Article

Efficacy of N-Acetylcarnosine in the Treatment of Cataracts

Authors:
  • Innovative Vision Products, Inc.
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Abstract

To evaluate the effects of 1% N-acetylcarnosine (NAC) solution on lens clarity over 6 and 24 months in patients with cataracts. Randomised, placebo-controlled study. 49 subjects (76 affected eyes) with an average age of 65.3 +/- 7.0 years with a diagnosis of senile cataract with minimum to advanced opacification in various lens layers. 26 patients (41 eyes) were allocated to topical NAC 1% eyedrops twice daily. The control group consisted of 13 patients (21 eyes) who received placebo eyedrops and 10 patients (14 eyes) who did not receive eyedrops. All patients were evaluated at entry and followed up every 2 months for a 6-month period (trial 1), or at 6-month intervals for a 2-year period (trial 2), for best-corrected visual acuity and glare testing. In addition, cataract was measured using stereocinematographic slit-images and retro-illumination examination of the lens. Digital analysis of lens images displayed light scattering and absorbing centres in two- and three-dimensional scales. The overall intra-reader reproducibility of cataract measurements (image analysis) was 0.830, and glare testing 0.998. After 6 months, 90% of NAC-treated eyes showed improvement in best corrected visual acuity (7 to 100%) and 88.9% showed a 27 to 100% improvement in glare sensitivity. Topographic studies indicated fewer areas of posterior subcapsular lens opacity and 41.5% of treated eyes had improvement in image analysis characteristics. The overall ratios of image analysis characteristics at 6 months compared with baseline measures were 1.04 and 0.86 for the control and NAC-treated group, respectively (p < 0.001). The apparent benefits of treatment were sustained after 24 months' treatment. No treated eyes demonstrated worsening of vision. The overall visual outcome in the control group showed significant worsening after 24 months in comparison with both baseline and the 6-month follow-up examination. The overall clinical results observed in the NAC-treated group by the 24-month period of examination differed significantly (p < 0.001) from the control group in the eyes with cortical, posterior subcapsular, nuclear or combined lens opacities. Tolerability of NAC eyedrops was good in almost all patients, with no reports of ocular or systemic adverse effects. Topical NAC shows potential for the treatment and prevention of cataracts.

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... Poor water solubility Chemically unstable Not supported by large groups clinical trials [59,62] N-acetyl carnosine Antioxidant properties Antiglycating properties reverse cataractous lenses Not supported by large groups clinical trials One-centre studies [75,76] effects such as stinging and transient burning sensation. [80] Water soluble analogues of bendazac have been recently chemically synthesised and showed potent anticataract activity in vitro. ...
... Selenite induced cataract in Sprague-Dawley rats was treated by N-acetylcysteine given intraperitoneally in a dose of 150 μg/g body weight, and the treated rats demonstrated a significant protection against cataract (only 14.3% developed dense cataract), compared with 50% cataract for the untreated group. [93] N-acetylcarnosine drops (1%) have demonstrated promising results with respect to treatment/prevention of senile cataract in human and showed good ocular tolerability for up to 6 [76] and 9 months. [75] In another study, the topical application of NAC (2% w/w) showed improvement in lens opacity of canine immature cataracts or nuclear sclerosis, whereas marginal reduction was recorded for mature cataract or cataract associated with intraocular inflammation. ...
... N-acetyl carnosine was found to have a dose-dependent hydrolysis while passing through the cornea before liberating carnosine in the anterior chamber 15-30 min after instillation onto rabbit eyes. [76] Flavonoids such as diosmin, curcumin and quercetin, and carotenoids such as β-carotene, lutein and lycopene are water insoluble antioxidants. ...
Article
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Objectives The search for anticataract drugs has been continuing for decades; some treatments no longer exist but antioxidants are still of much interest.Key findingsThe primary function of the human lens, along with the cornea, is to refract light so that it is correctly focused onto the retina for optimum image quality. With age, the human lens undergoes morphological, biochemical and physical changes leading to opacification. Age-related or senile cataract is one of the main causes of visual impairment in the elderly; given the lack of access to surgical treatment in many parts of the world, cataract remains a major cause of sight loss. Surgical treatment is the only means of treating cataract; this approach, however, has limitations and complications.SummaryThis review discusses the anatomy and physiology of the lens and the changes that are understood to occur with ageing and cataract formation to identify potential areas for effective therapeutic intervention. Experimental techniques and agents used to induce cataract in animal models, the advantages and disadvantages of potential pharmacological treatments specific barriers to delivery of exogenous antioxidants to the lens and the prospects for future research are discussed.
... Moreover, one of the mechanisms of detoxification from aldehydes, accumulating in inflammation, ischemia, and other pathological conditions was reported to be conjugation with carnosine [7][8][9][10]. Among other potential applications, carnosine-containing eye drops have been recommended for the treatment, dissolution and prevention of cataracts, in particular, senile cataracts [5,11]. From the viewpoint of biochemistry, it is difficult to envisage how carnosine can contribute to the dissolution of cataracts, regarded to be the end stage of metabolic and structural transformations including conformational changes and aggregation of proteins [12]. ...
... Tissue carnosine concentrations are influenced by the diet being lower in vegetarians [1,4,13]. If the presence of carnosine in body fluids is important for the preservation of the lens transparency [5,11] or some physiological functions [4,14], the incidence of cataracts or other pathological conditions among vegetarians/vegans would be higher than in the general population. On the contrary, vegetarians have been reported to have a lower risk of cataract than meat eaters: There was a strong relation between the cataract risk and a diet group, with a progressive decrease in risk of cataracts in high meat eaters to low meat eaters, fish eaters, vegetarians, and vegans [15]. ...
... Some generalizations regarding the oxidants/antioxidants balance, attempting to present it as universal biological concept, seem to be oversimplifications. The problem consists of several partly interrelated topics: Antioxidants and cancer [23], wine, ethanol and cardiovascular risk [28,32], radiation protection [33], lens transparency and cataract [5,11], flavonoids, healthy aging, menopause, atherosclerosis prevention [34], antioxidants, carnosine and diseases of the nervous system [22,[35][36][37], etc. Indications to the use of particular substances are questionable. ...
Article
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... The quantitative assessment of these glare effects was reported by our group, and an algorithm for using these clinical characteristics of vision to add glare effects to digital lens images in agerelated human cataracts was presented. [9][10][11][12] Disability glare (DG) results when a light source refl ects from or otherwise covers the visual task, like a veil, obscuring the visual target, reducing its contrast and making the viewer less able to see and discriminate what is being viewed. The problem is illustrated in Figure 1. ...
... We have recently designed an innovative Halometer DG tester (Figure 2A-E) that overcomes previous defi ciencies. [9][10][11][12] IVP patented the original Halometer DG concept and designed the vision diagnostic device for commercial implementation. [9][10][11][12] The Halometer DG tester is vital for aging drivers with poor vision resulting from aging, cataract, and ocular disease(s). ...
... [9][10][11][12] IVP patented the original Halometer DG concept and designed the vision diagnostic device for commercial implementation. [9][10][11][12] The Halometer DG tester is vital for aging drivers with poor vision resulting from aging, cataract, and ocular disease(s). Glare testing provides secondary information concerning cognitive and physical performance. ...
... L-carnosine has antioxidant effects, metal chelating, and antiglycation properties (Turner et al., 2021). These features protect aging ocular tissues from oxidative stress, glycation, and post-translational modification of structural (lens crystallins) as well as functional (enzymes) proteins in the human eye (Babizhayev et al., 2009(Babizhayev et al., , 2002. Recent reports highlight the role of L-carnosine as a potential anticancer agent (Gaafar et al., 2021;Turner et al., 2021). ...
... Scrapping of the corneal epithelium was induced using ethyl alcohol 70% v/v and utilized as a pharmacodynamic response to compare the corneal wound healing potential of LC when loaded in the optimized in situ gelling formulations (F-P3/CS1) in comparison with the control (1% LC solution). It has been previously shown that the size of the ulcers for eyes exposed to LC solution was markedly less compared to untreated eyes (Babizhayev et al., 2002). Whilst these findings are promising, we hypothesize that incorporating LC in optimized in situ gelling formulations would be advantageous. ...
... It is also known to have formed from oxidative stress. N-Acetyl Carnosine (NAC) is an ophthalmic drug which shows potential for treatment or even reversal of cataract [6][7][8]. A known antioxidant effect of the protein, L-carnosine, on cataractuous lens may allow us biochemically for exploring L-carnosine as a cause to converse or even avert development of cataract [9,10]. ...
... Although cytotoxicity studies indicate that there is not a significant difference between the control NAC and SLN-NAC. This may be attributed to the fact that NAC has been previously regularly used as eye drops for treatment of cataract in a lot of studies [6][7][8]. Our work proves that SLN-NAC has even lower cell toxicity than NAC. ...
Article
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The purpose of this study is to prepare and characterize solid lipid nanoparticles (SLN) of N-Acetyl Carnosine (NAC) to treat cataract since surgery necessitates equipments and professional help. Cataract is believed to be formed by the biochemical approach where the crystalline eye proteins lose solubility and forms high molecular weight masses. Added advantages of SLN of NAC (henceforth referred as SLN-NAC) in the study are reduced size, sustained release and better corneal penetration of drug. The method of preparation of SLN-NAC by Mill’s method is unique in itself. The size of the SLN-NAC was 75 ± 10 nm in the range of ideal for penetration. The in-vitro release study and the SLN-NAC formulations prepared with Mill’s method demonstrated sustained release up to 24 h following an initial burst after 1 h. The zeta potential of the prepared formulation was −22.1 ± 1 mV. Corneal permeation studies using goat corneas indicate that SLN-NAC penetration rate was higher than those from NAC eye drops. Corneal hydration studies indicated that the formulation caused no harm to the corneal cells. Therefore it may be concluded that SLN-NAC may revolutionize cataract treatment and reversal by improving drug permeation, reducing toxicity and no damage to corneal tissue.
... Cn was reported to be of importance for the antioxidant lens protection and preservation of its transparency, for prevention of certain neurologic and mental diseases. These potencies have been ascribed to the antioxidant properties of Cn [1,2,6,7]. Among other potential applications, Cn eye drops have been recommended for cataracts [1,6,7]. ...
... These potencies have been ascribed to the antioxidant properties of Cn [1,2,6,7]. Among other potential applications, Cn eye drops have been recommended for cataracts [1,6,7]. However, if Cn concentration in body fluids is of importance, the incidence of corresponding conditions in vegetarians or population groups consuming less meat would be higher than average, which, to the best of our knowledge, has never been reported. ...
Article
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The full text can be downloaded here. The initial version: https://ru.scribd.com/document/312685040/tmp6C02-tmp
... L-Carnosine is marketed as a prodrug in the form of Nacetylcarnosine (NAC) eye drops (1%). N-Acetyl carnosine was found to have a dose-dependent hydrolysis releasing carnosine into the anterior chamber 15-30 minutes after instillation onto ocular surface of rabbit lenses [18]. These eye drops have been considered to be promising with respect to treatment/prevention of senile cataract in human eyes and showed good ocular tolerability for up to 6 [18] and 9 [19] months. ...
... N-Acetyl carnosine was found to have a dose-dependent hydrolysis releasing carnosine into the anterior chamber 15-30 minutes after instillation onto ocular surface of rabbit lenses [18]. These eye drops have been considered to be promising with respect to treatment/prevention of senile cataract in human eyes and showed good ocular tolerability for up to 6 [18] and 9 [19] months. Topical application of NAC (2% w/w) showed improvements in lens opacities of canine immature cataracts or nuclear sclerosis, whereas a marginal reduction was recorded for mature cataract or cataracts associated with intraocular inflammation [20]. ...
Article
Full-text available
Purpose. L-Carnosine is a naturally occurring dipeptide which recently gained popularity as an anticataractogenic agent due to its purported antioxidant activities. There is a paucity of research and conclusive evidence to support such claims. This work offers compelling data that help clarify the mechanism(s) behind the anticataract properties of L-carnosine. Methods. Direct in vitro antioxidant free radical scavenging properties were assayed using three different antioxidant (TEAC, CUPRAC, and DPPH) assays. Indirect in vitro and ex vivo antioxidant assays were studied by measuring glutathione bleaching capacity and total sulfhydryl (SH) capacity of bovine lens homogenates as well as hydrogen-peroxide-stress assay using human lens epithelial cells. Whole porcine lenses were incubated in high galactose media to study the anticataract effects of L-carnosine. MTT cytotoxicity assays were conducted on human lens epithelial cells. Results. The results showed that L-carnosine is a highly potent antiglycating agent but with weak metal chelating and antioxidant properties. There were no significant decreases in lens epithelial cell viability compared to negative controls. Whole porcine lenses incubated in high galactose media and treated with 20 mM L-carnosine showed a dramatic inhibition of advanced glycation end product formation as evidenced by NBT and boronate affinity chromatography assays. Conclusion. L-Carnosine offers prospects for investigating new methods of treatment for diabetic cataract and any diseases that are caused by glycation.
... 54 A randomised double-blind clinical trial of NAC was performed on 49 patients with an average age of 65 where they received NAC eye drops twice a day or a placebo. 57 The eyes were assessed on several criteria such as best corrected visual acuity (BCVA), glare sensitivity, and lens clarity based on slit image and retro-illumination photographs. After 6 months of treatment, 90% of the NAC treated group showed BCVA improvement, 89% showed glare sensitivity improvement and the clarity of the treated lens improved in 42% of treated eyes. ...
... Similar results were also obtained after 2 years of NAC treatment. 57 Although the results were promising, many limitations were noted for the study including the limited number of patients, low statistical power, and being carried at two-different time points where many patients dropped out of the trial at the latest point (45%). However, in another in-vitro study carried out on cultured porcine lenses, L-carnosine was shown to have no or limited 11 antioxidant activity. ...
Thesis
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Chronic diseases are rising in incidence and prevalence because of the increase in life expectancy in many parts of the world and the advances in medicine that manage disease progression, rather than curing and alleviating the causes. Cataract is one such chronic condition. Identifying a therapeutic intervention that is successful in reversing or preventing cataracts may have applications for other chronic diseases of protein misfolding, such as diabetes and Alzheimer's disease as these have similar causation factors, notably oxidative stress and/or glycation. To date, surgery remains the only effective treatment for cataract and the search for alternatives is still ongoing. Cerium oxide nanoparticles (nanoceria) which have antioxidant, radioprotective and enzyme-mimetic properties have the potential to lead to an effective non-surgical treatment. However, nanoceria stability in physiological media is poor thus hindering their effective use in biomedical applications. In the work described in this thesis, a highly efficient one-pot synthesis of nanoceria (2–5 nm) has been achieved. The nanoparticles were coated with a novel hybrid coating (ethylene glycol, ethylene glycol monoand di- acetates) providing the formulation with superior colloidal stability in physiological media. The ethylene glycol coated nanoceria formulation (EGCNPs), up to concentrations of 200 μg/ml, is not toxic to human lens epithelial cells and has no adverse effect on the cellular morphology, proliferation rate, mitochondrial morphology, mitochondrial membrane potential, ATP level, DNA integrity and basal reactive oxygen species (ROS) level. Exceeding the safe concentration of nanoceria leads to genotoxicity and apoptotic cell death mediated by ROS elevation and mitochondrial damage, a mechanism which is comprehensively investigated for the first time in human lens epithelial cells (HLECs). EGCNPs uptake in HLECs was found to be endocytosisdependent and the nanoparticles localised extensively in the mitochondria. This localisation has enabled the nanoparticles to protect HLECs against oxidative stress, act as a catalase mimetic and increase reduced glutathione/oxidised glutathione ratio (GSH/GSSG). Furthermore, it is shown for the first time that these nanoparticles can protect lens proteins against glucose-induced glycation that is a major cause of cataract particularly in diabetics. Together, these results demonstrate great potential for nanoceria in protecting against cataract and should be taken to in-vivo studies.
... Enhanced oxidative stress causes carbonylation of proteins and peroxidative decomposition of unsaturated lipids (lipid peroxidation) in lens leading to the formation of protein carbonyls and malondialdehyde (MDA) respectively (Liu et al., 2017;Singh et al., 2001;Dalle-Donne et al., 2006). Apart from surgical interventions (implantation of artificial lens), drug based-treatment and/or prevention strategies for cataract are majorly based on oral or topical administration of antioxidants such as lanosterol (Zhao et al., 2015), N-acetyl cysteine (Babizhayev et al., 2002;Maddirala et al., 2017) and pyrrolidine dithiocarbamate (PDTC) (Mingyan et al., 2008;Wild and Mulcahy, 1999;Zhu et al., 2002). ...
... Antioxidants such as lanosterol (Zhao et al., 2015), N-acetyl cysteine (Babizhayev et al., 2002;Maddirala et al., 2017) and PDTC (Mingyan et al., 2008;Wild and Mulcahy, 1999;Zhu et al., 2002) are widely explored agents for the treatment of oxidative stress related disorders due to their ability to scavenge ROS including superoxide anion radicals. As a result, these agents can reduce oxidative stress induced HIF-1α stabilization and consequential neovascularization (Bir et al., 2013;Forsythe et al., 1996;Wood et al., 1996), and, protein carbonylation and lipid peroxidation (Negre-Salvayre et al., 2008). ...
Article
Topically administered delivery systems for ophthalmic applications have been studied for the treatment of anterior or posterior eye diseases. However, simultaneous treatment of both anterior and posterior eye diseases has not been explored. In this study, we fabricated a topically administrable polymeric nanoparticle (NP)- based delivery system consisting of pluronic®F-68 shell and polycaprolactone core for the simultaneous treatment of both anterior and posterior eye diseases. These NPs were loaded with pyrrolidine dithiocarbamate (PDTC) or triamcinolone acetonide (TA) separately. The drug loading in NPs was optimized to initially achieve a moderate burst release of PDTC followed by slow and sustained release of both PDTC and TA. The resultant delivery system was studied for its in vivo efficacy in a diabetic retinopathy (DR) and cataract rat model. The results demonstrated that administration of PDTC NPs + TA NPs minimized oxidative stress in lens as evidenced by reduced levels of protein carbonyls and malondialdehyde, and, ameliorated DR complications in retina as evidenced by reduced expression of hypoxia inducible factor-1α along with a reduction in number of neovascular tufts and acellular capillaries. Therefore, delivery of PDTC and TA using PCL-PF68 NPs could be a useful approach for simultaneous treatment of diabetic cataract and DR.
... Lanosterol reduces the aggregation level of lens protein which significantly reverse the cataract formation [11] . N-acetyl carnosine prevents cataract through inhibiting eye lens protein glycation formation caused by sugars [12] . The above mentioned drugs inhibit cataract formation through antiglycation of lens protein. ...
Article
Cataract is one of the leading causes for blindness among worldwide devoid of effective treatment. Glycation of γ-crystallin under hyperglycemic condition leads to diabetic cataract formation. It is important to design a drug which could inhibit lens protein glycation and prevent the diabetic cataract. The use of plant based natural compounds could have potential bioavailability and fewer toxicity. The current investigation aim is to determine the efficient phytochemicals for inhibition of γ-crystallin glycation. In this study the phytochemicals with anticataract property were virtually screened against γ-crystallin. The potent phytochemicals were filtered based on their interaction site and binding affinity. These phytochemicals were further scrutinized and evaluated with pharmacokinetics, druggability and Pharmacophore feature analysis. Among the phytochemicals, Alizarin (polyketide), Pseudobaptigenin (flavonoid) and Ellagic acid (tannin) are three phytochemicals which had preferred druglike behavior and binding affinity for the inhibition of glycation against γ-crystallin protein. The features of these three phytochemicals could be used as prototype for synthesizing new molecules against diabetic cataract.
... Curcumin (in turmeric spice) has been well established as an anti-cataract agent [22,23] but the question of its bioavailability still remains unanswered. In addition, N-acetylcarnosine (NAC) eye drops have been proven to be effective free radical scavengers in improving visual function in cataract patients [24,25]. This naturally occurring compound is believed to deacetylate and the resulting compound acts as an antioxidant and offers protection against glycation [26]. ...
... 48 The ophthalmic pro-drug carnosine-N-acetylcarnosine (NAC) has recently been developed for clinical use. 49 Babizhayev et al. found that after 6 months of NAC treatment, 96% of the treated eyes showed improvement in lens clarity as based on slit-lamp images and retroillumination photographs. Significantly, NAC was found to be able to reverse lens opacity in canine eyes, and a "melting snow" phenomenon was described. ...
Article
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In numerous epidemiological and animal models, it can be inferred that oxidative stress is a key factor in cataract formation. Production of reactive oxygen species and reduction of endogenous antioxidants both contribute to cataract formation. In the cataractogenous process, lens proteins lose sulfhydryl groups and become thiolated or cross-linked by disulfide bonds. The resultant high molecular weight aggregates become insoluble and affect lens transparency. All these are consequences of changes in the redox state. A mixed protein-thiol and protein-protein disulfide bond precedes the morphological changes of cataract. Normally, sustained high levels of reduced glutathione provide a protective effect, while depletion of glutathione causes damage to epithelial cells and fiber cells. UV rays in the ambient environment evoke reactive oxygen species formation and also contribute to cataracts. The reduction in free UV filters and increase in their binding to lens proteins make the lens more predisposed to UV damage and oxidation. In the aqueous humor of cataract lenses, there is a decrease in antioxidant enzymes and increase in nitric oxide, which demonstrates the relationship between oxidative stress and cataracts. Though surgical intervention is the standard treatment for cataracts, experimental medical therapies for cataracts are under extensive investigation. Carnosine, a pro-drug of carnosine-N-acetylcarnosine, bendazac, ascorbic acid, and aldose reductase inhibitors are under therapeutic evaluation, and prevention of cataract formation may be possible in the future.
... An ophthalmic pro-drug of carnosine, N-acetylcarnosine (NAC) has been developed for clinical use to control lipid peroxidation and ROS that promotes the formation of heavy molecular weight aggregates [30]. Discovery of the protective role of aspirin like analgesics in diabetic cataract opened up new avenues in medicinal treatment of cataract. ...
... Evidence has shown that the methylglyoxal glycation-induced tryptophan fluorescence polarization and scattered light intensity enhancements detected in the aggregated a-crystallin protein were attenuated upon exposure to carnosine [40]. Eye lens opacity in human was also found to be reversed by carnosine [133]. Attanasio and co-workers have made an attempt to explore how both L-form and D-form of carnosine affect the aggregation of bovine a-crystallin [41]. ...
Article
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Carnosine, a common dipeptide in mammals, has previously been shown to dissemble alpha-crystallin amyloid fibrils. To date, the dipeptide's anti-fibrillogensis effect has not been thoroughly characterized in other proteins. For a more complete understanding of carnosine's mechanism of action in amyloid fibril inhibition, we have investigated the effect of the dipeptide on lysozyme fibril formation and induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Our study demonstrates a positive correlation between the concentration and inhibitory effect of carnosine against lysozyme fibril formation. Molecular docking results show carnosine's mechanism of fibrillogenesis inhibition may be initiated by binding with the aggregation-prone region of the protein. The dipeptide attenuates the amyloid fibril-induced cytotoxicity of human neuronal cells by reducing both apoptotic and necrotic cell deaths. Our study provides solid support for carnosine's amyloid fibril inhibitory property and its effect against fibril-induced cytotoxicity in SH-SY5Y cells. The additional insights gained herein may pave way to the discovery of other small molecules that may exert similar effects against amyloid fibril formation and its associated neurodegenerative diseases.
... It can oppose glycation [140,141] and it can chelate divalent metal ions [142]. The important studies have produced clinical and experimental evidence of beneficial effects of N-acetylcarnosine in treating cataracts of the eyes; these and other ophthalmological benefits have been proven [14,15,[143][144][145][146][147][148][149][150][151]. Carcinine (β-alanyl histamine) is an imidazole dipeptide first discovered in the crustacean Carcinus maenas (reviewed in refs. ...
Article
It has been documented that telomere-associated cellular senescence may contribute to certain age-related disorders, and telomere length (TL) may be an informative biomarker of healthy aging. Hormone-brain-aging behavior-modulated telomere dynamics and changes in telomerase activity are consistent elements of cellular alterations associated with changes in proliferative state, and these processes are consequently considered as the new therapeutic drug targets for physiological control with advanced drug delivery and nutritional formulations. We raise and support a therapeutic concept of using nonhydrolyzed forms of naturally occurring neuron-specific imidazole dipeptide-based compounds carnosine and carcinine, making it clinically possible that slowing down the rate of telomere shortening could slow down the human aging process in specific tissues where proliferative senescence is known to occur, with the demonstrated evidence of telomere shortening that appeared to be a hallmark of oxidative stress and disease. Carnosine released from skeletal muscle during exercise may be transported into the hypothalamic tuberomammillary nucleus (TMN) histamine neurons and hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of carnosine on neurotransmission and hormone-like antiaging physiological function. The preliminary longitudinal studies of elderly individuals suggest that longer telomeres are associated with better survival, and an advanced oral nutritional support with nonhydrolyzed carnosine (or carcinine and patented compositions thereof) is a useful therapeutic tool for a critical TL maintenance that may fundamentally be applied in the treatment of age-related sight-threatening eye disorders, prolonged life expectancy, increased survival and chronological age of an organism in health control, smoking behavior, and disease. “Our pleasures were simple—they included survival.” —Dwight D. Eisenhower, 34th President of the United States, 1953–1961
... It is also available in the form of nanoformulation (Tzankova et al. 2019). Prodrug of carnosine, N-acetylcarnosine has been developed which controls the lipid peroxidation and ROS generation in the posterior subcapsular region of the eye (Babizhayev et al. 2002). Natural antioxidant molecules prevent the formation of free radicals which can damage the eye lens cells AU1 AU2 S. K. Paikra et al. (Moure et al. 2001). ...
Chapter
Vision is the most principal sensory organ present in every organism. The mechanism of vision lies behind the ocular cells and various nerves associated with it. Thus, impairment of any of them leads to a faulty photoreceptor. The defect in the eye can be treated by various approaches like refractive surgery, wearing lens or glasses, drug therapy, or nanoformulation. Among all therapy, nanoformulation is the new strategy for the treatment of ocular diseases which can easily pass the ocular barrier and the drug can be targeted at its right place. Thus, nanoformulations are used to treat optic neuropathy, choroidal neovascularization, diabetic retinopathy, and intraocular solid tumors. However, with the wide application, the toxicity of nanoformulation is also reported from various parts of the eye like eyelids, lacrimal apparatus, conjunctiva, periorbital tissues, cornea, lens, ciliary body, iris, retina, and optic nerve. The current chapter summarizes the effect of different drugs and nanoformulation on ocular cells. Nanocarrier-based delivery of polynucleotide at ocular tissue has also been discussed briefly in this chapter.
... The use of a prodrug might improve corneal permeation; some studies have shown promising results for such an approach in rabbit and in human eyes. [2][3][4] However, the process relies on the activity of ocular esterase, which is a protein, and as such might be susceptible to advanced glycation with ageing and/or be expressed in lower levels as an inevitable consequence of ageing. 5,6 Either way, the ocular bioavailability of the active form might be adversely affected and ultimately might affect the anticataractogenic potency. ...
Article
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This study reports on L-carnosine phytosomes as an alternative for the prodrug N-acetyl-L-carnosine as a novel delivery system to the lens. L-carnosine was loaded into lipid-based phytosomes and hyaluronic acid (HA)-dispersed phytosomes. L-carnosine-phospholipid complexes (PC) of different molar ratios, 1:1 and 1:2, were prepared by the solvent evaporation method. These complexes were characterized with thermal and spectral analyses. PC were dispersed in either phosphate buffered saline pH 7.4 or HA (0.1% w/v) in phosphate buffered saline to form phytosomes PC1:1, PC1:2, and PC1:2 HA, respectively. These phytosomal formulations were studied for size, zeta potential, morphology, contact angle, spreading coefficient, viscosity, ex vivo transcorneal permeation, and cytotoxicity using primary human corneal cells. L-carnosine-phospholipid formed a complex at a 1:2 molar ratio and phytosomes were in the size range of 380–450 nm, polydispersity index of 0.12–0.2. The viscosity of PC1:2 HA increased by 2.4 to 5-fold compared with HA solution and PC 1:2, respectively; significantly lower surface tension, contact angle, and greater spreading ability for phytosomes were also recorded. Ex vivo transcorneal permeation parameters showed significantly controlled corneal permeation of L-carnosine with the novel carrier systems without any significant impact on primary human corneal cell viability. Ex vivo porcine lenses incubated in high sugar media without and with L-carnosine showed concentration-dependent marked inhibition of lens brunescence indicative of the potential for delaying changes that underlie cataractogenesis that may be linked to diabetic processes.
... These peptides are used in medicine and cosmetic products. Their ability to prevent the aggregation of protein crystallins in the lens of the eye was found, which is used for the treatment and prevention of cataracts [1]. The binding of carnosine to hyaluronic acid with the formation of full or partial salt provides an expansion of the arsenal of agents used to stimulate the migration of fibroblasts and the formation of collagen III [2]. ...
Article
The dissolution enthalpies of Gly-L-His and β-Ala-L-His in phosphate-buffered saline and in micellar solution (SDS + phosphate-buffered saline) are measured at pH = 7.4 and T = 298.15 K. The enthalpies of the interaction of peptides with SDS micelles are determined as the enthalpies of transfer of peptides from a buffer solution to a micellar buffer solution. The proportions of different ionic forms for both peptides in the solution are compared. Three ionic forms coexist in Gly-L-His solution at pH = 7.4, while in β-Ala-L-His solution, only two forms predominate. A higher proportion of zwitterions and a larger contribution of electrostatic forces are characteristic for the interaction of micelle with β-Ala-L-His. But a greater endothermic contribution of partial dehydration of more hydrophobic peptide equalizes its overall interaction enthalpy with the effect for Gly-L-His. The interaction of micelles with peptide ions is accompanied by compensation of the negative ζ-potential and compression of micelles.
... Water insoluble molecules such as natural flavonoids (diosmin, curcumin, and quercetin) and carotenoids (β-carotene, lutein, and lycopene) are known by their poor bioavailability, which could weaken their potential for topical use (Freag et al. 2013). Anticataractogenic effect of topical N-acetyl carnosine (1% and 2%) has been demonstrated in humans and animals (Williams and Muunday 2006;Babizhayev et al. 2002Babizhayev et al. , 2009), but larger clinical trials are needed in order to evaluate its potential benefits. Potential inhibition of oxidative stress and cataract development by caffeine in mice with selenite-induced cataracts has been demonstrated (Varma et al. 2010). ...
Chapter
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According to the World Health Organization, cataract is the major cause of reversible visual impairment in the world. It is present as the cause of decreased visual acuity in 33% of the visual impaired citizens. With the increase of life expectancy in the last decades, the number of patients with cataract is expected to grow for the next 20 years. Nowadays, the only effective treatment for cataracts is surgery and its surgical outcomes have been increasingly satisfactory with the technological advancement. Pharmaceutical development has been also responsible for surgical outcomes enhancement. This includes the development of new ophthalmic viscoelastic devices (OVDs), intraocular dyes, mydriatics, miotics, anesthetics, irrigating solutions, and antibiotics. However, the increased costs and demand for cataract surgery may be hard to meet in the future unless clinical preventive and curative options are evaluated. In this chapter, we review the studies that addressed pharmacological applications in cataract.
... But it wasn't until 1996 that this approach became generally adopted. It reduces postoperative irritation and astigmatism, speeds up visual recovery, and reduces capsulotomy with contemporary foldable lenses (Babizhayev, 2002). But diabetic people may have worse vision than non-diabetics. ...
Article
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Glucose metabolic disorders and diabetic retinopathy is linked to an increased risk of cataracts. The anatomical components of the eye work together to focus a picture on the retina. The cornea, one of the eye's two major focusing structures, receives light. The pupil is the eye's next focusing component, and it is positioned directly after the crystalline lens, which is the eye's second focusing component. The cornea and lens focus light rays onto the retina, which initiates image processing and transmission to the occipital area of the brain. The lens of the eye becomes clouded, limiting light from reaching the retina. Blurred vision, glare, and reduced contrast sensitivity are all symptoms of cataracts. Studies have demonstrated that diabetic lenses have aberrant levels of electrolytes, glutathione, nucleotides, and carbohydrates. Cataracts are more common in those with type 1 and type 2 diabetes. Diabetes-related alterations in lens metabolism and cataract development are linked to hyperglycemia. According to a study of glucose metabolism pathways, several hyperglycemia-initiated activities are linked to cataract formation. Metabolic alterations in galactosemia-related cataracts are identical, indicating a similar biochemical origin. Aldose reductase (NADP + 1-oxidoreductase, EC 1.1.1.21) is a sugar alcohol synthase enzyme that transforms glucose or galactose into sugar alcohols (polyols). Increased intracellular polar alcohol levels promote lens fiber extension, vacuole formation, and opacification, while Aldose reductase inhibition prevents sugar cataract development. This article is a review on different studies and reports that encompasses diabetic retinopathy and cataracts.
... Among other proposed applications, carnosine eye drops reportedly have a potential for prevention and reversal of the cataract development [39,47,48]. The topical application of carnosine as an eye drop does not result in penetration into the eye. ...
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PART 2: https://www.researchgate.net/publication/335253828_Scientific_Papers_and_Patents_on_Substances_with_Unproven_Effects_Part_2
... It can oppose glycation [96,97] and it can chelate divalent metal ions [98]. The important studies have produced clinical and experimental evidence of beneficial effects of N-acetylcarnosine in treating cataracts of the eyes, these and other ophthamological benefits have been proven [99][100][101][102][103][104][105][106][107][108][109]. Carcinine (β-alanyl histamine) is an imidazole dipeptide first discovered in the crustacean Carcinus maenas [Reviewed in refs. ...
... D-carnosine prevents the development of atherosclerosis and renal disease in diabetic mice [158,159]. N-acetylcarnosine administered as eye drops significantly reduced lens opacity, and improved visual acuity and glare sensitivity [160]. Consumption of L-carnosine for three months improved signs of aging skin [161]. ...
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Numerous hypotheses including amyloid cascade, cholinergic, and oxidative have been proposed for pathogenesis of Alzheimer’s disease (AD). The data suggest that advanced glycation end products (AGEs) and its receptor RAGE (receptor for AGE) are involved in the pathogenesis of AD. AGE–RAGE stress, defined as a balance between stressors (AGE, RAGE) and anti-stressors (sRAGE, AGE degraders) in favor of stressors, has been implicated in pathogenesis of diseases. AGE and its interaction with RAGE-mediated increase in the reactive oxygen species (ROS) damage brain because of its increased vulnerability to ROS. AGE and ROS increase the synthesis of amyloid β (Aβ) leading to deposition of Aβ and phosphorylation of tau, culminating in formation of plaques and neurofibrillary tangles. ROS increase the synthesis of Aβ, high-mobility group box 1(HMGB1), and S100 that interacts with RAGE to produce additional ROS resulting in enhancement of AD pathology. Elevation of ROS precedes the Aβ plaques formation. Because of involvement of AGE and RAGE in AD pathology, the treatment should be targeted at lowering AGE levels through reduction in consumption and formation of AGE, and lowering expression of RAGE, blocking of RAGE ligand binding, increasing levels of soluble RAGE (sRAGE), and use of antioxidants. The above treatment aspect of AD is lacking. In conclusion, AGE–RAGE stress initiates, and Aβ, HMGB1, and S100 enhance the progression of AD. Reduction of levels of AGE and RAGE, elevation of sRAGE, and antioxidants would be beneficial therapeutic modalities in the prevention, regression, and slowing of progression of AD.
... Among other proposed applications, carnosine eye drops have been recommended for the treatment and prevention of cataracts [42,48]. The topical application of carnosine as eye drops does not result in penetration into the eye. ...
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The full text can be downloaded here and is available at: https://www.bibliomed.org/?mno=22857 PART 2: https://www.researchgate.net/publication/334948250_Drugs_and_dietary_supplements_with_unproven_effects_in_research_and_practice_Part_2 RUSSIAN: https://www.researchgate.net/publication/26234807_Ispytania_aterogennosti_lekarstvennyh_preparatov_i_pisevyh_dobavok_na_kulture_kletok_ocenka_dostovernosti_rezultatov_Trials_of_drugs_and_food_supplements_atherogenicity_on_cell_culture_assessment_of_v
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Cataract is the leading cause of world blindness. The only available treatment for cataract is surgery. Surgery requires highly-trained individuals with expensive operating facilities. Where these are not available, patients go untreated. A form of treatment that did not involve surgery would be a useful alternative for people with symptomatic cataract who are unable or unwilling to undergo surgery. If an eye drop existed that could reverse or even prevent progression of cataract, then this would be a useful additional treatment option.Cataract tends to result from oxidative stress. The protein, L-carnosine, is known to have an antioxidant effect on the cataractous lens, so biochemically there is sound logic for exploring L-carnosine as an agent to reverse or even prevent progression of cataract. When applied as an eye drop, L-carnosine cannot penetrate the eye. However, when applied to the surface of the eye, N-acetylcarnosine (NAC) penetrates the cornea into the front chamber of the eye (near to where the cataract is), where it is metabolised into L-carnosine. Hence, it is possible that use of NAC eye drops may reverse or even prevent progression of cataract, thereby improving vision and quality of life. To assess the effectiveness of NAC drops to prevent or reverse the progression of cataract. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), Allied and Complementary Medicine Database (AMED) (January 1985 to June 2016), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 June 2016. We handsearched the American Society of Cataract and Refractive Surgery (ASCRS) and the European Society of Cataract and Refractive Surgeons (ESCRS) meetings from 2005 until September 2015. We planned to include randomized or quasi-randomised controlled trials where NAC was compared to control in people with age-related cataract. We used standard methodological procedures expected by Cochrane. We identified two potentially eligible studies from Russia and the United States. One study was split into two arms: the first arm ran for six months, with two-monthly follow-up; the second arm ran for two years with six-monthly follow-up. The other study ran for four months with a data collection point at the start and end of the study only. A total of 114 people were enrolled in these studies. The ages ranged from 55 to 80 years.We were unable to obtain sufficient information to reliably determine how both these studies were designed and conducted. We have contacted the author of these studies, but have not yet received a reply. Therefore, these studies are assigned as 'awaiting classification' in the review until sufficient information can be obtained from the authors. There is currently no convincing evidence that NAC reverses cataract, nor prevents progression of cataract (defined as a change in cataract appearance either for the better or for the worse). Future studies should be randomized, double-masked, placebo-controlled trials with standardised quality of life outcomes and validated outcome measures in terms of visual acuity, contrast sensitivity and glare, and large enough to detect adverse effects.
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Purpose of review: Age-related cataract occurs when crystallin proteins in the lens partially unfold and subsequently aggregate. Physicians and traditional healers alike have been exploring pharmacologic cataract treatment for hundreds of years. Currently, surgery is the only effective treatment. However, there are an abundance of homeopathic and alternative remedies that have been suggested as treatment for cataract. This article reviews the current understanding of cataract development and discusses several homeopathic remedies purported to treat age-related cataract. Additionally, we will present an overview of evidence regarding the development of pharmacologic cataract reversal therapies. Recent findings: Some homeopathic therapies have been shown to prevent cataract development in experimental models. More studies are required to elucidate the potential medicinal and toxic properties of the various alternative therapies. However, in recent years, scientists have begun to investigate substances that address cataract by reversing lens protein aggregation. One such compound, lanosterol, was reported to reverse cataract opacity in vitro and in animal models. Subsequently, 25-hydroxycholesterol and rosmarinic acid were identified as having similar properties. Summary: Although challenges and uncertainties remain, further research has the potential to lead to the development of a nonsurgical therapeutic option for age-related cataract.
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Background: Numerous mutations in over 100 rod genes are the well-established cause of apoptotic death of these cells and development of night blindness in retinitis pigmentosa (RP). Cone death is either concomitant or follows rod death with resultant loss of critical peripheral and central day vision. As cones are generally not encumbered by genetic mutations, the causes of their death and its prevention are the central problems of RP research. Currently no FDA-approved medications are available for retarding RP progression. Hypothesis: It is proposed that cones, which are outnumbered 20:1 by rods, undergo apoptosis as a consequence of neurotrophic factor deficiencies and oxidative stresses accompanying massive rod death: increased retinal oxygen tension; leakage of lipid-peroxidation catalysts from disrupted membranes; reactive oxygen species from active/hyperactive microglia ingesting rod-apoptotic bodies. Accordingly we developed and tested a treatment regimen with a range of antioxidants in combination with the off-label use of deprenyl (1 mg/day), a safe antiapoptotic agent, which also upregulates eight neurotrophic factors. Since deprenyl inhibits only one of four mitochondrial apoptotic pathways, we added the antibiotic minocycline (100 mg/day) to our protocol at month 76. Minocycline complements deprenyl's therapeutic properties: it inhibits all four apoptotic pathways; inhibits apoptosis-initiating proteins; as phenol exerts powerful antioxidant properties; upregulates three antioxidant enzymes; downregulates oxidative/inflammatory microglia activities. Its safe long-term use for acne and rheumatoid arthritis received FDA approval; it passes the blood/brain and blood/retinal barriers readily; and because of its rapid and complete absorption causes no intestinal disturbances. The National Eye Institute has initiated in 2010 and 2011 clinical trials with minocycline (200 mg/day) for diabetic macular edema and retinal branch vein occlusion. Testing of hypothesis: The hypothesis was tested for 140 months with one RP patient monitored by Humphrey Perimetry, which was quantitated by two parameters: (a) sum of decibel units, (b) number of detected light sources (visual field). Although no decline was observed in these parameters during the first 50 months of treatment, they declined by 10-28% during months 50-65. These declines reversed upon introduction of minocycline: over the total 140-month treatment, the right eye visual field showed 0% decline and left eye 13.3% decline. Rate constants for logarithmic decline of visual field measured prior to treatment indicate that visual fields would have decreased by 64% and 70%, respectively by month 140 in the absence of treatment.
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Carnosine, a naturally occurring dipeptide, was recently reported to exhibit anticancer activity; however, the molecular mechanisms and regulators underlying its activity against tumor-associated angiogenesis remain unidentified. In this study, we evaluated the in vitro and in vivo antitumor effects of carnosine in EJ bladder cancer cells and EJ-xenografted BALB/c nude mice, respectively. In addition, in vitro capillary tube formation of HUVECs, ex vivo aortic ring and in vivo Matrigel plug assays were employed to examine the antiangiogenic potential of carnosine. Carnosine significantly inhibited EJ cell proliferation. Flow cytometric and immunoblot analyses indicated that carnosine modulated regulators of the G1 cell cycle phase, including cyclin D1, CDK4 and p21WAF1. The mitogen-activated protein kinases, ERK and p38, but not JNK or AKT, responded to carnosine. Carnosine inhibited the migratory and invasive potential of EJ cells by inhibiting MMP-9 activity, which was associated with suppression of binding activity of NF-κB, SP-1 and AP-1. In xenograft tumors, carnosine exhibited antitumor activity equivalent to cisplatin, but no weight loss occurred in carnosine-treated mice. In HUVECs, carnosine inhibited VEGF-mediated proliferation, colony tube formation, migration and invasion. The antiangiogenic activity of carnosine was partially due to the suppression of VEGFR-2-mediated ERK/AKT/eNOS signaling and MMP-2. Furthermore, using aortic ring and Matrigel plug assays, we confirmed the antiangiogenic activity of carnosine. Given that targeting tumor-associated angiogenesis is a proven effective therapeutic strategy, our results may provide valuable information for the development of preventive or therapeutic agents for bladder cancer patients.
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Cataracts in Small Animals are shown to be at least partially caused by oxidative damage to lens epithelial cells (LECs) and the internal lens; biomarkers of oxidative stress in the lens are considered as general biomarkers for life expectancy in the canine and other animals. Telomeres lengths and expressed telomerase activity in canine LECs may serve as important monitors of oxidative damage in normal LECs with documented higher levels of telomerase activity in cata-ractous LECs during cells' lifespan. Loss of functional telomere length below a critical threshold in LECs of canines dur-ing the effect of UV and chronic oxidative stress or metabolic failure, can activate programs leading to LEC senescence or death. Telomerase is induced in LECs of canines at critical stages of cataractogenesis initiation and exposure to oxidative stress through the involvement of catalytically active prooxidant transition metal (iron) ions. This work documents that transition metal ions (such as, ferrous ions- catalytic oxidants) might induce premature senescence in LECs of canines, telomere shortening with increased telomerase activity as adaptive response to UV light, oxidative and metabolic stresses. The therapeutic treatment with 1% N -acetylcarnosine (NAC) prodrug delivery is beneficial for prevention and dissolution of ripe cataracts in canines. This biological activity is based on the findings of ferroxidase activity pertinent to the dipep-tide carnosine released ophthalmically from NAC prodrug of L-carnosine, stabilizing properties of carnosine on biological membranes based on the ability of the imidazole-containing dipeptides to interact with lipid peroxidation products and reactive oxygen species (ROS), to prevent membrane damage and delute the associated with membrane fragements pro-tein aggregates. The advent of therapeutic treatment of cataracts in canines with N -acetylcarnosine lubricant eye drops through targeting the prevention of loss of functional telomere length below a critical threshold and "flirting" with an indi-rect effect with telomerase expression in LECs of canines during the effects of UV, chronic oxidative stress increases the successful rate of cataract management challenges in home veterinary care.
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Carnosine (β-alanyl-l-histidine) was discovered in 1900 as an abundant non-protein nitrogen-containing compound of meat. The dipeptide is not only found in skeletal muscle, but also in other excitable tissues. Most animals, except humans, also possess a methylated variant of carnosine, either anserine or ophidine/balenine, collectively called the histidine-containing dipeptides. This review aims to decipher the physiological roles of carnosine, based on its biochemical properties. The latter include pH-buffering, metal-ion chelation, and antioxidant capacity as well as the capacity to protect against formation of advanced glycation and lipoxidation end-products. For these reasons, the therapeutic potential of carnosine supplementation has been tested in numerous diseases in which ischemic or oxidative stress are involved. For several pathologies, such as diabetes and its complications, ocular disease, aging, and neurological disorders, promising preclinical and clinical results have been obtained. Also the pathophysiological relevance of serum carnosinase, the enzyme actively degrading carnosine into l-histidine and β-alanine, is discussed. The carnosine system has evolved as a pluripotent solution to a number of homeostatic challenges. l-Histidine, and more specifically its imidazole moiety, appears to be the prime bioactive component, whereas β-alanine is mainly regulating the synthesis of the dipeptide. This paper summarizes a century of scientific exploration on the (patho)physiological role of carnosine and related compounds. However, far more experiments in the fields of physiology and related disciplines (biology, pharmacology, genetics, molecular biology, etc.) are required to gain a full understanding of the function and applications of this intriguing molecule.
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Patients suffering from the severe complications associated with both insulin- (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM): nephropathy, retinopathy, neuropathy, and atherosclerosis are still largely left without a prospect of an efficient treatment. The accelerated formation of advanced glycation end-products (AGEs) due to elevated glycemia has repeatedly been reported as a central pathogenic factor in the development of diabetic microvascular complications. Glucose and α-dicarbonyl compounds chemically attach to proteins and nucleic acids without the aid of enzymes. Initially, chemically reversible Schiff base and Amadori product adducts form in proportion to glucose concentration. The major biological effects of excessive nonenzymatic glycosylation are leading to increased free radical production and compromised free radical inhibitory and scavenger systems, inactivation of enzymes; inhibition of regulatory molecule binding; crosslinking of glycosylated proteins and trapping of soluble proteins by glycosylated extracellular matrix (both may progress in the absence of glucose); decreased susceptibility to proteolysis; abnormalities of nucleic acid function; altered macromolecular recognition and endocytosis; and increased immunogenicity. This study demonstrates the progress in development of patented carnosine mimetics resistant in formulations to enzymatic hydrolysis with human carnosinases that are acting as a universal form of antioxidant , deglycating and transglycating agents that inhibit sugar-mediated protein cross-linking , chelate or inactivate a number of transition metal ions (including ferrous and copper ions), possess lipid peroxidase type of activity and protection of antioxidant enzymes from inactivation (such as in a case of superoxide dismutase). Carnosine biological mimetics react with methylglyoxal and they are described in this study as a glyoxalase mimetics. The imidazole-containing carnosine biological mimetics can react with a number of deleterious aldehydic products of lipid peroxidation and thereby suppress their toxicity. Carnosine and carcinine can also react with glycated proteins and inhibit advanced glycation end product formation. These studies indicate a therapeutic role for imidazole-containing antioxidants (non-hydrolized carnosine, carcinine, D-carnosine, ophthalmic prodrug N-acetylcarnosine, leucyl-histidylhidrazide and patented formulations thereof) in therapeutic management strategies for Type 2 Diabetes.
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It has been documented that telomere-associated cellular senescence may contribute to certain age-related disorders, including an increase in cancer incidence, wrinkling and diminished skin elasticity, atherosclerosis, osteoporosis, weight loss, age-related cataract, glaucoma and others. Shorter telomere length in leukocytes was associated cross-sectionally with cardiovascular disorders and its risk factors, including pulse pressure and vascular aging, obesity, vascular dementia, diabetes, coronary artery disease, myocardial infarction (although not in all studies), cellular turnover and exposure to oxidative and inflammatory damage in chronic obstructive pulmonary disease . It has been proposed that telomere length may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging. The data reveal that telomere dynamics and changes in telomerase activity are consistent elements of cellular alterations associated with changes in proliferative state and in this article these processes are consequently considered as the new therapeutic drug targets for physiological control with advanced drug delivery and nutritional formulations. In particular, the presence of highly specific correlations and early causal relationships between telomere loss in the absence of telomerase activity and replicative senescence or crisis, and from the other side, telomerase reactivation and cell immortality, point to a new and important treatment strategies or the therapeutic manipulation during treatment of age related disorders and cancer. Once better controls and therapeutic treatments for aging and age-related disorders are achieved, cellular rejuvenation by manipulating telomeres and enzyme telomerase activity may reduce some of the physiological declines that accompany aging. In this work we raise and support a therapeutic concept of using non-hydrolized forms of naturally occurring imidazole-dipeptide based compounds carnosine and carcinine, making it clinically possible that slowing down the rate of telomere shortening could slow down the human aging process in specific tissues where proliferative senescence is known to occur with the demonstrated evidence of telomere shortening appeared to be a hallmark of oxidative stress and disease. The preliminary longitudinal studies of elderly individuals suggest that longer telomeres are associated with better survival and an advanced oral nutritional support with non-hydrolized carnosine (or carcinine and patented compositions thereof) is a useful therapeutic tool of a critical telomere length maintenance that may fundamentally be applied in the treatment of age-related sight-threatenting eye disorders, prolong life expectancy, increase survival and chronological age of an organism in health control, smoking behavior and disease.
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Telomere length is emerging as a biomarker for aging and survival, is paternally inherited and associated with parental lifespan. Telomere-associated cellular senescence may contribute to certain age-related disorders, including an increase in cancer incidence, wrinkling and diminished skin elasticity, atherosclerosis, osteoporosis, weight loss, age-related cataract, glaucoma and others. Shorter telomere length in leukocytes was associated cross-sectionally with cardiovascular disorders and its risk factors, including pulse pressure and vascular aging, obesity, vascular dementia, diabetes, coronary artery disease, myocardial infarction (although not in all studies), cellular turnover and exposure to oxidative and inflammatory damage in chronic obstructive pulmonary disease . Effective regulation of abnormal therapeutic targets of an age-related disease requires the alteration of either the topological structure or dynamic characteristics of telomeres which are DNA-protein structures at the ends of eukaryotic chromosomes, the DNA of which comprise noncoding repeats of guanine-rich sequences. Telomeric DNA plays a fundamental role in protecting the cell from recombination and degradation, including those as the metabolic super-achievers in the body, organ systems in a given target network of a disease and aging. In order to manage and control the complex direct and indirect target hubs, in this paper, a review of the recent patents is made analyzing techniques, new approaches developed during the last years in adaptive pharmacology directed at slowing and preventing the loss of telomere length that may slow aging using pharmaceutical and nutritional module-based designs, such as with regard to the timing of administration of imidazole-containing dipeptides. We discuss our recent identification of the role of neuron-specific imidazole-containing dipeptide based compounds (L-carnosine, N-acetylcarnosine, carcinine) that regulate and therapeutically control telomere shortening, telomerase activity and cellular senescence. We support a therapeutic concept of using non-hydrolized forms of naturally occurring imidazole-dipeptide based compounds carnosine and carcinine, making it clinically possible that slowing down the rate of telomere shortening could slow down the human aging process in specific tissues where proliferative senescence is known to occur with the demonstrated evidence of telomere shortening appeared to be a hallmark of oxidative stress and disease. The preliminary longitudinal studies of elderly individuals suggest that longer telomeres are associated with better survival and an advanced oral pharmaconutrition provision with non-hydrolized carnosine (or carcinine and patented compositions thereof) is a useful therapeutic tool of a critical telomere length maintenance (allowing indirectly to manipulate with telomerase activity) that may fundamentally be applied in the therapeutic treatment of age-related sight-threatenting eye disorders, Diabetes Mellitus, sarcopenia (that is the gradual loss of muscle mass) that can affect elderly people and subjects under the effect of exhausting exercises and physical load, prolong life expectancy, increase survival and chronological age of an organism in health control, smoking behavior , metabolic syndrome increasing the risk of developing cardio-vascular diseases, age-related neurodegenerative diseases, including Alzheimer's disease and cognitive impairment.
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Hypothalamic releasing and inhibiting hormones are major neuroendocrine regulators of human body metabolism being driven directly to the anterior pituitary gland via hypothalamic-hypophyseal portal veins. The alternative physiological or therapeutic interventions utilizing the pharmaco-nutritional boost of imidazole-containing dipeptides (non-hydrolized oral form of carnosine, carcinine, N-acetylcarnosine lubricant eye drops) can maintain health, enhance physical exercise performance and prevent ageing. Carnosine (β-alanyl-L-histidine) is synthesized in mammalian skeletal muscle. There is an evidence that the release of carnosine from the skeletal muscle sarcomeres moieties during physical exercise affects autonomic neurotransmission and physiological functions. Carnosine released from skeletal muscle during exercise acts as a powerful afferent physiological signaling stimulus for hypothalamus, may be transported into the hypothalamic tuberomammillary nucleus (TMN), specifically to TMN-histamine neurons and hydrolyzed herewith via activities of carnosine-degrading enzyme (carnosinase 2) localized in situ. Through the colocalized enzymatic activity of Histidine decarboxylase in the histaminergic neurons, the resulting L-histidine may subsequently be converted into histamine , which could be responsible for the effects of carnosine on neurotransmission and physiological function. Carnosine and its imidazole-containing dipeptide derivatives are renown with anti-aging, antioxidant, membrane protective, metal ion chelating , buffering, anti-glycation/ transglycating activities used to prevent and treat a spectrum of age-related and metabolic diseases, such as neurodegenerative disease, sight threatening eye diseases, Diabetes mellitus and its complications, cancers and other disorders due to their wide spectrum biological activities. The precursor of carnosine (and related imidazole containing compounds) synthesis in skeletal muscles beta-alanine is used as the oral supplement by athletes to achieve the fine sporting art results due to the buffering activities of carnosine and its related imidazole-containing compounds which contribute to maintenance of the acid-base balance in the acting muscles. This work originally emphasizes that overall data indicate on the signaling activities of carnosine in skeletal and cardiac muscles switching on the mechanisms of exercise-induced telomere protection and point to the stress response and growth/cellular proliferation pathways as high-priority candidates for the ongoing studies and therapeutic concepts. The therapeutic interventions utilizing the specific oral formulation (Can-C Plus), timing dosing and pharmaco-nutritional boost of imidazole-containing dipeptides can maintain health, enhance physical exercise performance and prevent aging. The patented therapeutic concept protects the existence of the interesting physiological major activities, better controls and therapeutic treatments for aging/age-related disorders (including age-related loss of muscle mass and muscle function) using carnosine dipeptide for cellular rejuvenation and manipulating telomeres and enzyme telomerase activity that may reduce some of the physiological declines that accompany aging.
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Abstract Cataract is a progressive loss of eye lens transparency which is adversely reflected in the loss of vision. Constant exposure to oxidative stress, environmental elements, metabolic disorders, and genetic variations contributes to the patho-mechanism of cataract. However, oxidative stress, mutations, truncations, deamidations, and glycation play a crucial role in the pathophysiology of cataractogenesis resulting in alterations of the epithelial cell metabolism, lenticular proteins structure, and function that are elusive. Recent lifestyle modification and occupational exposure to high intensity light increases the incidence of cataract in an alarming rate that has raised serious public health concern among the aging population (>40). Awareness on the modifiable risk factors would therefore be an ideal target for public health interventions. Pioneering results from various research backgrounds has proven that prevention of cataractogenesis by effective health education, intake of nutraceuticals would prioritize primary and secondary prevention strategies to the community.
Chapter
Background: Cataract is the leading cause of world blindness. The only available treatment for cataract is surgery. Surgery requires highly-trained individuals with expensive operating facilities. Where these are not available, patients go untreated. A form of treatment that did not involve surgery would be a useful alternative for people with symptomatic cataract who are unable or unwilling to undergo surgery. If an eye drop existed that could reverse or even prevent progression of cataract, then this would be a useful additional treatment option.Cataract tends to result from oxidative stress. The protein, L-carnosine, is known to have an antioxidant effect on the cataractous lens, so biochemically there is sound logic for exploring L-carnosine as an agent to reverse or even prevent progression of cataract. When applied as an eye drop, L-carnosine cannot penetrate the eye. However, when applied to the surface of the eye, N-acetylcarnosine (NAC) penetrates the cornea into the front chamber of the eye (near to where the cataract is), where it is metabolised into L-carnosine. Hence, it is possible that use of NAC eye drops may reverse or even prevent progression of cataract, thereby improving vision and quality of life. Objectives: To assess the effectiveness of NAC drops to prevent or reverse the progression of cataract. Search methods: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), Allied and Complementary Medicine Database (AMED) (January 1985 to June 2016), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 June 2016. We handsearched the American Society of Cataract and Refractive Surgery (ASCRS) and the European Society of Cataract and Refractive Surgeons (ESCRS) meetings from 2005 until September 2015. Selection criteria: We planned to include randomized or quasi-randomised controlled trials where NAC was compared to control in people with age-related cataract. Data collection and analysis: We used standard methodological procedures expected by Cochrane. Main results: We identified two potentially eligible studies from Russia and the United States. One study was split into two arms: the first arm ran for six months, with two-monthly follow-up; the second arm ran for two years with six-monthly follow-up. The other study ran for four months with a data collection point at the start and end of the study only. A total of 114 people were enrolled in these studies. The ages ranged from 55 to 80 years.We were unable to obtain sufficient information to reliably determine how both these studies were designed and conducted. We have contacted the author of these studies, but have not yet received a reply. Therefore, these studies are assigned as 'awaiting classification' in the review until sufficient information can be obtained from the authors. Authors' conclusions: There is currently no convincing evidence that NAC reverses cataract, nor prevents progression of cataract (defined as a change in cataract appearance either for the better or for the worse). Future studies should be randomized, double-masked, placebo-controlled trials with standardised quality of life outcomes and validated outcome measures in terms of visual acuity, contrast sensitivity and glare, and large enough to detect adverse effects.
Article
Cataract formation represents a serious problem in the elderly, with approximately 25% of the population aged >65 years and about 50% aged >80 years experiencing a serious loss of vision as a result of this condition. Not only do cataracts diminish quality of life, they also impose a severe strain on global healthcare budgets. In the US, 43% of all visits to ophthalmologists by Medicare patients are associated with cataract. Surgery represents the standard treatment of this condition, and 1.35 million cataract operations are performed annually in the US, costing $US3.5 billion (year of costing, 1998). Unfortunately, the costs of surgical treatment and the fact that the number of patients exceeds surgical capacities result in many patients being blinded by cataracts worldwide. This situation is particularly serious in developing countries; worldwide 17 million people are blind because of cataract formation, and the problem will grow in parallel with aging of the population. In any event, surgical removal of cataracts may not represent the optimal solution. Although generally recognised as being one of the safest operations, there is a significant complication rate associated with this surgical procedure. Opacification of the posterior lens capsule occurs in 30–50% of patients within 2 years of cataract removal and requires laser treatment, a further 0.8% experience retinal detachments, approximately 1% are rehospitalised for corneal problems, and about 0.1% develop endophthalmitis. Although the risks are small, the large number of procedures performed means that 26 000 individuals develop serious complications as a result of cataract surgery annually in the US alone. Thus, risk and cost factors drive the investigation of pharmaceutical approaches to the maintenance of lens transparency. The role of free radical-induced lipid oxidation in the development of cataracts has been identified. Initial stages of cataract are characterised by the accumulation of primary (diene conjugates, cetodienes) lipid peroxidation (LPO) products, while in later stages there is a prevalence of LPO fluorescent end-products. A reliable increase in oxiproducts of fatty acyl content of lenticular lipids was shown by a direct gas chromatography technique producing fatty acid fluorine-substituted derivatives. The lens opacity degree correlates with the level of the LPO fluorescent end-product accumulation in its tissue, accompanied by sulfhydryl group oxidation of lens proteins due to a decrease of reduced glutathione concentration in the lens. The injection of LPO products into the vitreous has been shown to induce cataract. It is concluded that peroxide damage of the lens fibre membranes may be the initial cause of cataract development. N-acetylcarnosine (as the ophthalmic drug Can-C™), has been found to be suitable for the nonsurgical prevention and treatment of age-related cataracts. This molecule protects the crystalline lens from oxidative stress-induced damage, and in a recent clinical trial it was shown to produce an effective, safe and long-term improvement in sight. When administered topically to the eye in the form of Can-C™, N-acetylcarnosine functions as a time-release prodrug form of L-carnosine resistant to hydrolysis with carnosinase. N-acetylcarnosine has potential as an in vivo universal antioxidant because of its ability to protect against oxidative stress in the lipid phase of biological cellular membranes and in the aqueous environment by a gradual intraocular turnover into L-carnosine. In our study the clinical effects of a topical solution of N-acetylcarnosine (Can-C™) on lens opacities were examined in patients with cataracts and in canines with age-related cataracts. These data showed that N-acetylcarnosine is effective in the management of age-related cataract reversal and prevention both in human and in canine eyes.
Article
Morphological and biophysical techniques described in this study have shown that membrane derangement occurs in human cataractous lenses. The data suggest that these disruptions were globules, vacuoles, multilamellar membranes and clusters of highly undulating membranes. Deleterious structural damage of the lens fibre cell plasma membranes serve as the primary light-scattering centres that cause the observed lens opacity. Nuclear cataract, a major cause of loss of lens transparency in the aging human, has been thought to be associated with oxidative damage, particularly at the site of the nuclear plasma membrane. Phospholipid molecules modified by oxygen accumulate in the lipid bilayer, change its geometry and impair lipid-lipid and protein-lipid interactions in lenticular fibre membranes. Lipid peroxidation (LPO) is a causative and pathogenic factor in cataract. Increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides, oxy-derivatives of phospholipid fatty acids) and end-fluorescent LPO products have been detected in the lipid moieties of aqueous humour samples and human lenses obtained from patients with senile and complicated cataracts as compared with normal donors. In the present study, a rapid and simple high-performance liquid chromatographic (HPLC) assay for determination of imidazole-containing dipeptides in the aqueous humour of the eye was developed. The method was applied to determine the pharmacokinetic parameters and the time-course of N-acetylcarnosine and L-carnosine-related product in the eye, following a single dosage of topical ocular administration of peptide. Utilising data from pharmacokinetic studies and the specific purity of the N-acetylcarnosine (NAC) ingredient as a source of the pharmacological principle L-carnosine, we have created an ophthalmic time-release prodrug form including the US FDA-approved carboxymethylcellulose lubricant and other essential ingredients (Can-C™, private label Nu-Eyes™). This formulation increases the intraocular absorption of L-carnosine in the aqueous humour and optimises its specific antioxidant activity in vivo while reducing the toxic effects of lipid peroxides on the crystalline lens. L-carnosine that enters the aqueous humour can accumulate in the lens tissue for a reasonable period of time. The presence of L-carnosine in transparent crystalline lenses during normal aging was detected and its concentration in this case was about 25μM. At different stages of cataract development, the level of L-carnosine drastically decreased, reaching about 5μM in ripe human cataracts. However, administration of pure L-carnosine (1% solution) to the rabbit eye (instillation or subconjunctival injection) does not lead to accumulation of this natural compound in the aqueous humour at the time level over 30 minutes at a concentration exceeding that in placebo-treated matched eyes, and its effective concentration is exhausted more rapidly. Use of NAC prodrug eye drops optimises the clinical effects of L-carnosine in the treatment of ophthalmic disorders (such as prevention and reversal of cataracts in human and animal [canine] eyes). The data provided predict a clinical effect with NAC ophthalmic prodrug, and show that the magnitude and duration of this effect are directly related to the bioavailability of L-carnosine released from NAC in the aqueous humour of the anterior eye segment. The ophthalmic NAC drug shows promise in the treatment of a range of ophthalmic disorders that have a component of oxidative stress in their pathogenesis (including cataract, glaucoma, dry eye, vitreous floaters, inflammatory disorders, and corneal, retinal and systemic diseases [such as diabetes mellitus and its ophthalmic complications]). There is a need for further and better collaboration between Innovative Vision Products’ cataract control and ophthalmic services, improved education of people affected by cataract, a commitment that N-acetylcarnosine eye drops will be the preferred treatment before orthodox cataract surgery is attempted, and consideration of outcomes and a possible role of the NAC drug cataract treatment as source of referral for orthodox surgical, ophthalmic and optometric services.
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The effect of a mixture of N-acetylcarnosine and D-pantethine (1 : 1, m/m) on UV-A induced cataract in rats was studied. It is shown that instillation of a 5% mixture into the eyes or intraperitoneal injections (25 or 150 mg/kg) inhibit the formation of cataracts, starting from 82nd day of the experiment (p < 0.03), after which the protective effect of the mixture significantly increases (p = 0.0003). UV-A irradiation significantly (p < 0.01) increased the content of water-insoluble proteins in the lens. The use of the mixture of N-Acetylcarnosine and D-pantethine prevented (p < 0.001) an increase in the content of water-insoluble proteins caused by UV-A irradiation. Gel permeation chromatography data showed that, in the control group, water insoluble proteins consist of 3 fractions (40 kDa, 100 - 200 kDa, and1000 kDa). UV-A irradiation reduced the amount of protein in fraction 1 and increases the amount of protein in the fractions 2 and 3. The use of the mixture of N-acetylcarnosine and D-pantethine reduced the effects of UV-A light. The authors attribute the effect of the N-acetylcarnosine and D-pantethine mixture to their chaperone-like properties.
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Imidazole dipeptides (ID), such as carnosine (β-alanyl-L-histidine), are compounds widely distributed in excitable tissues of vertebrates. ID are also endowed of several biochemical properties in biological tissues, including antioxidant, bivalent metal ion chelating, proton buffering, and carbonyl scavenger activities. Furthermore, remarkable biological effects have been assigned to such compounds in age-related human disorders and in patients whose activity of serum carnosinase is deficient or undetectable. Nevertheless, the precise biological role of ID is still to be unraveled. In the present review we shall discuss some evidences from clinical and basic studies for the utilization of ID as a drug therapy for age-related human disorders.
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The only treatment for cataract in clinic is the clouded lens removal combined with artificial lens implantation. In this study, nifedipine (NFP), a classic vasodilator, was loaded in a U.S. FDA-approved polymer PLA-PEG to form NFP-loaded PLA-PEG micelles as a novel eye drop to prevent oxidative cataract formation and progression at the early stage. The NFP-loaded PLA-PEG micelles not only showed satisfactory biocompatibility and bioavailability, but also efficiently improved the anti-cataract ability through the inhibition of extracellular calcium ions influx. This study may provide a new insight into the development of cataract treatment.
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Diabetes mellitus (DM) defines metabolic disorders, characterised by elevated levels of blood glucose. Chronic hyperglycaemic state promotes consequently the formation of advanced glycation end products (AGEs) and the expression of their receptor (RAGE) which aggravate many diabetic complications. Due to the relevant role of AGEs and RAGE, several therapeutic approaches with an anti-AGE or RAGE-antagonizing effect are investigated. These therapeutic options include AGE cross-link breakers, AGE inhibitors, RAGE antagonists, drugs clinically approved for various indications like antidiabetic, antihypertensive drugs or statins, as well as dietary and phytotherapeutic approaches. The aim of this review is to give an overview of these therapeutic approaches, their outcomes in clinical studies and their role in the management of diabetes and its complications.
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Oxidative stress is one of the most important risk factors for cataractogenesis. Previous studies have indicated that BDS-II, a Kv3 channel blocker, plays pivotal roles in oxidative stress-related diseases. This study demonstrates that BDS-II exerts a protective effect on cataractogenesis. Specifically, BDS-II was observed to inhibit lens opacity induced by H2O2. BDS-II was also determined to inhibit cataract progression in a sodium selenite-induced in vivo cataract model by inhibiting reduction of the total GSH. In addition, BDS-II was demonstrated to protect human lens epithelial cells against H2O2-induced cell death. Our results suggest that BDS-II is a potential pharmacological candidate in cataract therapy.
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The proportion of the global population aged 60 years and over is steadily increasing and projected to increase to almost 30 % in 2050. Among the various health problems, eye and vision problems are serious issues in the elderly. These may be manifested as basic functional disabilities or a decline in the receptive, storage, and analytical capacities of the central visual system. The major eye disorders of aging are cataract, age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy. Although there are treatment methods (e.g., medications and surgical interventions) for these conditions, they are still very challenging areas due to the delicate and critical nature of the eye tissues. Compared with drug delivery to other parts of the body, drug delivery to the eye has met with significant challenges posed by various ocular barriers, which are inherent and unique to the ocular anatomy. In addition, in the case of the aging population, there are added difficulties due to multiple diseases and health problems, the several medications being taken together and the physical and psychological difficulties, including disabilities, dependence, fears, and apprehensions: opening packages, swallowing oral medication and/or reading leaflet information, fear of surgery, and device insertion and removal.
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Influenza A is a viral disease of global dimension, presenting with high morbidity and mortality in annual epidemics, and in pandemics which are of infrequent occurrence but which have very high attack rates. Influenza vaccines of the future must be directed toward use of conserved group-specific viral antigens, such as are present in transitional proteins which are exposed during the fusion of virus to the host cell. Influenza probes reveal a continuing battle for survival between host and parasite in which the host population updates the specificity of its pool of humoral immunity by contact with and response to infection with the most recent viruses which possess altered antigenic specificity in their hemagglutinin (HA) ligand. It is well known that the HA protein is found on the surface of the influenza virus particle and is responsible for binding to receptors on host cells and initiating infection. Polymorphonuclear neutrophils (PMN) have been reported to be involved in the initial host response to influenza A virus (IAV). Early after IAV infection, neutrophils infiltrate the airway probably due to release of chemokines that attract PMN. Clearly, severe IAV infection is characterized by increased neutrophil influx into the lung or upper respiratory tract. Carnosine (β-alanyl-L-histidine) and anserine (N-β-alanyl-1-methyl-L-histidine) are found in skeletal muscle of most vertebrates, including those used for food; for example, 100 g of chicken breast contains 400 mg (17.6 mmol/L) of carnosine and 1020 mg (33.6 mmol/l) of anserine. Carnosine-stimulated respiratory burst in neutrophils is a universal biological mechanism of influenza virus destruction. Our own studies reveal previously unappreciated functional effects of carnosine and related histidine containing compounds as a natural biological prevention and barrier against Influenza virus infection, expand public understanding of the antiviral properties of imidazole-containing dipeptide based compounds, and suggest important interactions between neutrophills and carnosine related compounds in the host response to viruses and bacteria. Carnosine and anserine were also found to reduce apoptosis of human neutrophils . In this way these histidine-containing compounds can modulate the Influenza virus release from neutrophills and reduce virus dissemination through the body of the organism. This review points the ability of therapeutic control of Influenza viral infections associated with modulation by oral non-hydrolized forms of carnosine and related histidine-containg compounds of PMN apoptosis which may be involved at least in part in the pathophysiology of the disease in animals and humans. The data presented in this article, overall, may have implications for global influenza surveillance and planning for pandemic influenza therapeutic prevention with oral forms of non-hydrolized natural L-carnosine as a suitable alternative to the conventional vaccination for various flu ailments.
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Hydrogen peroxide inhibition of maximum Ca2+-ATPase and Na+,K+-ATPase activity was measured in a membrane-enriched preparation of rabbit lens cortical fibers and epithelium. At 5 X 10(-6) M hydrogen peroxide maximum Ca2+-ATPase activity was inhibited by 39%, while maximum Na+,K+-ATPase activity was stimulated. Ca2+-ATPase activity was almost completely inhibited at 5 X 10(-4) M hydrogen peroxide, in comparison to Na+,K+-ATPase activity, which was only inhibited by 28% at a concentration of hydrogen peroxide an order of magnitude larger. The addition of catalase to hydrogen peroxide-pretreated samples did not reverse the inhibition of Ca2+-ATPase by hydrogen peroxide.
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Isocratic reverse phase analytical high performance liquid chromatography (HPLC) has been used to examine naturally occurring imidazoles of cardiac and skeletal muscles. Elution of muscle extracts with a phosphate buffer mobile phase from columns packed with hypersil ODS (5 micron) resulted in good separation of the skeletal muscle imidazole-containing dipeptides carnosine and anserine. Measured concentrations corresponded to published values. N-Acetyl forms that were not commercially available were prepared from their parent compounds and their identities verified by NMR-spectroscopy. Examination of frog cardiac muscle confirmed the presence of N-acetylhistidine and also indicated the presence of its 1-methyl derivative. Extracts of mammalian cardiac muscle were examined by HPLC which indicated the presence of low concentrations of carnosine but substantial amounts of N-acetyl forms of histidine, 1-methylhistidine, carnosine and anserine. Fractions corresponding to the numerous peaks were examined using staining systems specific for certain chemical features and compared to results obtained for commercial or synthetic standards. Results of these tests supported the chromatographic data. The total concentrations in cardiac muscle of these imidazole-containing substances (approx. 10 mM) is sufficient to alter significantly the sensitivity of their contractile apparatus to calcium ions.
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The oxidation state of methionine and cysteine in normal and cataractous lenses is reported. In young lenses no oxidation was detected in any protein fraction examined. Only the intrinsic membrane fraction and membrane-related components showed evidence of oxidation in old (60-65 years of age) normal lenses. However, in a similar age group, with the development of cataract, progressive, dramatic changes were observed. With severe cataracts, 60% or more of the methionine in membrane-associated components was found in the methionine sulfoxide form, and methionine sulfone was observed in one case. Most of the cysteine was found oxidized to either the disulfide form or putative cysteic acid. Mixed disulfides with glutathione were observed. Oxidative changes in soluble components as illustrated by alpha-crystallin occurred more gradually. The data clearly support the viewpoint that extensive oxidation of lens proteins occurs with cataract and that it begins at the lens fiber membrane.
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Oxidation of membrane, protein followed by extensive oxidation of lens cytosol proteinsaccompanies the development of cataract. A possible oxidant involved in the process may be H2O2. Determination of in vivo H2O2 levels in the aqueous, humor from cataract patients indicates a wide range from 10 to 660 μm. In seven of 17 cataract cases, significantly higher concentrations of H2O2 were noted in the aqueous fluid than was found with putative normal human cases. The H2O2 concentration determined from the cataractous lens population was found to be right skewed and lognormally distributed. The mean aqueous H2O2 concentration in cataractous patients was 69 μm (n=17) while for the putative normal patients it was 24 μm (n=5). These normal values were, within experimental error, the same as levels found in other normal animal aqueous: primates 27 μm (n=6) and bovine 25 μm (n=12). The total human primate aqueous H2O2 concentration was found to be normally distributed with a mean value of 26 μm. A small (P<0·1) but significant correlation was observed between high aqueous H2O2 and elevated lens H2O2. No significant correlation (P>0·1) was found with aqueous ascorbate levels. The source of presumptive exogenous H2O2 remains unknown.
Article
The authors have determined the content of the primary (diene conjugates), secondary (ketodienes) and the final (Schiff bases) free radical oxidation products (f.r.0.) of the lipids and also the content of the total and non-protein bound thiols in the human crystalline lenses at different stages of cataract development (the degree of clouding of the lens was determined by quantitative morphometric analysis). The involvement of the process of f.r.o. of the lipids in the genesis of clouding of the lens has been demonstrated. It is shown that the total thiols of the lens fibres are rapidly inactivated with increase in the intensity of the f.r.o. reactions of the lipids through drop in the level of glutathione. These processes promote the formation of high molecular weight protein aggregates in the lens and progression of the cataract. The coefficients of the linear correlation between these parameters are presented. It is concluded that the development of cataract may be prevented by lowering the level of accumulation of lipid peroxides and maintaining a high concentration of reduced glutathione in the lens.
Article
The objective of this manuscript is to test the efficacy of N(α)- acetylcarnosine for the treatment of senile cataract in humans. It was designed as a randomized controlled trial. Forty-nine subjects - volunteers (76 eyes) with an average age of 65.3 ± 7.0 years were enrolled and randomized into two groups at diagnosis of senile cataract. Changes in lens clarity were measured and quantitated over 6 to 24 months thereafter. Patients administered 1% N(α)-acetylcarnosine (NACA) (26 patients, 41 eyes = Group II), placebo composition (13 patients, 21 eyes) topically (two drops, twice daily) to the conjunctival sac, or were untreated (10 patients, 14 eyes); two latter groups of patients were combined into the control (reference) group I. Patients were evaluated upon entry, at every 2-month (Trial 1) and 6-month (Trial 2) intervals for best corrected visual acuity (b/c VA), by ophthalmoscopy, original techniques of glare test (Trial 1), stereocinematographic slit-image and retro-illumination photography with subsequent interactive digital image analysis and 3D computer graphics of the lens light scattering/absorbing centers. The intra-reader reproducibility of measuring techniques for cataractous changes was good with the overall average of correlation coefficients for image analytical data 0.830 and glare test readings 0.998. Group I of patients demonstrated the variability in densitometric readings of lens cloudings, negative advance in glare sensitivity over 6 months, and gradual deterioration of VA and gross transmissivity of lenses over 24 months comparatively to baseline and the 6- month follow-up examinations. As compared with baseline examination, over 6 months 41.5% of the eyes treated with NACA presented a significant improvement of the gross transmissivity degree of lenses, 90.0% of the eyes showed a gradual improvement in VA to 7-100% and 88.9% of the eyes ranged a 27-100% improvement in glare sensitivity. Topographic study demonstrated less density and corresponding areas of opacification in posterior subcapsular and cortical morphological regions of the lens consistent with VA up to 0.3. The total study period over 24 months revealed that the beneficial effect of NACA is sustainable. No cases resulted in a worsening of VA and image analytical readings of lenses in the NACA-treated group of patients. In most of the patients drug tolerance was good. Statistical analysis revealed the significant differences over 6 and 24 months in cumulative positive changes of overall characteristics of cataracts in the NACA-treated group II from the control group I. The N-acetylated imidazole-containing peptidomimetic NACA is proposed as an effective and physiologically acceptable drug for nonsurgical treatment of age-related and senile cataracts.
Article
Congress and the Health Care Finance Administration have recently targeted cataract extraction procedures for particular scrutiny and cost containment. The reasons have been amply stated: cataract surgery now accounts for 12% of the entire Medicare budget and is presently the most frequently performed surgical procedure reimbursed by Medicare.1 Given the apparent threefold or greater increase in the annual number of cataract operations in the past decade and the prediction by some that the number of intraocular lens (IOL) implantations will approach 2 million per year,2 regulators view cataract surgery as a growing threat to the health care budget. The Health Care Finance Administration has tried, largely in vain, to contain costs by reducing reimbursement. Increasing attention is therefore being given to the indications for surgery and ways to reduce what appears to be the inexorable growth in the number of cataract operations. Continued collection and analysis of
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Based on in vitro culture studies, it has been proposed that the photochemical generation of superoxide in the intraocular chambers provides a significant cataractous insult. Rat lens when maintained in medium generating excessive O is damaged as indexed by deterioration of the cation pump. If O levels are low (ambient levels), peroxidative degradation of lipids has been observed. These reactions are intuitively deleterious to tissue physiology and may contribute to the manner through which light may be toxic to lens in the long run, giving rise to senile cataracts. It was interesting to note that these deleterious reactions could be attenuated greatly by physiological levels of ascorbic acid. The significance of these in vitro studies to the in vitro situatiion as offered by the diurnal habitat of mankind remains yet to be known, but studies simulating such situation in experimental animal models are in progress.
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Abstract— We have compared the relative abilities of some putative biological protectors to block oxidation of 2,5-bis(hydroxymethyl)furan (BHMF)† in illuminated solutions containing the photosensitizer rose bengal and in the separated-surface-sensitizer (S-S-S) system involving pure singlet oxygen (1ΔAgO2). While L-histidine is a well-known quencher of singlet oxygen, free L-histidine is not commonly found in high concentrations in nature. L-Carnosine (β-alanyl-L-histidine), however, is present in the striated muscles of many organisms, most notably mammals, in concentrations up to 40 mM. At neutral pH, carnosine quenched singlet oxygen more effectively than did equimolar histidine, both in solubilized sensitizer studies and in the S-S-S system. In the pure singlet oxygen system, 1 mM carnosine reduced the rate of BHMF oxidation as effectively as 3 mM histidine alone, or a mixture of 3 mM histidine and 3 mMβ-alanine. The fungal product L-ergothioneine (2-thiol-L.-histidine betaine) and its synthetic analogue, 2-thiolhistidine, at 1 mM blocked photosensitized BHMF oxidation using solubilized rose bengal, as did urate at 0.5 mM. All three compounds failed to reduce the rate of BHMF oxidation by singlet oxygen in the S-S-S system, however. Homocarnosine (-γ-aminobutyryl-L-histidine) gave levels of protection against BHMF oxidation identical to histidine, but is present in the central nervous system only at micromolar concentrations. Neither 1 mM imidazole nor 5 mM urea reduced BHMF oxidation in either system. We conclude that some prevalent biomolecules may afford protection either by preventing singlet oxygen production (urate, L-ergothioneine) or by intercepting singlet oxygen once formed (L-carnosine). Such protective devices may be of importance in natural systems.
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A major high molecular weight disulfide-linked protein has been isolated from cataractous lenses. It is only present in the water-insoluble protein fractions. This species has not been found in normal lenses of comparable age. Upon reduction of this fraction, polypeptides having molecular weights of approximately 60,000, 43,000, and 20,000 as well as a noncharacterized heterogeneous species are released. Similar sized polypeptides have been found in various noncovalently linked aggregates in both normal and cataractous lenses. Examination of the disulfide-linked protein fraction indicates that approximately 70% of the sulfhydryl groups are in the oxidized state. Although little change in the sizes of the other major polypeptides in the water-insoluble fraction is observed upon reduction, these components were also found to contain an appreciable disulfide content. Such results indicate that the only major lens fraction containing disulfide-linked polypeptide is the high molecular weight species and that the disulfides present in the remaining fractions are either intrachain disulfides or link polypeptides to small peptides.
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Glucocorticoid-induced cataracts in chick embryos were monitored by an image analysis system. Opacities in the lens visually showed a complex pattern with significant changes in the cortical and nuclear regions. An electronic image analyser produced an image in which contrast represented different zones of lens opacification in the frontal plane and documented objective lens findings such as the precise topography of the opacities, density and opacity measurements, geometric measurements of boundary surfaces and of regional areas. Parameters of lens clouding were evaluated quantitatively by measuring the optical density index and the area of the zones of clouding outlined with equi-densities. The light intensity standard graded different morphological areas of the lens into up to 256 grey levels. The data were entered and stored quantitatively into a computer. The lens images thus picked up by the TV camera and digitally stored in a frame buffer of the measuring system could be reliably transformed into a 2-D or 3-D picture of lens clouding. The approach demonstrated by the current study provides a sensitive and meaningful measure of cataractous changes for lens laboratory research.
Article
It has been suggested by Sjostrand and his colleagues that an index of scatter by the ocular media may be derived from contrast sensitivity measured with and without a glare source. This index was tested under different conditions of stimulus luminance and found not to be constant and thus to not reflect a property of the media. Invest Ophthalmol Vis Sci 33:688-690,1992 Vos, Walraven, and van Meeteren 1 have proposed an empirical light scattering factor for the ocular me- dia (LSF) in terms of the illuminance on the eye from a glare source (E), an equivalent veiling luminance (Leq), and the glare angle (GA). Rearranging their equation (3) gives the following expression: LSF = Leq/E = k/(GA + 0.13) 2 - 8 for (0.15° < GA < 8°). (1) Paulsson and Sjostrand 2 have suggested that mea- surements of LSF may be developed into a useful clin- ical index of light scatter in the ocular media by deriv- ing an expression for LSF in terms of the contrast threshold without a glare source (Mj), threshold with a glare source (M2), mean luminance of the contrast target (L), and glare illuminance (E, same as above):
Article
Carnosinase from human plasma was purified 18,000-fold to apparent homogeneity in a four step procedure. The dipeptidase was partially inactivated during DEAE-cellulose chromatography; however, it reactivated slowly when concentrated and stored at 4 degrees C. In the second purification step, hydroxylapatite column chromatography, two forms of the enzyme were separated from one another. Human serum carnosinase was found to be a glycoprotein with a pI of 4.4 and a subunit Mr of 75,000; the active enzyme was a dimer, the two subunits being connected by one or more disulfide bonds. The enzyme was especially active in hydrolyzing carnosine and anserine, preferring dipeptides with histidine in the C-terminal position. In most human tissues, the concentration of serum carnosinase was proportional to the percentage of trapped blood in the sample. However, the brain contained about 9 times more enzyme than expected, based on the amount of trapped blood present. The physiological function of this enzyme seems to be the hydrolysis of homocarnosine in the brain and the splitting of carnosine and anserine in the blood stream. Six higher primates were found to have serum carnosinase. Twelve nonprimate mammals were tested; all were lacking the serum enzyme except for the Golden hamster, which had very high concentrations of a carnosinase having somewhat different properties than the higher primate enzyme.
Article
Biochemical evidence suggests that oxidative stress caused by accumulation of free radicals is involved in the pathogenesis of senile cataracts. If so, appropriate amounts of the antioxidant vitamins C and E might be expected to prevent or retard the process. Such activity has been observed in several in vitro and in vivo studies of experimentally-induced cataracts. A recent epidemiologic study found that cataract patients tended to have lower serum levels of vitamins C, E, or carotenoids than did control subjects. The present investigation, which compared the self-reported consumption of supplementary vitamins by 175 cataract patients with that of 175 individually matched, cataract-free subjects, revealed that the latter group used significantly more supplementary vitamins C and E (P = 0.01 and 0.004, respectively). Because the results suggested a reduction in the risk of cataracts of at least 50%, a randomized, controlled trial of vitamin supplementation in cataract prevention may be warranted.
Article
The cataractous lenses of patients with retinitis pigmentosa have been studied by electron microscopy. The posterior subcapsular opacities showed common ultrastructural features. Large areas of disruption of the lens fibre pattern were observed which showed an increase in the number of fibre membranes per unit area. In many regions an elaborate and regular folding of membranes was noted which produced complex 'figure-of-eight' and 'tramline' patterns, as well as membranous lamellar bodies. Masses of various size globules were also identified. It has been established that injection into the vitreous body of the rabbit eye of a suspension of liposomes prepared from phospholipids containing lipid peroxidation products induces the development of posterior subcapsular cataract. Such modelling of cataract is based on a type of clouding of the crystalline lens similar to that observed in cataract resulting from diffusion of toxic lipid peroxidation products from the retina to the lens through the vitreous body on degeneration of the photoreceptors. Saturated liposomes (prepared from beta-oleoyl-gamma-palmitoyl-L-alpha-phosphatidylcholine) do not cause clouding of the lens, which demonstrates the peroxide mechanism of the genesis of this form of cataract. Clouding of the lens is accompanied by accumulation of fluorescing lipid peroxidation products in the vitreous body, aqueous humor and the lens and also by a fall in the concentration of reduced glutathione in the lens. From the results it is concluded that lipid peroxidation may initiate the development of cataract.
Article
A method of classifying cataractous changes in excised human lenses, based on separate and independent photographic documentation, with consequent quantitative evaluation of lens opacification is proposed. The degree of lens clouding was evaluated quantitatively by measuring the optical density index and the area of the zones of clouding with certain optical density parameters (equidensities) by use of an image analyser. This technique produced an image in which contrast represented different zones of lens clouding in the frontal projection, and allowed their contribution to the total lens area to be determined. The precise topography of the opacities was established. The classification data obtained for different clinical types of cataracts can be simplified according to the needs of the scientist in his effort to measure clinically or scientifically significant quantitative associations between laboratory measures and cataractous changes.
Article
Lipid peroxidation was shown to be an initiatory cause of cataract development in some cases. It has been established that injection into the vitreous body of the rabbit eye of a suspension of liposomes prepared from phospholipids containing lipid peroxidation products induces the development of posterior subcapsular cataract. Such modelling of cataract is based on a type of clouding of the crystalline lens similar to that observed in cataract resulting from diffusion of toxic lipid peroxidation products from the retina to the lens through the vitreous body on degeneration of the photoreceptors. Saturated liposomes (prepared from dipalmitoylphosphatidylcholine) did not cause clouding of the lens, which demonstrated the peroxide mechanism of the genesis of this form of cataract. Clouding of the lens was accompanied by accumulation of fluorescing lipid peroxidation products in the vitreous body, aqueous humor and the lens and also by a fall in the concentration of reduced glutathione in the lens. The ability of L-carnosine (beta-alanyl-L-histidine) to interact directly with lipid peroxidation products suggested its anticataract properties. The effect of L-carnosine on inhibiting or reversing the formation of cataract induced by the administration of lipid peroxidation products was discovered. This phenomenon appeared to be related with normalization of the peroxide metabolism parameters in the crystalline lens. In view of the data, an aqueous solution of L-carnosine is physiologically acceptable in effective nonsurgical treatment of cataracts.
Article
It has been established that the development of cataract is accompanied by the formation of various fluorophores in the lipid fraction of the lens. These lipid-fluorescing products have been separated chromatographically according to polarity and molecular weight. It is shown that the initial stages of the development of cataract are characterized by the appearance of lipid fluorophores in the near ultraviolet and violet regions of the spectrum (excitation maximum 302-330 nm, emission maximum 411 nm) with low polarity and a small molecular weight; the maturing of the cataract is characterized by an increase in the intensity of the long-wave fluorescence of the lipids in the blue-green region (430-480 nm) and by the formation of polymeric high-molecular-weight fluorescing lipid products with high polarity. It has been demonstrated that the appearance of lipid fluorophores in the crystalline lens is associated with the free radical oxidative modification of the phospholipids and fatty acids in cataract.
Article
UV-spectrophotometry and fluorescent analysis were used to study lipid extracts from lenses, aqueous humour and blocks containing trabecular and Schlemms canal tissues, obtained from 49 eyes of patients with primary open-angle glaucoma (POAG). Accumulation of the primary, secondary, and end products of lipid peroxidation (LPO) (diene and triene conjugates, Schiff's bases) was noted in the studied extracts. Significant differences in the levels of all the mentioned LPO products in comparison with the control were observed. The data may be considered as an evidence of LPO participation in destruction of the trabecule and Schlemm's canal in POAG.
Article
The role of free-radical-induced lipid oxidation in the development of human lens opacity was studied. Physico-chemical parameters of the lens fiber membranes at different stages of cataract have been investigated. The deterioration of lens fiber plasma membranes structure preceding formation of large aggregates in lenticular matter, leading to lens opacity, was observed by electron microscopy. Initial stages of cataract were characterized by the accumulation of primary (diene conjugates, cetodienes) lipid peroxidation (LPO) products, while in the later stages there was a prevalence of end LPO fluorescent products. Reliable increase in oxiproducts of fatty acyl content of lenticular lipids was shown by direct gas chromatography technique obtaining fatty acid fluorine-substituted derivatives. The lens opacity degree is found to correlate with the level of the end LPO fluorescent product accumulation in its tissue, accompanied by SH group oxidation of crystallins due to decrease of reduced glutathione concentration in the lens. The injection of LPO products into the vitreous has been shown to induce cataract. It was concluded that peroxide damage of the lens fiber membranes may be the initiatory cause of cataract development.
Article
The experimental results suggest that the antioxidative function of carnosine is one of the most important manifestations of its biological role. The ability of carnosine to interact directly with lipid peroxidation products was demonstrated. The effects of carnosine on partial restoration of lens transparency in dog eyes with senile cataract which is known to be caused by lipid peroxidation were demonstrated "in vitro" and "in vivo".
Article
A free radical mechanism of cataractogenesis involving enzymatic and nonenzymatic reactions, is proposed. Supporting experimental evidence is briefly reviewed. H2O2, which is one of the toxic metabolites of oxygen, was significantly increased 2-3 fold in ocular humors in several experimental cataracts and in human senile cataract. Various cataractogenic agents were also found to increase H2O2 in ocular humors in vivo prior to cataract formation. Enzymatic defenses against O2-. and H2O2 provided by superoxide dismutase, catalase and glutathione peroxidase were impaired in cataracts. In some cataracts, catalase and superoxide dismutase were affected earlier. Malondialdehyde (MDA), a major breakdown product of lipid peroxides was significantly increased by 2-4-fold in human senile cataract, in cataracts induced in rabbit and rat, and in hereditary cataracts in mice. All the reactive species of O2 (O2-., H2O2, OH. and 1 delta gO2) may participate in initiating lipid peroxidation of lens in vitro. Various scavengers of these species were capable of preventing lenticular lipid peroxidation, amongst which OH. scavengers were found to be the most effective. Biological antioxidant, vitamin E afforded 44% prevention of lipid peroxidation in lens. The important observation was that vitamin E was therapeutically effective in about 50% of animals in arresting cataract induced in rabbit by 3-aminotriazole. In these rabbits, H2O2 and ascorbic acid of ocular humors and MDA of lens were close to normal. It is our working hypothesis that the carbonyl groups of MDA and amino groups of amino acids, proteins, nucleic acids and their bases, and phospholipids could interact in a cross-linking reaction producing high molecular weight aggregates by Schiff-base conjugate formation in addition to disulfide cross-linking of proteins, and finally resulting in cataract.
Article
The mechanism of oxidative damage to the lens through intraocular photochemical generation of superoxide and its derivatization to other oxidants such as singlet oxygen, hydroxyl radical and hydrogen peroxide has been studied. Rat lenses when organ cultured aerobically in TC 199 containing additional amounts of riboflavin were damaged as demonstrated by an inhibition of the uptake of Rb 86 against a concentration gradient. The pump was not affected by light if the culture was conducted in the basal TC 199. However, light was observed to induce significant peroxidative degradation of the tissue lipids even in the basal medium, the degradation being indicated by the formation of malonaldehyde. Both the inhibition of the pump as well as the peroxidative degradation of the tissue lipids, were attenuated considerably by scavengers of superoxide and hydrogen peroxide. In addition, the lipid degradation was prevented by vitamins C and E. The results suggest that the photodynamic injury to the lens cation pump as well as to membrane lipids is incumbent upon an initial generation of superoxide and its derivatization to other oxidants. Thus, the ocular lens is susceptible to oxidative insult and physiological damage through photocatalytic generation of various oxygen radicals. Large concentrations of ascorbic acid in the aqueous humor seems to be able to provide significant protection against such an insult. Thus, this may be one of the functions of high concentration of ascorbic acid in the aqueous humor. The implication of oxidative stress has also been examined in the genesis of cataracts in vivo. Treatment with vitamin E of the Emory mouse led to a decrease in the rate of cataract progression suggesting that at least in some instances an oxidative stress could participate in the formation of cataracts. Oxygen radicals may inflict damage at multifarious biochemical sites. Human lens lipids were also shown to have an absorption maxima at 239 nm indicating their susceptibility to oxidative degradation. In addition the lipid extract has fluorescence similar to that of lipofuscins. The levels of MDA were higher in the brunescent cataracts as compared to that in the nonbrunescent cataracts. The implications of oxidative stress towards the genesis of cataracts in humans is being explored further.
Article
Dipivefrin is a prodrug of epinephrine which is hydrolyzed to epinephrine after absorption into the eye. The major site of this hydrolysis is shown to be the cornea. Some dipivefrin is absorbed unchanged into ocular tissues, but most appears as epinephrine and its metabolites within 15 min after topical application. Metanephrine is the major metabolite of epinephrine found in ocular tissues. It is found as soon as 15 min aftter application of either dipivefrin or epinephrine and appears in all the tissues tested. The data indicate that the peinephrine which is liberated by hydrolysis of topically applied dipivefrin is metabolized similarly to topically applied epinephrine. The monoamine oxidase metabolites of epinephrine appear 1 to 3 hr after treatment and are found mainly in the aqueous humor. After ocular application of either compound there appear to be uptake and storage of the exogenous epinephrine in the iris plus ciliary body. There is also some storage of unmetabolized epinephrine in the cornea.
Article
Carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) are natural imidazole-containing compounds found in the non-protein fraction of mammalian tissues. Carcinine was synthesized by an original procedure and characterized. Both carnosine and carcinine (10-25 mM) are capable of inhibiting the catalysis of linoleic acid and phosphatidylcholine liposomal peroxidation (LPO) by the O2(-.)-dependent iron-ascorbate and lipid-peroxyl-radical-generating linoleic acid 13-monohydroperoxide (LOOH)-activated haemoglobin systems, as measured by thiobarbituric-acid-reactive substance. Carcinine and carnosine are good scavengers of OH. radicals, as detected by iron-dependent radical damage to the sugar deoxyribose. This suggests that carnosine and carcinine are able to scavenge free radicals or donate hydrogen ions. The iodometric, conjugated diene and t.l.c. assessments of lipid hydroperoxides (13-monohydroperoxide linoleic acid and phosphatidylcholine hydroperoxide) showed their efficient reduction and deactivation by carnosine and carcinine (10-25 mM) in the liberated and bound-to-artificial-bilayer states. This suggests that the peroxidase activity exceeded that susceptible to direct reduction with glutathione peroxidase. Imidazole, solutions of beta-alanine, or their mixtures with peptide moieties did not show antioxidant potential. Free L-histidine and especially histamine stimulated iron (II) salt-dependent LPO. Due to the combination of weak metal chelating (abolished by EDTA), OH. and lipid peroxyl radicals scavenging, reducing activities to liberated fatty acid and phospholipid hydroperoxides, carnosine and carcinine appear to be physiological antioxidants able to efficiently protect the lipid phase of biological membranes and aqueous environments.
Article
Blindness due to cataract continues to take a heavy toll on economic, social, and personal resources. Research into factors that may cause or prevent cataracts is of the highest priority. In this paper, the epidemiological evidence is summarized on the role of sunlight exposure and antioxidants for cataract. To date, there are consistent findings linking ultraviolet B (UV-B) radiation to cataract, particularly cortical and posterior subcapsular opacities. Antioxidants are likely to exert a protective effect against oxidative stress in the lens, but the current epidemiologic data present less coherent support for this hypothesis. Difficulties in summarizing these data include different methods for assessing antioxidant status, widely varying populations, and different research designs. Nevertheless, most studies have found some measure of antioxidant status to be associated with some type of cataract. Future research directions are described.
Article
Lipid peroxidation (LPO) could be one of the mechanisms of cataractogenesis, initiated by enhanced production of oxygen free radicals in the eye fluids and tissues and impaired enzymatic and non-enzymatic defences of the lens. The increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides) and end fluorescent LPO products were detected in the lipid moiety of the aqueous humor samples obtained from patients with cataract as compared to normal donors. Isolated human transparent and cataractous lenses and normal mouse and rabbit lenses were incubated with liposomes in organ culture in the presence and absence of LPO inhibitors, free radical scavengers and enzymes (catalase, superoxide dismutase (SOD)) in order to examine the potential of the lenses to induce LPO in the surrounding medium. LPO assayed spectrophotometrically were diene and triene conjugates, and malonaldehydes (MDA) were determined as thiobarbituric acid-reactive material. A chemiluminescence detection catalysed by peroxidase was used to measure H2O2 and O2-. was assayed spectrophotometrically using cytochrome C reduction. The level of lipid peroxides in liposomes was significantly (2.5-4.5-fold) higher after 3 h of incubation of the transparent lenses (or the lenses at the initial stage of cataract) than after the proper time of incubation of human mature cataractous lenses and virtually no oxidation of liposomes was detected in the absence of the lens. LPO in this system was decreased in the presence of free radical scavengers and enzymes that degrade H2O2 (EDTA, SOD, L-carnosine, chelated iron and catalase). The most effective agent was EDTA which chelates the free metal cations required to generate O2-. radicals that initiate the free radical process culminating in LPO. Lenses generated more H2O2 into the medium in the presence of exogenous ascorbate. Release of the oxidants, (O2-., H2O2, OH. and lipid hydroperoxides) by the intact lenses in the absence of respiratory inhibitors indicates that these metabolites are normal physiological products inversely related to the lens life-span potential (maturity of cataract) generated, probably, through the metal-ion catalysed redox-coupled pro-oxidant activation of the lens reductants (ascorbic acid, glutathione).
Article
Lipid peroxidation (LPO) is a causative factor of cataract. The increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides) and end fluorescent LPO products, were detected in the lipid moieties of the aqueous humor samples obtained from patients with senile and complicated cataracts as compared to normal donors. The degrees of lens clouding were assessed quantitatively by measuring the optical density indices and areas of equidensities using digital image analysis. Human cataractous lenses showed decreased activity of glutathione peroxidase (GPX, catalyzing reduction of organic hydroperoxides including hydroperoxides of lipids). The apparent Km for tert-butylhydroperoxide was 0.434 mM for human normal and cataractous lens GPX. When lenses were exposed for 1 h at 37 degrees C to linoleic acid hydroperoxide (LOOH, 0.5 mM) or egg phosphatidyl-choline hydroperoxide (PLOOH, 1 micro mol per 112 micro mol of phospholipid) in liposomes suspended in the incubation medium, normal, immature and mature human cataractous lenses showed a significant loss in the residual content of liberated LOOH to 62%, 38% or 17%, correspondingly, but little or no reduction was observed with PLOOH in liposomal membranes. Human, rabbit or mice transparent or immature cataractous lenses induced significantly more absorbance changes in conjugated diene, iodometric and TBA-reactive substance measurements when incubated with liposomal membranes which were decreased in the presence of free radical scavengers and antioxidant enzymes (EDTA, SOD, L-carnosine, chelated iron, catalase). Injection into the vitreous body of the rabbit eye of a suspension of liposomes prepared from phospholipids containing LPO products induced the development of posterior subcapsular cataract. Saturated liposomes did not cause clouding of the lens. This modelling of cataract was accompanied by accumulation of fluorescing LPO products in the vitreous body, aqueous humor and the lens and also by a fall in the concentration of GSH in the lens. The peroxidative damage to the lens cell membranes and biomolecules induced in the lack of reductive detoxification of phospholipid hydroperoxides is proposed as the triggering mechanism of cataractogenesis.
Article
The naturally occurring compound N alpha-acetylcarnosine (NAC) is proposed as the prodrug of L-carnosine (C) resistant to enzymatic hydrolysis by human serum carnosinase. Rabbit eyes were treated with 1% NAC, C or placebo and extracts of the aqueous humor from the anterior eye chamber were analyzed for imidazole content by reverse phase analytical high performance liquid chromatography (HPLC), thin-layer (TLC) and ion-exchange chromatographic techniques. The topical administration of pure C to the rabbit eye did not lead to accumulation of this compound in the aqueous humor over 30 min in concentration exceeding that in the placebo-treated matched eye. NAC showed dose-dependent hydrolysis in its passage from the cornea to the aqueous humor, releasing C after 15. 30 min of ocular administration of prodrug in a series of therapeutical modalities: instillation < or = subconjunctival injection < or = ultrasound induced phoresis. Different treatment techniques showed excellent toleration of 1% NAC by the eye. Once in the aqueous humor, C might act as an antioxidant and enter the lens tissue when present at effective concentrations (5-15 mmol/l). The advantage of the ophthalmic prodrug NAC and its bioactivated principle C as universal antioxidants relates to their ability to give efficient protection against oxidative stress both in the lipid phase of biological membranes and in an aqueous environment. NAC is proposed to treat ocular disorders which have the component of oxidative stress in their genesis (cataracts, glaucoma, retinal degeneration, corneal disorders, ocular inflammation, complications of diabetes mellitus, systemic diseases).
Article
This communication briefly reviews aspects of oxidative stress and disease, particularly maturity onset cataract. The review considers a number of issues such as why lens and cataract research is important, what is oxidative stress, its relationship to disease and how does a tissue defend itself against such stress. Three diseases (chronic lung disease, diabetes and Alzheimer's disease) in which oxidative stress has differing roles are briefly discussed. The impact of oxidative stress upon the development of maturity onset cataract is considered and approaches are delineated which will establish the importance of such stress.
Article
The naturally occurring compound Nalpha-acetylcarnosine is proposed as a prodrug of L-carnosine that is resistant to enzymatic hydrolysis by carnosinase. Eyes of rabbits were treated with 1% Nalpha-acetylcarnosine, L-carnosine, or placebo and extracts of the aqueous humor from the anterior eye chamber were analyzed for imidazole content by reverse-phase analytical high performance liquid chromatography (HPLC) and thin-layer (TLC) and ion-exchange chromatographic techniques. Topical administration of pure L-carnosine to the rabbit eye did not lead to accumulation of this compound in the aqueous humor over 30 min in concentration exceeding that in the placebo-treated matched eye. Nalpha-Acetylcarnosine showed dose-dependent hydrolysis in its passage from the cornea to the aqueous humor, releasing L-carnosine after l5-30 min of ocular administration of the prodrug in a series of therapeutic modalities: instillation < or = subconjunctival injection < or = ultrasound-induced phoresis. Different treatment techniques showed excellent toleration of 1%Nalpha-acetylcarnosine by the eye. Once in the aqueous humor, L-carnosine might act as an antioxidant and enter the lens tissue when present at effective concentrations (5-l5 mM). The advantage of the ophthalmic prodrug Nalpha-acetylcarnosine and its bioactivated principle L-carnosine as universal antioxidants relates to their ability to give efficient protection against oxidative stress both in the lipid phase of biological membranes and in aqueous environments. Nalpha-Acetylcarnosine is proposed for treatment of ocular disorders that have a component of oxidative stress in their genesis (cataracts, glaucoma, retinal degeneration, corneal disorders, ocular inflammation, complications of diabetes mellitus, and systemic diseases).
Article
A study was designed to document and quantify the changes in lens clarity over 6 and 24 months in 2 groups of 49 volunteers (76 eyes) with an average age of 65.3 +/- 7.0 enrolled at the time of diagnosis of senile cataracts of minimal to advanced opacification. The patients received N-acetylcarnosine, 1% sol (NAC) (26 patients, 41 eyes = Group II), placebo composition (13 patients, 21 eyes) topically (two drops, twice daily) to the conjunctival sac, or were untreated (10 patients, 14 eyes); the placebo and untreated groups were combined into the control (reference) Group I. Patients were evaluated upon entry, at 2-month (Trial 1) and 6-month (Trial 2)-intervals for best corrected visual acuity (b/c VA), by ophthalmoscopy and the original techniques of glare test (for Trial 1), stereocinematographic slit-image and retro-illumination photography with subsequent scanning of the lens. The computerized interactive digital analysis of obtained images displayed the light scattering/absorbing centers of the lens into 2-D and 3-D scales. The intra-reader reproducibility of measuring techniques for cataractous changes was good, with the overall average of correlation coefficients for the image analytical data 0.830 and the glare test readings 0.998. Compared with the baseline examination, over 6 months 41.5% of the eyes treated with NAC presented a significant improvement of the gross transmissivity degree of lenses computed from the images, 90.0% of the eyes showed a gradual improvement in b/c VA to 7-100% and 88.9% of the eyes ranged a 27-100% improvement in glare sensitivity. Topographic studies demonstrated less density and corresponding areas of opacification in posterior subcapsular and cortical morphological regions of the lens consistent with VA up to 0.3. The total study period over 24 months revealed that the beneficial effect of NAC is sustainable. No cases resulted in a worsening of VA and image analytical readings of lenses in the NAC-treated group of patients. In most of the patients drug tolerance was good. Group I of patients demonstrated the variability in the densitometric readings of the lens cloudings, negative advance in glare sensitivity over 6 months and gradual deterioration of VA and gross transmissivity of lenses over 24 months compared with the baseline and 6-month follow-up examinations. Statistical analysis revealed the significant differences over 6 and 24 months in cumulative positive changes of overall characteristics of cataracts in the NAC-treated Group II from the control Group I. The N-acetylated form of natural dipeptide L-carnosine appears to be suitable and physiologically acceptable for nonsurgical treatment for senile cataracts.
Article
1. 1. Soluble proteins of normal lenses contain much more cysteine than cystine. 2. 2. The oxido-reductive equilibrium between the two amino acids is shifted toward cystine in lenses with senile cataract. 3. 3. This shift already appears in the non-opaque portions of partial cataracts. 4. 4. The sum of cysteine and cystine in the albumoid is considerably increased in total cataracts. 5. 5. The possible significance of these changes for the pathogenesis of cataract is discussed.
N-Acetylcarnosine, a natural histidine-containing dipeptide, as a potent ophthalmic drug in treatment of human cataracts Image analysis of the lens opacities induced in developing chick embryo by glucocorticoid
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Babizhayev MA, Deyev AI, Yermakova VN, et al. N-Acetylcarnosine, a natural histidine-containing dipeptide, as a potent ophthalmic drug in treatment of human cataracts. Peptides 2001; 22 (6): 979-94 36. Babizhayev MA, Zhukotskii AV, Sologub AA. Image analysis of the lens opacities induced in developing chick embryo by glucocorticoid. Exp Eye Res 1992; 55: 521-37
Lipid peroxidation in open-angle glaucoma 371-7 Correspondence and offprints: Dr Mark A. Babizhayev, Innovative Vision Products, Inc., Moscow Division Suite 74, Russia. E-mail: markbabizhayev@yahoo.com N-Acetylcarnosine in Cataracts 103  Adis International Limited. All rights reserved
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Babizhayev MA, Bunin AYa. Lipid peroxidation in open-angle glaucoma. Acta Ophthalmol (Copenh) 1989; 67: 371-7 Correspondence and offprints: Dr Mark A. Babizhayev, Innovative Vision Products, Inc., Moscow Division, Ivanovskaya 20, Moscow 127434, Suite 74, Russia. E-mail: markbabizhayev@yahoo.com N-Acetylcarnosine in Cataracts 103  Adis International Limited. All rights reserved. Drugs R&D 2002; 3 (2)
Free radical oxidation of lipids and thiol groups in genesis of cataract Babizhayev MA. Lipid fluorophores of the human crystalline lens with cataract
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Leading causes of visual impairment worldwide
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Photochemical mechanisms in cataract formation Mechanisms of cataract formation in human lens
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Pharmaceuticals containing N-acetylcarnosine aluminium salt for treatment of gastric ulcer Japanese Patent Nippon Chemiphar Co. Ltd
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Pharmaceutical compositions containing N-acetylcarnosine for the treatment of cataract
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= deterioration; improve. = improvement; unchang. = unchanged
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Deterior. = deterioration; improve. = improvement; unchang. = unchanged. References
Detection, characterization, and quantification of carnosine and other histidyl derivatives in cardiac and skeletal muscle
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O'Dowd JJ, Robins DJ, Miller DJ. Detection, characterization, and quantification of carnosine and other histidyl derivatives in cardiac and skeletal muscle. Biochim Biophys Acta, 1988; 967: 241-9