [8].
Mutations myocilin (MYOC), optineurin (OPTN), and TANK binding kinase 1 (TBK1), may cause primary open-angle glaucoma (POAG) that is inherited as a Mendelian trait [9]. Prevalence of Myocilin mutations in juvenile onset open angle glaucoma (JOAG) is higher among familial forms of JOAG and hence they need to be screened for Myocilin. Myocilin associated with JOAG [10].
Pathogenic MYOC variants appear to be population-associated in open angle glaucoma. Many of the probable pathogenic variants are over represented in some of the populations causing doubt of their status as monogenic disease-causing variants [11].
Myocilin, a glaucoma-associated protein with unknown function, has been found elevated in some glaucomatous ocular tissues. TM from high tension glaucoma (HTG), normal tension glaucoma(NTG), and exfoliative glaucoma (ExG) patients were shown to have increased myocilin immuno-reactivity when compared with normal tissue[12].
Increased extracellular matrix (ECM) deposition and endoplasmic reticulum stress induction was observed in the TM of mutant myocilin transduced quadrants. These findings suggest that the ex-vivo cultured human corneoscleral segment model is cost-effective and can be used as a pre-screening tool to study the effects of glaucoma factors and anti- glaucoma therapeutics on the TM [13].
Ghanem et al. [14] revealed a statistically significant higher myocilin level in HTG patients compared to control patients. Also, the study identified myocilin as a protein elevated in 37% of HTG aqueous humor samples in concentration per volume and as a percent of the total aqueous humor protein. These findings are supported by Jacobson et al [15], who found a trend toward elevated myocilin levels in human glaucomatous
aqueous humor. Also, Konz et al [16], reported structural changes in the juxtacanalicular tissue including an increase in myocilin in the extracellular pathways of aqueous humor in human OAG eyes.
Tamm [17] considered that mutations in the MYOC gene that encodes for myocilin are causative for some forms of juvenile and adult-onset OAG. In the TM, myocilin is found within the cytoplasm of TM cells and in the juxtacanalicular region in association with fibrillar extracellular matrix components.
Ghanem et al. [14] concluded that the percentage of senile cataract patients who were positive for myocilin in the aqueous humor was as low as 2.3%. On the other hand, the percentage of glaucoma patients who were positive for myocilin was as high as 17.7%. This finding, revealed that myocilin concentration in the aqueous humor of normal eyes is below the threshold level of detection for the commercially available kits.
Both myocilin protein and MYOC gene has been reported in some form in human [18]. Possible functions for the myocilin protein include: modifying the expression of other protein products [19], misfolding of the mutant myocilin in the endoplasmic reticulum (ER) can lead to ER cytotoxicity and mechanical blockage of the angle [20].
Ghanem et al. [14] reported non-significant relationship between the IOP and the aqueous humor myocilin concentration. Although the average IOP in the HTG group was the highest observed (19.5 ± 2.2 mmHg), the correlation with the myocilin concentration was not statistically significant. Also, they reported non-significant correlation between mean deviation of the visual field and aqueous humor myocilin levels among the various subtypes of glaucoma.
The expression of human intraocular myocilin is considered to be the result from the secretion of ocular resident cells including TM, vitreous humor, lamina cribrosa, ciliary body, ciliary epithelium, stromal and smooth muscles of the iris, corneal endothelium and stroma, corneoscleral meshwork, surface of the rods and cones, neurons of the inner and outer nuclear layer, and optic nerve ganglion cells [21,22].
Topical therapy (beta blocker, prostaglandin analog, carbonic anhydrase inhibitor, and alpha agonist) was not associated with myoclin levels in aqueous humor. There was no association found between the myocilin levels in the aqueous humor and number of topical anti-glaucomatous drugs (r=0.546; F=0.121;r=0.452, F=0.152, respectively, One-way ANOVA) Ghanem et al. [14].
Ghanem et al. [14] revealed that aqueous humor myocilin levels were statistically significant in the glaucoma subgroups than in the cataract group, with a highly statistically significant difference observed for HTG patients among glaucoma subtypes (ExG and NTG) when compared with control patients. The elevation of intraocular expression of myocilin may be responsible for nerve damage. This finding, suggest targeting myocilin as a mean to inhibit the neurodegenerative mechanisms associated with glaucoma.
Ghrelin
Ghrelin is the endogenous ligand for the human G protein-coupled growth hormone secret agogue receptor-type 1a (GHS-R1a). It is a 28-amino-acid peptide hormone described in the rat's stomach oxyntic mucosa in 1999 by Kojima et al. [23]. Production of ghrelin has also been identified, in smaller amounts, in every tissue studied, including for example, the brain, [23] pituitary gland, small intestine, adrenal gland, kidney, liver, myocardium, and eye [24,25].
The acylated form of the ghrelin is a relatively unstable molecule and exerts mostly neuroendocrine effects after binding to the GHS-R1a [23]. The des-acylated form (des-acyl-ghrelin) of the peptide constitutes more than 90% of the total circulating ghrelin, [5] does not bind to the GHS- R1a and exhibits important peripheral metabolic and cardiovascular effects [26,27].
Ghrelin is a peptide that exerts both endocrine and paracrine effects, as it is involved in the regulation of metabolic balance and energy homeostasis, cardiovascular function [26].Ghrelin expression in vascular endothelial cells and its effects on vascular smooth muscle cells, including an endothelium-independent vasodilatory effect of similar potency and efficacy between both the acylated and des-acylated forms of ghrelin[25].
Ghrelin has emerged as the first identified circulating hormone. Ghrelin is also the only known circulating appetite enhancing hormone. Ghrelin plays a significant role in neurotrophy, particularly in the hippocampus, and is essential for cognitive adaptation to changing environments and the process of learning [28,29].
Study have shown that circulating ghrelin can pass the blood-brain barrier in a complex and highly regulated process [30]. In the eye, the role of the blood–aqueous barrier and the extent to which circulating ghrelin can affect its aqueous levels is not known.
Ghrelin's mRNA observed in the iris posterior segment and in the non- pigmented segment has been reported in glaucoma, an optic nerve damage which presents as the main cause an increase in IOP [31].
A statistically insignificant aqueous humor total ghrelin levels were lower than those of the control subjects but not parallel with the acylated ghrelin levels in glaucoma patients. The relative increase in the ghrelin/acylated ghrelin ratio in glaucoma cases supports the view that proportional increases of acylated ghrelin might play a role in the pathogenesis of glaucoma [32].
A statistically significant decrease in the ghrelin aqueous humor level in POAG patients compared with control patients was reported with Katsanos et al. [33] Ghanem et al. [34], found that plasma ghrelin level in POAG patients were lower 586.51±134.45 pg/ml than in the control group (621.36±123.61pg/ml) but non-statistically significant when compared with the controls(p=0.456). Katsanos et al. [33], found that plasma levels of ghrelin were higher 490.5 ±156.0 pg/ml, in the open angle glaucoma than in the control group (482.2 ±125.4 pg/ml) but non-statistically significant (Mann-Whitney test, p=0.897).
Ghanem et al. [34], revealed non-significant differences in aqueous levels of total ghrelin in patients with POAG compared with controls. These findings may indicate a role of ghrelin on the tissues that are anatomically and functionally related to the aqueous production and/or circulation. However, all glaucoma patients enrolled in this study were under topical treatment without glaucoma therapy drugs. Another potential explanation of our findings is that glaucoma medication causes the concentration of ghrelin to be lower. A third potential explanation for our findings may be related to the higher IOP levels that glaucoma patients generally have.
Ghanem et al. [34], reported a significant difference in aqueous levels of total ghrelin in POAG patients compared with controls. Others studies, found the same results on other ethnics. This revealed that there is no potential genetic difference between our study and other studies.
Ghanem et al. [34], found that there was non-significant correlation between either ghrelin levels with the POAG visual field loss at any stage which may indicate absence of potential secondary consequences such as ischemia, hypoxia, or reactive oxygen species caused by glaucomatous damage. Also, they reported a significant correlation between the aqueous humor and plasma levels of ghrelin results suggested that ghrelin in aqueous humor was related to breakdown of blood-retinal barrier.
Hepcidin Prohormone
The Hepcidin prohormone (Hep) is a small peptide produced in the liver. Human Hep is produced from an 84 amino acid precursor, including a putative single peptide. Hep is an important peptide hormone that plays a critical role in the regulation of iron efflux from numerous cell types, including intestinal cells, macrophages, and hepatocytes [36].
A study found that Hep is expressed in Müller cells, photoreceptor cells, and retinal pigmented epithelium. The expression of Hep in the retina points to the local intraocular regulation of iron metabolism, separate from a dependence on the circulating liver-derived hormone: circulating Hep would likely be inaccessible to intraocular tissues due to the presence of blood-ocular barriers37.
Transforming growth factors (TGF-β2)and hepcidin form a self- sustained feed-forward loop through iron-catalyzed reactive oxygen species (ROS). This loop is partially disrupted by a hepcidin antagonist and an anti-oxidant, implicating iron and ROS in TGF-β2-mediated POAG [38].
Hep is a small peptide produced in the liver. Human Hep is produced from an 84 amino acid precursor, including a putative single peptide. Hep binds to and induces the degradation of ferroprotein, an iron exporter expressed in specific cell types, as the receptor for this iron-regulatory hormone [39].
Hep is responsible for iron homeostasis, decreasing iron uptake from the intestine, and release from the liver in conditions of iron overload. Conversely, Hep syntheses are decreased in iron deficiency, resulting in increased iron uptake from the intestine and release from liver stores[40].
A study found that Hep is expressed in Muller cells, photoreceptor cells, and retinal pigmented epithelium in an expression pattern similar to that of ferroprotein, suggesting that this transporter may play a role in the maintenance of iron homeostasis within the retina. The increase in Hep expression correlates with a decrease in ferroprotein expression, as well as an increase in oxidative stress and apoptosis [41].
Iron metabolism in the eye include the regulation of glutamate production and secretion, glutathione synthesis, and the activity of hypoxia induciblefactor-1 (HIF-1). HIF-1 has been shown to have either a clinically or experimentally mediating or contributing role in several oxygen-dependent retinal diseases such as glaucoma.42-45 Gnana Parksam et al. [46] found that Hep is expressed in Müller cells, photo receptors, and RPE in an expression pattern similar to that of ferroproteins.
Ghanem et al. [47], found that concentration of Hep in the aqueous humor of the POAG group was statistically significantly lower than that of the control group (25.28±23.06 ng/m1 Vs 89.21±14.25 ng/m1). Sorkhabi et al. [48], revealed that the mean aqueous humor Hep concentration in eyes with POAG was significantly higher than those controls (34.55±23.01 ng/ml versus 20.82± 24.63 ng/ml).
Ghanem et al. [47] and Sorkhabi et al [48], found that plasma Hep level in POAG patients were higher but non-statistically significant when compared with the controls. These findings may indicate a role of Hep on the tissues that are anatomically and functionally related to the glaucomatous optic neuropathy, which consequently, induce iron metabolism de-regulation and additive deterioration. Another potential explanation is that glaucoma medication causes the concentration of Hep to be lower. A third potential explanation may be secondary to a cascade of the higher IOP levels that glaucoma patients generally have.
Ghanem et al. [47], revealed a statistically significant decrease levels of Hep in aqueous humor associated with non-significant serum changes. It may be explained that the Hep levels reflect increased protein turnover, which might play a role in the pathophysiology of POAG or result from the disease process. Also, they reported a non-significant correlation between Hep levels with the POAG visual field loss at any stage may indicate absence of potential secondary consequences such as ischemia, hypoxia, or reactive oxygen species caused by glaucomatous damage.
There was significant correlation between the aqueous humor and plasma levels of Hep results suggested that levels Hep in aqueous humor were related to breakdown of blood-retinal barrier and/ or ocular blood. This correlation supported that Hep may be consequence with glaucomatous damage Ghanem et al. [47].
Transforming growth factors
Transforming growth factors (TGFs) constitute a family of multifunctional polypeptides of approximately 25 kDa, and exhibit pleiotropic regulatory actions upon most vertebral cell types [49,50]. Depending on the cell type, they regulate proliferation, migration, differentiation, cytokine production, synthesis of extracellular matrix, wound healing, immunosuppression, and in vivo angiogenesis [51].
TGF-β exists in at least five genetically distinct isoforms, β1-β5[52]. Among these, only three isoforms, namely β1, β2, and β3 are expressed in human ocular tissues[52]. TGF-β2 is regarded as the major isoform in the eye [49,51]. Elevated levels of TGF-β2 have been detected in the AH of glaucomatous eyes [53]. A distinct structural change in the TM of patients with POAG is the increase in fibrillar extracellular matrix in the juxtacanalicular region of the TM.
Suberoylanilide hydroxamic acid (SAHA) prevents TGF-β2-induced increases in outflow resistance and regulates the non-Smad pathway of TGF-β signaling in TM and Schlemm's canal cells [54]. The activation and proliferation of human Tenon's fibroblasts play a vital role in the fibrosis in the pathology of the scar formation after the glaucoma filtration surgery. Transforming growth factor β1 (TGFβ1)/Smads signaling has been reported to promote fibrosis [55].
TGFβ1, MMP-9 and fibronectin protein expression were upregulated in tears, tenon’s capsule and aqueous humor samples in PXG compared to PXF, though the MMP-9 protein activity was downregulated in PXG compared with control or PXF [56].
TGF-β2 signaling may be involved, as TGF-β2 is significantly increased in the AH of patients with POAG. In cultured human TM cells, TGF-β2 causes an increase in extracellular matrix deposition [57]. The concentration of TGF-β2 has been previously measured in several studies [58]. The results have shown that the levels of total TGF-β2 in the aqueous samples of POAG are elevated and have suggested that minimizing TGF- β2 levels may help to prevent the ageing process in the TM as seen in POAG [58].
Ghanem et al. [59], revealed a significant increase in aqueous humor levels of total TGF-B2 and mature TGF-B2 in POAG eyes compared to the corresponding value of eyes with senile cataract and PACG (P, 0.001).Also, they reported an increased expression of TGF-B2 in POAG patients.
Matrix Metalloproteinases
Intraocular matrix metalloproteinase (MMP) activity and its relationship to the aqueous humor outflow pathway have been quantified in normal and glaucomatous canine eyes [60,61], and elevated levels of intraocular MMP-2 and MMP-9 have been documented with glaucoma[60].
Immunohistochemistry has been used to identify MMP-2 and MMP-9 in normal and glaucomatous eyes and specifically localized within trabecular meshwork cells, the extracellular matrix, and inflammatory cells [61].
The MMP9 gene polymorphisms are associated with POAG and intraocular pressure in POAG patients; rs1799750 of MMP1 was associated with the earlier age of manifestation of the disease symptoms[62]. The aqueous humor of POAG and PEXG patients contained several miRNAs that have been linked to tissue development, neurological disease and cellular organization [63].
In addition, PEXS initiation is tightly connected with the dysregulation of ECM homeostasis since aberrant expression of ECM molecules is linked to both the accumulation and low degradation of pseudo exfoliation material [64].
Regulation of the extracellular matrix is carried out by proteolytic enzymes - metalloproteinases in particular - as well as specific inhibitors of their activity (tissue metalloproteinases inhibitors). Pathogenesis of various types of glaucoma, decrease in stability of the intraocular liquid outflow, proves the role of MMR in the ganglionic apoptosis, remodeling of the optic disk and change of lamina cribrosa in primary open-angle glaucoma [65].
Ghanem et al. [66], reported that a statistically significant increases in aqueous humor levels of TIMP-2 in XFG patients compared to the corresponding values of POAG patients or controls. Also, The MMP-2 aqueous humor level was significantly increased in the XFG patients when compared with controls (P < 0.001). In addition, the total protein level in the aqueous humor of eyes of the XFG patients was significantly higher than in POAG patients or controls (P < 0.001). A positive correlation was found between MMP-2 in aqueous humor samples of XFG patients(P < 0.001).
Auto antibodies
By enzyme-linked immunosorbent assay (ELISA), Tezel and coworkers [67] compared the serum immunoreactivity to glycosaminoglycans, and by immunohistochemistry they compared the distribution patterns of glycosaminoglycans in the optic nerve head of POAG eyes versus controls. Authors found that these autoantibodies may increase the susceptibility of the optic nerve head to damage in these patients by changing the functional properties of the lamina cribrosa, its vasculature, or both [67].
The glutathione S-transferase (GST) supergene family, which encodes detoxification enzymes, is widely expressed in mammalian tissue cytosols and membranes. GST is present in glial and neuronal cells of the central nervous system and in the retina [68]. Increased titers of autoantibodies to GST in some patients with POAG may represent a generalized response to tissue stress and/or damage as a consequence of the glaucomatous neurodegeneration process and thereby secondary production of serum antibodies to GST in the glaucomatous retina [68].
Approximately 20% of POAG patients possess a serum antibody against neuron specific enolase (NSE), and the maximum IOP levels in POAG patients with anti-NSE antibody are statistically lower than those without the antibody [69]. It has been suggested that the anti-NSE antibody can reach the retina through circulation and cause retinal ganglion cell damage and progression of visual field loss in addition to elevated IOP [70], and that the presence of serum autoantibody against NSE may be clinically useful for predicting the progression of visual field loss in POAG patients[71].
Antibodies and proteins associated with glaucoma that can be detected for example by microarray and mass spectrometric analyzes, which (i) provide information about expression profiles and associated molecular signaling pathways, (ii) can possibly be used as a diagnostic tool in future and, (iii) can identify possible targets for therapeutic approaches [72].
Epitope analyses identified the third extracellular loop of the β2-AR as the target of the inhibitory β2-AAbs, being of IgG3 subtype in PEXS patients. In contrast, patients with PEXG showed β2-agAAbs (5.6 ± 0.9 U), but no inhibitory ones. The β2-agAAbs levels of patients with PEXG and primary OAG patients (3.9 ± 2.8 U; p > 0.05)were at a similar level [73].
Serum titers of antibodies against heat shock proteins [74], and the entire IgG autoantibody patterns against different retina, optic nerve, and optic nerve head antigens in sera have been investigated [75]. Another study was carried out to investigate the levels of anti-Helicobacter pylori IgG antibodies in the AH and serum of POAG patients. A significant increase of Helicobacter pylori IgG antibody levels was demonstrated, suggesting that the titer of anti-Helicobacter pylori IgG antibody in the AH might reflect the severity of glaucomatous damage in POAG patients.
Yuki et al. [77], analyzed the serum of POAG patients for Chlamydia pneumoniae and Chlamydia trachomatis immunoglobulin G antibody titers by ELISA, and found significantly higher immunoglobulin G titers for Chlamydia pneumoniae in POAG patients than in controls. This may indicate either a common factor that causes susceptibilities to both glaucoma and Chlamydia pneumoniae infection, or that Chlamydia pneumoniae may be a causal factor for developing POAG [77].
Brain-derived neurotrophic factor
The brain-derived neurotrophic factor (BDNF) is important for RGC survival. It also maintains the function of RGCs and protects them from apoptosis. The eyes are similar to the brain regarding the anatomy and function. The blood-ocular barrier surrounds the eyes and shares features with the blood–brain barrier. The aqueous humor fills the anterior chamber and contains anti-inflammatory and other factors similar to those in cerebrospinal fluid [78].
Brain-derived neurotrophic factor is one of the polypeptide growth factors known to be vital components for building up and preserving of neurons. BDNF is transported to the retinal ganglion cell bodies through a retrograde axonal transportation system and the synaptic connections within [79].
BDNF crosses the blood–brain barrier and as a result, the level of this factor in the blood can relatively reflect its concentration in the brain. BDNF levels in serum were determined in POAG patients and controls by ELISA [79]. The authors concluded that BDNF in the serum might be a useful biochemical marker for early detection of POAG.
BDNF levels in serum and AH were markedly lower in the glaucoma groups (POAG and NTG) than in the control group. When comparing the NTG and POAG groups, the average serum BDNF level was significantly lower in the NTG group than in the POAG group. The difference in the mean BDNF levels in AH between the POAG and NTG groups was not statistically significant. Thus, serum BDNF levels were lower in patients with NTG than in those with POAG. BDNF could be a causative systemic biomarker in NTG [1].
Cystatin C
Cystatin C is a low molecular weight protein that is a member of the cystatin superfamily of cysteine protease inhibitors. It is filtered by the kidney and then metabolized by the tubules so that it cannot be collected in the urine and does not reappear in the blood [80].
It is produced by all nucleated cells in the body. Its production rate is not affected by the subject’s diet, but its levels are affected by either hyper-or hypothyroidism and they fluctuate with other markers of inflammation such as C-reactive protein [80].
Cystatins, and in particular cystatin C, have been shown to be involved in many biological events and have not always been related to protease inhibition; examples include a neural stem cell factor, osteoclast differentiation, pathophysiological process in brain ischemia as well as in atherosclerotic plaque development [81].
A significant increase in protein levels of POAG (p =.0009); interestingly, a similar increase in PACG compared to cataract (p <.0001) and POAG (p =.02). Proteomics analysis identified 184, 190, and 299 proteins in control, POAG and PACG. OPN was increased in POAG and PACG compared to control. The precursor form of cathepsin D was increased in POAG and decreased in PACG, though not significant compared to control. Cystatin C was also increased in both POAG and PACG compared to control [82].
Duan and coworkers [83], reported a significant increase of cystatin C was observed in the AH of POAG patients. The increase was similar to the changes in cerebrospinal fluid of Alzheimer’s disease, suggesting that POAG shares similar mechanisms with Alzheimer’s disease.
Primary open-angle glaucoma is a neurodegenerative disease, which is characterized by retinal ganglion cells loss. In primary open-angle glaucoma, intraocular pressure is the most crucial risk factor, whereas in normal-tension glaucoma, both intraocular pressure and hemodynamic factors are considered important. Thus, the pathophysiology of neurodegenerative changes in glaucoma should be fully understood
Conflict of interest
All authors have no conflicts of interest that are directly relevant to the content of this review.
Funding: No sources of funding were used to conduct this review.
Reviewer disclosures: No relevant financial or other relationships to disclose.
Declaration of interest: No financial affiliations or financial involvement with any organization or entity with a financial competing with the subject matter or materials discussed in the review.
The authors have no propriety interest.
Consent for publication: Not applicable
Availability of data: All data generated during this review are included in this study
Standards of reporting: CONSORT guidelines were followed
Author’s contributions: Authors interpreted and discussed the data, and wrote the first version of the manuscript. All authors read and approved the final manuscript.
Acknowledgement: The authors thank Taha Baker for his care and diligence during writing the paper.
Abbreviations
POAG: primary open angle glaucoma; IOP: intraocular pressure; TM: trabecular meshwork; AH: aqueous humor; ELISA: enzyme-linked immunosorbent assay; ECM: extracellular matrix
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Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.
The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.
Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.
Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”
Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner
My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.
My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.
My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.
