Anales De La Real Academia Nacional De Farmacia, 2019
espanolMelatonina es una neurohormona sintetizada en varias estructuras oculares, aparte de su fu... more espanolMelatonina es una neurohormona sintetizada en varias estructuras oculares, aparte de su fuente original, la glandula pineal. Es de gran importancia por varias funciones, como el mantenimiento de valores saludables de presion intraocular. Ademas, disminuye la presion intraocular en el caso de glaucoma. Esta nuerohormona se controla mediante la activacion de un fotopigmento responsable de las tareas no relacionada con la formacion de imagenes en el ojo, este fotopigmento es la Melanopsina, presente en una subclase de celulas ganglionares de la retina y, muy recientemente, se descubrio en diferentes estructuras oculares. Cuando la melanopsina se activa por el componente de longitud de onda corta de la luz, suprime la sintesis de melatonina. Esta accion esta controlada principalmente por la luz que podria afectar varias funciones, incluida la regulacion de la presion intraocular. En este sentido, el presente trabajo destaca la historia y la importancia de la relacion entre la melatonina y la melanopsina para mantener una homeostasis ocular saludable. EnglishMelatonin is a neurohormone synthesized in several ocular structures apart from its original source, the pineal gland. It is of great importance in several functions such as maintaining a healthy values of intraocular pressure. Moreover, it decreases intraocular pressure in the case of glaucoma. This nuerohormone is controlled by the activation of a photopigment responible for non-image forming tasks in the eye, this photopigment is Melanopsin, present in a subclass of retinal ganglion cells, and very recently, it was discovered in different ocular structures. When Melanopsin is activated by the short wavelength component of light, it supresses Melatonin synthesis. This action is controlled mainly by light could affect several functions including the regulation of intraocular pressure. In this sense, the present work highlights the history and importance of the relationship between both Melatonin and Melanopsin to maintain a healthy ocular homeostasis.
Anales De La Real Academia Nacional De Farmacia, Apr 24, 2019
Melatonin is a neurohormone synthesized in several ocular structures apart from its original sour... more Melatonin is a neurohormone synthesized in several ocular structures apart from its original source, the pineal gland. It is of great importance in several functions such as maintaining a healthy values of intraocular pressure. Moreover, it decreases intraocular pressure in the case of glaucoma. This nuerohormone is controlled by the activation of a photopigment responible for non-image forming tasks in the eye, this photopigment is Melanopsin, present in a subclass of retinal ganglion cells, and very recently, it was discovered in different ocular structures. When Melanopsin is activated by the short wavelength component of light, it supresses Melatonin synthesis. This action is controlled mainly by light could affect several functions including the regulation of intraocular pressure. In this sense, the present work highlights the history and importance of the relationship between both Melatonin and Melanopsin to maintain a healthy ocular homeostasis
Oxidative stress, generated because of an imbalance between reactive oxygen species (ROS) generat... more Oxidative stress, generated because of an imbalance between reactive oxygen species (ROS) generation and elimination, is associated with lens damage and cataract progression. ROS generation is known to activate NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-cointaining 3) inflammasome, and is believed to be an important link between oxidative stress and inflammation, that is also related to cataract development. Potential oxidative hazard to the lens by white light-emitting diode (LED) light, a source of illumination commonly used nowadays, has been suggested, although available information is limited. In this work, we evaluated the cytotoxicity induced by hydrogen peroxide (an oxidative stressor agent) and white LED light in lens epithelial cells as well as melatonin ability to counteract the effects induced by them. Melatonin is a neurohormone secreted by different ocular structures that could be useful to alleviate oxidative damage induced by different oxidative stressors in lens. Particularly, the modulation of Nrf2 (nuclear erythroid 2-related factor)/Keap 1 (Kelch-like ECH-associated protein 1), an essential oxidative stress regulator, and NLRP3 activity by melatonin was evaluated in lens epithelial cells. ROS levels rose after white LED light exposure and cell viability was reduced after challenge with oxidative stressor agents. Melatonin prevented cell death triggered by hydrogen peroxide and white LED light, precluded ROS generation induced by white LED light and promoted antioxidant lens capacity through upregulation of Nrf2 protein levels and SOD activity. NLRP3, caspase-1 and IL1-β expression significantly increased in human lens cells exposed to H2O2 or irradiated with white LED light. Activation of NLRP3 inflammasome triggered by oxidative stressors was also abrogated by melatonin. Attenuation of inflammatory and cytotoxic effects induced by oxidative stressors provided by melatonin in lens indicate the interest of this molecule as a potential therapeutic agent for cataract prevention/management.
Journal of Photochemistry and Photobiology B: Biology, 2021
Melatonin is mainly secreted by the pineal gland, and it is also produced by various ocular struc... more Melatonin is mainly secreted by the pineal gland, and it is also produced by various ocular structures such as the lens. It has been recently demonstrated that melatonin ocular synthesis can be induced by blocking the blue component of white light by means of filters. Melatonin exhibits antioxidant properties that can be useful to face light-induced oxidative stress as well as oxidative events associated to ocular pathologies like cataracts. Moreover, as oxidative stress is a main event in cataract development, changes in melatonin levels could happen and be relevant in the progression of this pathology, a subject that remains uncertain. The goal of this work was to analyze the ability of a short wavelength light blocking (yellow) filter to modulate endogenous melatonin concentration and the antioxidant and cytoprotective actions induced by yellow filter's use in lens. Furthermore, we evaluated the potential changes in aqueous humor melatonin concentration from patients with cataracts. In human lens epithelial cells, white light-emitting diode (LED) light challenge reduced melatonin secretion, protein levels of the enzymes involved in melatonin synthesis (hydroxyindole-O-methyltransferase and unphosphorylated and phosphorylated forms of arylalkylamine N-acetyltransferase) and cell viability whereas increased reactive oxygen species production. Yellow filter exposure precluded melatonin secretion reduction and protected cells from oxidative damage. Consistent with cataract patient's results, significantly lower levels of melatonin were observed in aqueous humor of alloxan-induced diabetic cataract rabbits as compared to those of control rabbits. In contrast, aqueous humor melatonin levels of diabetic cataract animals maintaining in cages covered with a yellow filter resembled control values. This recovery seems to be mediated by the induction of melatonin biosynthetic enzymes protein expression. Yellow filter also preserved Nrf2 lens protein expression and superoxide dismutase protein levels and activity in diabetic animals. Modulation of endogenous ocular melatonin concentration using blocking filters might be a promising approach to prevent premature lens opacification.
BackgroundThere is currently a lack of information regarding ocular tropism and the severe acute ... more BackgroundThere is currently a lack of information regarding ocular tropism and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Globally, the cumulative number of coronavirus disease 2019 (COVID-19) cases is increasing daily. Thus the potential for ocular transmission and manifestations of SARS-CoV-2 requires more investigation.MethodsA systematic search of electronic databases for ocular transmission and manifestations of SARS-CoV-2 was performed. Pooled cross-sectional studies were used for conducting a meta-analysis to estimate the prevalence of ocular transmission of SARS-CoV-2 to the respiratory system and ocular manifestations (associated symptoms) of SARS-CoV-2.ResultsThe highest prevalence of SARS-CoV-2-positive tears using reverse transcription polymerase chain reaction was found to be 7.5%. However, the highest prevalence of ocular conjunctivitis associated with SARS-CoV-2 was 32%. Thus, SARS-CoV-2 can evidently infect the eye, as revealed in the conjunct...
Background: Experiments in the late nineties showed an inverse relationship in the eye levels of ... more Background: Experiments in the late nineties showed an inverse relationship in the eye levels of melatonin and dopamine, thereby constituting an example of eye parameters that are prone to circadian variations. The underlying mechanisms are not known but these relevant molecules act via specific cell surface dopamine and melatonin receptors. This study investigated whether these receptors formed heteromers whose function impact on eye physiology. We performed biophysical assays to identify interactions in heterologous systems. Particular heteromer functionality was detected using Gi coupling, MAPK activation, and label-free assays. The expression of the heteroreceptor complexes was assessed using proximity ligation assays in cells producing the aqueous humor and human eye samples. Dopamine D3 receptors (D3Rs) were identified in eye ciliary body epithelial cells. We discovered heteromers formed by D3R and either MT1 (MT1R) or MT2 (MT2R) melatonin receptors. Heteromerization led to th...
This is a pre-registered study, i.e. a study whose hypotheses and experiments designed to address... more This is a pre-registered study, i.e. a study whose hypotheses and experiments designed to address these hypotheses have been deposited in a database before starting the experiments. The study aims at assessing the Gs versus Gi coupling and the potency of melatonin in the human version of melatonin MT1 and MT2 G-protein-coupled receptors expressed in HEK-293T cells. The results show that these receptors are Gi but not Gs coupled. By using a standard procedure of modulation of 0.5 µM forskolin-induced cAMP levels, it was found that the potency on MT2 receptor-mediated actions is in the low nanomolar range, but the potency on MT1 receptor is in the high nanomolar range. The potency of melatonin to stimulate the MT2 receptor is similar to that of a selective agonist, N-[2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethyl]butanamide (IIK7). Overall, the data on the potency of melatonin on its receptors will provide a new look for melatonin research. It is important to consider this findin...
Melatonin regulates intraocular pressure (IOP) whose increase leads to glaucoma and eye nerve deg... more Melatonin regulates intraocular pressure (IOP) whose increase leads to glaucoma and eye nerve degeneration. Aiming at elucidating the role of melatonin receptors in humour production and IOP maintenance, we here demonstrate that glaucoma correlates with disassembly of α1-adrenergic/melatonin receptor functional units in cells producing the aqueous humour. Remarkably, α1-adrenoceptor-containing complexes do not coupled to the cognate Gq protein and, hence, phenylephrine activation of these receptors does not lead to Ca2+ mobilization. Functional complexes are significantly decreased in models of glaucoma and, more importantly, in human samples of glaucoma patients (GP). In such glaucomatous conditions phenylephrine produces, via α1-adrenoceptor activation, an increase in cytoplasmic [Ca2+] that is detrimental in glaucoma. The results led to hypothesize that using melatonin, a hypotensive agent, plus blockade of α1-adrenergic receptors may normalize pressure in glaucoma. Remarkably, c...
Anales De La Real Academia Nacional De Farmacia, 2019
espanolMelatonina es una neurohormona sintetizada en varias estructuras oculares, aparte de su fu... more espanolMelatonina es una neurohormona sintetizada en varias estructuras oculares, aparte de su fuente original, la glandula pineal. Es de gran importancia por varias funciones, como el mantenimiento de valores saludables de presion intraocular. Ademas, disminuye la presion intraocular en el caso de glaucoma. Esta nuerohormona se controla mediante la activacion de un fotopigmento responsable de las tareas no relacionada con la formacion de imagenes en el ojo, este fotopigmento es la Melanopsina, presente en una subclase de celulas ganglionares de la retina y, muy recientemente, se descubrio en diferentes estructuras oculares. Cuando la melanopsina se activa por el componente de longitud de onda corta de la luz, suprime la sintesis de melatonina. Esta accion esta controlada principalmente por la luz que podria afectar varias funciones, incluida la regulacion de la presion intraocular. En este sentido, el presente trabajo destaca la historia y la importancia de la relacion entre la melatonina y la melanopsina para mantener una homeostasis ocular saludable. EnglishMelatonin is a neurohormone synthesized in several ocular structures apart from its original source, the pineal gland. It is of great importance in several functions such as maintaining a healthy values of intraocular pressure. Moreover, it decreases intraocular pressure in the case of glaucoma. This nuerohormone is controlled by the activation of a photopigment responible for non-image forming tasks in the eye, this photopigment is Melanopsin, present in a subclass of retinal ganglion cells, and very recently, it was discovered in different ocular structures. When Melanopsin is activated by the short wavelength component of light, it supresses Melatonin synthesis. This action is controlled mainly by light could affect several functions including the regulation of intraocular pressure. In this sense, the present work highlights the history and importance of the relationship between both Melatonin and Melanopsin to maintain a healthy ocular homeostasis.
Anales De La Real Academia Nacional De Farmacia, Apr 24, 2019
Melatonin is a neurohormone synthesized in several ocular structures apart from its original sour... more Melatonin is a neurohormone synthesized in several ocular structures apart from its original source, the pineal gland. It is of great importance in several functions such as maintaining a healthy values of intraocular pressure. Moreover, it decreases intraocular pressure in the case of glaucoma. This nuerohormone is controlled by the activation of a photopigment responible for non-image forming tasks in the eye, this photopigment is Melanopsin, present in a subclass of retinal ganglion cells, and very recently, it was discovered in different ocular structures. When Melanopsin is activated by the short wavelength component of light, it supresses Melatonin synthesis. This action is controlled mainly by light could affect several functions including the regulation of intraocular pressure. In this sense, the present work highlights the history and importance of the relationship between both Melatonin and Melanopsin to maintain a healthy ocular homeostasis
Oxidative stress, generated because of an imbalance between reactive oxygen species (ROS) generat... more Oxidative stress, generated because of an imbalance between reactive oxygen species (ROS) generation and elimination, is associated with lens damage and cataract progression. ROS generation is known to activate NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-cointaining 3) inflammasome, and is believed to be an important link between oxidative stress and inflammation, that is also related to cataract development. Potential oxidative hazard to the lens by white light-emitting diode (LED) light, a source of illumination commonly used nowadays, has been suggested, although available information is limited. In this work, we evaluated the cytotoxicity induced by hydrogen peroxide (an oxidative stressor agent) and white LED light in lens epithelial cells as well as melatonin ability to counteract the effects induced by them. Melatonin is a neurohormone secreted by different ocular structures that could be useful to alleviate oxidative damage induced by different oxidative stressors in lens. Particularly, the modulation of Nrf2 (nuclear erythroid 2-related factor)/Keap 1 (Kelch-like ECH-associated protein 1), an essential oxidative stress regulator, and NLRP3 activity by melatonin was evaluated in lens epithelial cells. ROS levels rose after white LED light exposure and cell viability was reduced after challenge with oxidative stressor agents. Melatonin prevented cell death triggered by hydrogen peroxide and white LED light, precluded ROS generation induced by white LED light and promoted antioxidant lens capacity through upregulation of Nrf2 protein levels and SOD activity. NLRP3, caspase-1 and IL1-β expression significantly increased in human lens cells exposed to H2O2 or irradiated with white LED light. Activation of NLRP3 inflammasome triggered by oxidative stressors was also abrogated by melatonin. Attenuation of inflammatory and cytotoxic effects induced by oxidative stressors provided by melatonin in lens indicate the interest of this molecule as a potential therapeutic agent for cataract prevention/management.
Journal of Photochemistry and Photobiology B: Biology, 2021
Melatonin is mainly secreted by the pineal gland, and it is also produced by various ocular struc... more Melatonin is mainly secreted by the pineal gland, and it is also produced by various ocular structures such as the lens. It has been recently demonstrated that melatonin ocular synthesis can be induced by blocking the blue component of white light by means of filters. Melatonin exhibits antioxidant properties that can be useful to face light-induced oxidative stress as well as oxidative events associated to ocular pathologies like cataracts. Moreover, as oxidative stress is a main event in cataract development, changes in melatonin levels could happen and be relevant in the progression of this pathology, a subject that remains uncertain. The goal of this work was to analyze the ability of a short wavelength light blocking (yellow) filter to modulate endogenous melatonin concentration and the antioxidant and cytoprotective actions induced by yellow filter's use in lens. Furthermore, we evaluated the potential changes in aqueous humor melatonin concentration from patients with cataracts. In human lens epithelial cells, white light-emitting diode (LED) light challenge reduced melatonin secretion, protein levels of the enzymes involved in melatonin synthesis (hydroxyindole-O-methyltransferase and unphosphorylated and phosphorylated forms of arylalkylamine N-acetyltransferase) and cell viability whereas increased reactive oxygen species production. Yellow filter exposure precluded melatonin secretion reduction and protected cells from oxidative damage. Consistent with cataract patient's results, significantly lower levels of melatonin were observed in aqueous humor of alloxan-induced diabetic cataract rabbits as compared to those of control rabbits. In contrast, aqueous humor melatonin levels of diabetic cataract animals maintaining in cages covered with a yellow filter resembled control values. This recovery seems to be mediated by the induction of melatonin biosynthetic enzymes protein expression. Yellow filter also preserved Nrf2 lens protein expression and superoxide dismutase protein levels and activity in diabetic animals. Modulation of endogenous ocular melatonin concentration using blocking filters might be a promising approach to prevent premature lens opacification.
BackgroundThere is currently a lack of information regarding ocular tropism and the severe acute ... more BackgroundThere is currently a lack of information regarding ocular tropism and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Globally, the cumulative number of coronavirus disease 2019 (COVID-19) cases is increasing daily. Thus the potential for ocular transmission and manifestations of SARS-CoV-2 requires more investigation.MethodsA systematic search of electronic databases for ocular transmission and manifestations of SARS-CoV-2 was performed. Pooled cross-sectional studies were used for conducting a meta-analysis to estimate the prevalence of ocular transmission of SARS-CoV-2 to the respiratory system and ocular manifestations (associated symptoms) of SARS-CoV-2.ResultsThe highest prevalence of SARS-CoV-2-positive tears using reverse transcription polymerase chain reaction was found to be 7.5%. However, the highest prevalence of ocular conjunctivitis associated with SARS-CoV-2 was 32%. Thus, SARS-CoV-2 can evidently infect the eye, as revealed in the conjunct...
Background: Experiments in the late nineties showed an inverse relationship in the eye levels of ... more Background: Experiments in the late nineties showed an inverse relationship in the eye levels of melatonin and dopamine, thereby constituting an example of eye parameters that are prone to circadian variations. The underlying mechanisms are not known but these relevant molecules act via specific cell surface dopamine and melatonin receptors. This study investigated whether these receptors formed heteromers whose function impact on eye physiology. We performed biophysical assays to identify interactions in heterologous systems. Particular heteromer functionality was detected using Gi coupling, MAPK activation, and label-free assays. The expression of the heteroreceptor complexes was assessed using proximity ligation assays in cells producing the aqueous humor and human eye samples. Dopamine D3 receptors (D3Rs) were identified in eye ciliary body epithelial cells. We discovered heteromers formed by D3R and either MT1 (MT1R) or MT2 (MT2R) melatonin receptors. Heteromerization led to th...
This is a pre-registered study, i.e. a study whose hypotheses and experiments designed to address... more This is a pre-registered study, i.e. a study whose hypotheses and experiments designed to address these hypotheses have been deposited in a database before starting the experiments. The study aims at assessing the Gs versus Gi coupling and the potency of melatonin in the human version of melatonin MT1 and MT2 G-protein-coupled receptors expressed in HEK-293T cells. The results show that these receptors are Gi but not Gs coupled. By using a standard procedure of modulation of 0.5 µM forskolin-induced cAMP levels, it was found that the potency on MT2 receptor-mediated actions is in the low nanomolar range, but the potency on MT1 receptor is in the high nanomolar range. The potency of melatonin to stimulate the MT2 receptor is similar to that of a selective agonist, N-[2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethyl]butanamide (IIK7). Overall, the data on the potency of melatonin on its receptors will provide a new look for melatonin research. It is important to consider this findin...
Melatonin regulates intraocular pressure (IOP) whose increase leads to glaucoma and eye nerve deg... more Melatonin regulates intraocular pressure (IOP) whose increase leads to glaucoma and eye nerve degeneration. Aiming at elucidating the role of melatonin receptors in humour production and IOP maintenance, we here demonstrate that glaucoma correlates with disassembly of α1-adrenergic/melatonin receptor functional units in cells producing the aqueous humour. Remarkably, α1-adrenoceptor-containing complexes do not coupled to the cognate Gq protein and, hence, phenylephrine activation of these receptors does not lead to Ca2+ mobilization. Functional complexes are significantly decreased in models of glaucoma and, more importantly, in human samples of glaucoma patients (GP). In such glaucomatous conditions phenylephrine produces, via α1-adrenoceptor activation, an increase in cytoplasmic [Ca2+] that is detrimental in glaucoma. The results led to hypothesize that using melatonin, a hypotensive agent, plus blockade of α1-adrenergic receptors may normalize pressure in glaucoma. Remarkably, c...
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