Добірка наукової літератури з теми "Photo-pharmacology"

Click chemistry is an extremely powerful method for covalent conjugation of molecular entities quickly and efficiently. Click chemistry knitted the threads between two different molecular entities that have created interesting structures for more than 15 years with a wide range of applications, including in interesting fields such as synthetic chemistry, medicinal science, biochemistry, material science, pharmacology and catalysis. Due to the schematic modification and incorporation of azide and alkyne groups within biological scaffolds, azide-alkyne cycloaddition (AAC) is still the leading methodology among click chemistry. This review focuses on the mechanism, scope, and applications of the CuAAC reaction, RuAAC reaction, and the recent development of photo-click reactions, and their applications cover the literature from the last ten years.

Conformational biosensors to monitor the activation state of G protein-coupled receptors are a useful addition to the molecular pharmacology assay toolbox to characterize ligand efficacy at the level of receptor proteins instead of downstream signaling. We recently reported the initial characterization of a NanoBRET-based conformational histamine H3 receptor (H3R) biosensor that allowed the detection of both (partial) agonism and inverse agonism on living cells in a microplate reader assay format upon stimulation with H3R ligands. In the current study, we have further characterized this H3R biosensor on intact cells by monitoring the effect of consecutive ligand injections in time and evaluating its compatibility with photopharmacological ligands that contain a light-sensitive azobenzene moiety for photo-switching. In addition, we have validated the H3R biosensor in membrane preparations and found that observed potency values better correlated with binding affinity values that were measured in radioligand competition binding assays on membranes. Hence, the H3R conformational biosensor in membranes might be a ready-to-use, high-throughput alternative for radioligand binding assays that in addition can also detect ligand efficacies with comparable values as the intact cell assay.

In recent years in the dental field, new types of materials and techniques for the manufacturing of dental crowns and analog implants have been developed to improve the quality of these products. The objective of this article was to perform the surface characterization and determine the properties of Co-Cr alloy samples fabricated by the direct metal laser sintering (DMLS) process and coated by e-gun technology with thin films of Ta2O5 and ZnO. Both oxides are frequently used for dental products, in pharmacology, cosmetics, and medicine, due to their good anticorrosive, antibacterial, and photo-catalytic properties. Following the deposition of thin oxide films on the Co-Cr samples fabricated by DMLS, a very fine roughness in the order of nanometers was obtained. Thin films deposition was realized to improve the hardness and the roughness of the Co-Cr parts fabricated by the DMLS process. Surface characterization was performed using SEM-EDS, AFM, and XRD. AFM was used to determine the roughness of the samples and the nanoindentation curves were determined to establish the hardness values and modulus of elasticity.

Melanin and melanoma tumors are two fields of increasing interest in biomedical research. Melanins are ubiquitous biopigments with adaptive value and multiple functions, and occur in the malignant melanoma. Although several chemical structures have been proposed for eumelanin, molecular modeling and orbitals indicate that a planar or spiral benzoquinone-porphycene polymer would be the model that better explains the broad-band light and ultrasound absorption, electric conductivity, and graphite-like organization shown by X-ray crystallography and electron microscopy. Lysosomes and melanosomes are selectively labeled by vital probes, and melanin also binds to metal cations, colorants, and drugs, with important consequences in pharmacology, pathology, and melanoma therapy. In addition to traditional and recent oncologic treatments, photodynamic, photothermal, and ultrasound protocols represent novel modalities for melanoma therapy. Since eumelanin is practically the ideal photothermal and ultrasound sensitizer, the vibrational decay from photo-excited electrons after NIR irradiation, or the electrochemical production of ROS and radicals after ultrasound absorption, induce an efficient heating or oxidative response, resulting in the damage and death of tumor cells. This allows repetitive treatments due to the remaining melanin contained in tumoral melanophages. Given that evolution and prognosis of the advanced melanoma is still a concern, new biophysical procedures based on melanin properties can now be developed and applied.

Cyanobacteria are the first oxygenic photosynthesis performing prokaryotes. They are considered to have fast growth, amenability to genetic modifications towards photo-autotrophy. Have the ability to grow under heterotrophic conditions with minimum available sunlight to obtain energy by utilizing organic carbon as its substrate. Cyanobacteria are diversely spread in marine, freshwater, terrestrial habitats which differ from each other concerning their structural and functional metabolism. It produces bioactive compounds which are toxic to animals as well as humans which are produced in freshwater habitats whereas marine species of cyanobacteria produce secondary metabolites which are involved in the production of new drugs and also show potential in various fields such as Biotechnological applications, pharmacology, agriculture sustainability, and environmental remediation. Cyanobacteria also produce non-toxic compounds which help in protecting plants by producing phytohormones, siderophores, and UV protective or absorbing compounds. Marine cyanobacterial bioactive compounds are involved in several bioactivities such as antiviral, antialgal, antiprotozoal, antifungal activities, etc. Freshwater species are involved in forming harmful cyanobacterial blooms which are highly toxic to animals as well as humans (Ex: cyanotoxins, hepatotoxins, etc). Different strategies are used to detect the cyanobacterial compounds under in-vivo and in-vitro cultures. To analyze the quality and safety of water, screening methods are necessary to detect possible toxic compounds present in the environmental habitats. Screening methods include microscopy assay, physiological methods, chemical methods, biochemical-based methods, and molecular-based methods. All these methods of screening help in characterizing, identifying the cyanobacterial toxins and also have a few limitations in their reliability, sensitivity, and limit in the detection of the compounds.

OBJECTIVE: The clinical pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and associated drug interactions of the novel antimigraine drug sumatriptan are reviewed. DATA SOURCES: English-language publications pertaining to sumatriptan were identified via a search of the MEDLINE computerized database. STUDY SELECTION: Open and controlled clinical studies were reviewed in assessing clinical efficacy, although only the results of controlled, randomized trials form the basis for the conclusions pertaining to the effectiveness of sumatriptan. DATA EXTRACTION: The primary measure of drug effectiveness in all clinical studies was significant improvement in headache severity scores. Secondary measures included functional ability, time to relief, rescue medication use, associated symptoms of nausea/vomiting and photo/phonophobia, and, in some studies, headache recurrence rate. These data were obtained from each published clinical trial and used in the overall analysis of sumatriptan efficacy. DATA SYNTHESIS: Sumatriptan is a serotonin agonist that has been studied for the acute treatment of migraine and cluster headache. The drug appears to work via specific serotonin receptors to mediate selective vasoconstriction within the cranial vasculature and to prevent the release of inflammatory mediators from trigeminal nerve terminals. The recommended dose of sumatriptan is 6 mg given subcutaneously at the onset of headache; an oral formulation is under investigation. In the published clinical trials of the oral and subcutaneous dosage forms to date, sumatriptan was effective in reducing headache severity from moderate/severe to mild/absent in approximately 70–80 percent of patients treated with active drug, compared with only 20–30 percent in the placebo groups, and 48 percent in the oral ergotamine tartrate/caffeine (Cafergot)-treated group. Secondary measures of effectiveness also favored sumatriptan. There may be a higher rate of headache recurrence with sumatriptan compared with placebo or Cafergot, although further study is necessary to confirm this observation. Adverse effects associated with sumatriptan administration generally were mild and transient and included tingling, warm/hot sensations, and pressure and tightness in the chest and neck. No significant drug interactions have yet been identified. CONCLUSIONS: Sumatriptan appears to represent a safe and effective alternative to the ergot alkaloids for the abortive treatment of acute migraine. However, further clinical trials, especially those yielding comparative data with current antimigraine agents, are needed to determine the full therapeutic contribution of sumatriptan.

In pharmacology, it is common to evaluate the influence of external effectors (for example, temperature, pH, and presence of a second drug) on dose-response relations by the potency factor (PF50): [Formula: see text] where ED50 (± effector) denotes the 50% effective dose in the presence and in the absence of the effector, respectively. In this paper, the external effector is ultraviolet (UV) light, and PF50 is referred to as the photoirritancy factor (PIF). There are two parameters which limit the applicability and toxicological reliability of the PIF. Firstly, the physical properties (for example, water solubility) of the chemical tested and the constraints of the biological test system may make it difficult, or even impossible, to achieve sufficiently high doses to observe 50% of the maximal response. In such cases, no numeric value of the potency factor can be computed. Secondly, the potency factor does not take into account the absolute change in response induced by UV light, i.e. depending on the shape of the ±UV dose-response curves, the absolute change in response may be small although the PIF is large, and vice versa. This paper proposes a more general measure of phototoxicity, the mean photo effect (MPE), which can be assessed from pairs of dose-response curves, even if the 50% response level is not reached in one curve or in both. The MPE is a weighted average of PIFd values across different dose levels (d being common to both dose-response curves). The absolute response changes, ΔRd, i.e. the differences between the -UV curve and the +UV curve are used as weighting factors. The numerical computation of the MPE is based on theoretical curves obtained by fitting a mathematical model to the experimental dose-response data. Plotting PIFd and ΔRd versus the corresponding doses permits differences in the shapes of the two curves to be assessed, and possible alterations in the toxic mechanisms induced by UV light to be revealed. The variance of MPE is estimated by a bootstrap procedure. The use of the MPE is illustrated by its application to dose-response data obtained with a human keratinocyte assay of fibroblasts in the EU/COLIPA international validation project on photoirritancy.

La mélatonine (MLT) est une hormone principalement synthétisée dans la glande pinéale, suivant un rythme circadien avec des niveaux élevés pendant la nuit. La MLT régule de nombreuses fonctions physiologiques, telles que le sommeil, les rythmes biologiques et la douleur. Ces effets sont médiés par l'activation de ces deux récepteurs MT1 et MT2, membres de la famille des récepteurs couplés aux protéines G (RCPG), qui se couplent préférentiellement aux protéines Gi/o. Les récepteurs de la MLT sont des cibles thérapeutiques, cependant, le mécanisme par lequel ils affectent la physiologie n'est pas encore clair. Il existe un intérêt croissant pour le développement des ligands ciblant ces récepteurs. Une approche intéressante consiste à concevoir des molécules dont l'activité peut être modulée par la lumière, car la lumière peut moduler les systèmes physiologiques avec une précision spatio-temporelle, une faible toxicité et sans danger. Dans ce travail, nous avons décrit la synthèse et l'évaluation pharmacologique d'une nouvelle famille de ligands des récepteurs de la MLT avec des propriétés photo-activables, y compris les molécules photo-changeables et celles mise en cage. Les composés en cage sont des molécules qui attachent de manière covalente un groupe photo-labile à une biomolécule, la rendant inactive. La lumière déclenche ainsi une réaction photolytique qui libère la molécule active au site d'action. Suite à la stratégie de mise en cage, nous avons synthétisé quatre composés. Nous avons démontré que tous ces ligands libéraient la MLT active, dont nous avons ensuite évalué l'affinité de liaison et la capacité à inhiber la production d'AMPc. Comme attendu, les composés ont montré une importante baisse de l'affinité et par conséquence de la puissance sur les récepteurs MT1 et MT2. Après illumination, les composés ont montré d'excellentes valeurs de pKi et EC50, en accord avec une libération efficace de MLT. Parmi eux, le composé MCS-0382 a montré les propriétés les plus intéressantes, affichant une différence d'affinité de plus de 1000 fois entre avant et après photolyse. Une fois la méthode de photolyse validée, nous avons voulu appliquer ces outils pour étudier le rôle des récepteurs mitochondriaux MT1. Par conséquent, le MCS-0382 a été utilisé comme modèle pour générer un composé ciblant les mitochondries, le MCS-1145. De plus, un détecteur d'AMPc basé sur la technique du BRET (CAMYEL) a été utilisé pour surveiller en temps réel la production intracellulaire d'AMPc induite par le ligand. Les résultats de ce test ont confirmé l'accumulation de MCS-1145 dans les mitochondries et nous ont permis de voir des réponses différentes par rapport au MCS-0382 non ciblé. De plus, deux autres composés photo-changeables ont été synthétisés. Les molécules photo-changeables sont des molécules qui s'isomérisent de manière réversible entre deux isomères lors de l'illumination, conduisant à des effets biologiques différents. Suite à la stratégie d'azologisation, nous avons incorporé un pont azoïque à un ligand non indolique dérivé de la MLT. Les deux composés ont efficacement répondu à la lumière. Cependant, seul le MCS-0468 a présenté des différences dans les tests fonctionnels après illumination. En effet, le trans-MCS-0468 était inactif sur les voies ERK et AMPc pour MT1, tandis que la forme cis présentait un effet agoniste. Pour MT2, la lumière a induit une perte de puissance de MCS-0468 sur l'inhibition de l'AMPc, et aucune activation de ERK n'a été détectée. Fait intéressant, MCS-0468 n'a pas induit de recrutement de b-arrestine2 sur MT1, se comportant ainsi comme un ligand biaisé pour les voies médiées par la protéine G sur MT1. En conclusion, nous avons développé et caractérisé les premiers ligands photo-activables pour les récepteurs de la MLT, présentés comme de potentiels outils pour étudier les mécanisme d'action de ces récepteurs, leur implication dans les réponses physiologiques et le rôle des récepteurs mitochondriaux MT1
Melatonin (MLT) is a hormone that is primarily synthesized in the pineal gland, following a circadian rhythm with high levels in the night. MLT regulates many physiological functions, such as sleep, biological rhythms, immune responses, retinal physiology and pain. These effects are mediated by the activation of two members of the G protein-coupled receptor (GPCR) family, MT1 and MT2 receptors, which couple preferentially to Gi/o subfamily proteins. MLT receptors are potential therapeutic targets, however, the mechanism by which they affect physiology is still unclear. There is an increasing interest in developing therapeutic tools targeting MLT receptors. One interesting approach is to design ligands whose activity can be modulated by light, as light can modulate physiological systems with a high spatiotemporal precision, low toxicity and safety. In this work, we described the synthesis and pharmacological evaluation of a novel family of melatonin receptor ligands with photo-activable properties, including photoswitches and caged molecules. Caged compounds are light-sensitive probes that covalently attach a photo-labile group into a biomolecule, rendering it inactive. Light triggers a photolytic reaction that releases the active molecule at the site of action. Following the caging strategy, we synthesized four compounds, which presented different photo-cleavable groups at the N1- position of MLT. We demonstrated that all ligands released active MLT with relatively high yields, and we evaluated then their binding affinity and capacity to inhibit cAMP production. As expected, they displayed an important decrease in binding affinity on both MT1 and MT2 before uncaging, and their potencies were correspondingly reduced. After illumination, the compounds showed excellent apparent pKi and EC50 values, in agreement with an efficient release of MLT. Among them, compound MCS-0382 showed the most interesting properties, displaying more than 1000-fold difference in affinity before and after photolysis. Once validated the uncaging methodology for melatonin receptors, we wanted to apply these tools to study the role of mitochondrial MT1 receptors. Therefore, MCS-0382 was used as a scaffold to generate a mitochondria-targeted compound. MCS-1145 presented similar properties to those of MCS-0382, in terms of uncaging efficiency, binding affinity and potency. Additionally, a BRET-based cAMP sensor (CAMYEL) was employed to monitor ligand-induced intracellular production of cAMP in real-time. Results with this assay confirmed the selective accumulation of MCS-1145 in the mitochondria and allowed us to see different responses in comparison to non-targeted MCS-0382. Furthermore, two photoswitchable compounds were synthesized. Photoswitches are molecules that reversibly isomerize between two isomeric forms upon illumination, leading to different biological effects. Following the azologization strategy, we incorporated an azo bridge to a non-indolic melatonin derivative ligand. Both compounds responded efficiently to light, however, only MCS-0468 presented significant differences in functional assays after illumination. Indeed, trans-MCS-0468 was inactive on ERK and cAMP pathways for MT1, while the cis-enriched form displayed a clear agonistic effect on both pathways. For MT2, light induced a potency loss of MCS-0468 on the inhibition of cAMP pathway, and no ERK activation was detected, neither before nor after isomerization. Interestingly, MCS-0468 did not induce beta-arrestin2 recruitment on MT1, thus behaving as a biased cis-on ligand for G protein-mediated pathways on MT1. In conclusion, we have developed and characterized the first photo-activable ligands for MLT receptors, presented as potential tools to study the mechanism of action of MT1 and MT2, their implication in physiological responses and the role of mitochondrial MT1 receptors

A bench-scale tubular reactor with recirculation was built in order to study the efficiency of the photocatalytic oxidation of phenol on fluidized titanium oxide-coated silica gel beads. A UV-C lamp placed along the central vertical axes of the reactor was used as source of photons. A bed of silica gel beads was fluidized by means of fluid recirculation and forced to follow upward helical flow around the lamp. Anatase was successfully synthetized on silica gel particles of average diameters 224, 357 and 461 µm, as confirmed by scanning electron micrographs, through a sol-gel technique using a titanium (iv)isopropoxide / hydrochloric acid / ethanol precursor. Data was obtained from multiple 8-hours photocatalytic experiments using a determined mass of beads fluidized in an aqueous solution of known initial phenol concentration. Contaminant degradation with irradiation time was measured as COD. Beads that had been subjected to three consecutive coating procedures produced an 8-h removal efficiency 10% higher than beads with a single coat. 20 g L-1 of silica beads was found to be the optimum load for the experimental reactor configuration regardless of beads size, although efficiency increased with decreasing size of the latter. Experimental results confirmed that the efficiency of phenol photocatalytic degradation decreases with increasing pollutant concentration. Also, the highest removal was achieved with initial pH 3, and it decreased with increasing pH. When NaCl was added to the solution, COD removal increased with increasing salinity. Additionally, it was found that dissolved oxygen is indispensable for photocatalysis to proceed, and that saturation of the treated mixture with oxygen was effectively achieved by keeping the liquid surface in contact with pure oxygen at 1 atm. Finally, statistical analysis of the data showed that photocatalytic mineralization of phenol-derived COD under the experimental conditions follows exponential decay. Based on this finding, a correlation model was proposed for the accurate prediction (minimum R2 = 0.9840) of the COD removal efficiency of the reactor for any given initial COD.

Nowadays, resveratrol, a polyphenolic phytoalexin is increasingly included in the formulas of cosmetic products and dermatology as an active ingredient, as a consequence of the well-known health beneficial properties, namely antioxidant, anti-inflammatory, anti-viral and anti-bacterial effects. This important compound can be biosynthesized naturally by plants or by industrial synthetic processes. Apart from its anti-inflammatory and antioxidant effects, a broad spectrum of effects has been attributed to the use of this compound such as anti-aging, skin-whitening, anti-angiogenic, collagen I and III stimulation (in fibroblasts) and estrogen-like effects, as well as the ability to protect cells against hydrogen peroxide-induced oxidative stress and UV-irradiation-mediated cell death. In cosmetology and dermatology has been popular because of its ability to penetrate the skin barrier and its anti-aging activity. In fact, resveratrol as an important impact on the regulation of inflammation and, as consequence, repair-related processes in skin. Furthermore, when administered either topically or orally has been proven to be safe and also to overcome the skin barrier. This review will focus in its potential application on melasma treatment and in photo-aging. Resveratrol chemistry, pharmacology, mechanism of action and evidence of its efficacy as photo skin aging protector and its potential use in melasma is discussed.