Methylxanthines Research Articles

Inclusion of 1,3-dimethylxanthine improved quality parameters of bull semen

Methylxanthines are a unique class of drug, derived from the purine base xanthine and 1,3-dimethylxanthine (Theophylline) is the most commonly used methyl xanthine. The present study was conducted to study the effect of supplementation of 1,3-dimethylxanthine in semen extender on sperm motility and morphological parameters of semen. A total of 15 semen ejaculates were collected from three adult cattle bulls. Each ejaculate was divided into five groups. First group was kept as control (C) in which samples were diluted with Tris-egg yolk-glycerol extender and samples of other 4 groups (T-5, T-10, T-20 and T-40) were supplemented with 1,3-dimethylxanthine at a dose rate of 5, 10, 20 and 40 mM respectively. The diluted semen samples were incubated at 37°C in water bath and evaluated for various seminal parameters at 15 and 30 min of incubations. Sperm motility, sperm kinetic parameters and sperm abnormalities of semen of all groups were assessed using computer assisted sperm analyser (CASA). Morphological parameters of spermatozoa of control and supplemented groups were also evaluated. The results revealed that 1,3-dimethylxanthine supplementation resulted in significant increase in motile sperm concentration, kinematic parameters, sperm viability, sperms with intact plasma membrane as compared to other groups. However, sperm abnormalities viz., bent tail, coiled tail, distal droplet and distal midpiece reflex varied non-significantly in all groups. Thus, it can be concluded that 1,3-dimethylxanthine (Theophylline) inclusion at 10 mM concentration in semen extender improved the quality of semen.

Parsimonious Effect of Pentoxifylline on Angiogenesis: A Novel Pentoxifylline-Biased Adenosine G Protein-Coupled Receptor Signaling Platform.

Angiogenesis is the physiological process of developing new blood vessels to facilitate the delivery of oxygen and nutrients to meet the functional demands of growing tissues. It also plays a vital role in the development of neoplastic disorders. Pentoxifylline (PTX) is a vasoactive synthetic methyl xanthine derivative used for decades to manage chronic occlusive vascular disorders. Recently, it has been proposed that PTX might have an inhibitory effect on the angiogenesis process. Here, we reviewed the modulatory effects of PTX on angiogenesis and its potential benefits in the clinical setting. Twenty-two studies met the inclusion and exclusion criteria. While sixteen studies demonstrated that pentoxifylline had an antiangiogenic effect, four suggested it had a proangiogenic effect, and two other studies showed it did not affect angiogenesis. All studies were either in vivo animal studies or in vitro animal and human cell models. Our findings suggest that pentoxifylline may affect the angiogenic process in experimental models. However, there is insufficient evidence to establish its role as an anti-angiogenesis agent in the clinical setting. These gaps in our knowledge regarding how pentoxifylline is implicated in host-biased metabolically taxing angiogenic switch may be via its adenosine A2BAR G protein-coupled receptor (GPCR) mechanism. GPCR receptors reinforce the importance of research to understand the mechanistic action of these drugs on the body as promising metabolic candidates. The specific mechanisms and details of the effects of pentoxifylline on host metabolism and energy homeostasis remain to be elucidated.

Xanthine and Methyl Xanthine Molecules in Reactions with Low-Energy Electrons

Intense signals of [M–H]– ions have been detected in the low-energy region of the resonance electron capture mass spectra of xanthine and its methyl derivatives. It was assumed that xanthine molecules can act as radioprotectors in living cells. It was concluded that the discovered release of the carbonyl and methyl groups is associated with xanthine metabolism reactions in the tissues of living organisms.

Xanthine and Methyl Xanthine Molecules in Reactions with Low-Energy Electrons

Xanthine and Methyl Xanthine Molecules in Reactions with Low-Energy Electrons

A Comparative Study of Montelukast and Salbutamol in Bronchial Asthma

Current asthma drug therapy is highly effective, having evolved from naturally occurring substances via logical pharmaceutical developments. Pharmacology has played an important role in the development of asthma drugs, and several key experimental findings have been published in this journal. Understanding the pharmacology of effective drug therapies has also taught us a lot about the mechanisms underlying asthma. 2-Adrenoceptor agonists, which evolved from catecholamines in the adrenal medulla, are the most effective bronchodilators, whereas corticosteroids, which evolved from catecholamines in the adrenal cortex, are by far the most effective controllers of the underlying inflammatory process in the airways. A combination inhaler containing a long-acting 2-agonist and a corticosteroid - an improved form of adrenal gland extract - is the current "gold standard" of asthma therapy. Theophylline, a dietary methyl xanthine, and chromoglycate, a plant-derived substance, have both been widely utilized in the treatment of asthma, but their molecular mechanisms are still unknown. Pharmacology has been crucial in enhancing natural products to create effective, long-lasting, and secure asthma medications, but it has faced difficulties in developing new classes of anti-asthma treatments. Leukotriene antagonists, the only brand-new type of anti-asthma therapy established in the previous 30 years, are less efficient than currently available medications. Corticosteroids are less successful than new, more focused medicines that target particular cytokines, but more focused medications run the risk of having side effects that may not be tolerable. Pharmacology, not molecular genetics, appears to be the most likely direction for future advancements in asthma treatment.

Global health-care interventions for preterm and low birthweight infants.

Journal of Paediatrics and Child HealthVolume 58, Issue 9 p. 1702-1703 Heads UpFree Access Global health-care interventions for preterm and low birthweight infants First published: 25 August 2022 https://doi.org/10.1111/jpc.16191 edited by Craig Mellis (craig.mellis@sydney.edu.au) AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In December 2020, a World Health Organization guideline development group expert meeting identified 24 research questions (framed as PICO: population, intervention, comparator and outcomes) for global health-care interventions for preterm and low birthweight (LBW) infants. Two researchers looked for systematic reviews in the last 3 years which addressed these research questions.1 The researchers found nine systematic reviews. Eight reviews of 121 studies and 25 465 preterm or LBW infants published in the last 36 months ‘fully’ addressed 8 of the 24 research questions (continuous positive airways pressure (CPAP) any, CPAP early, CPAP prophylactic), donor human milk, emollients, formula milk, multicomponent fortifier and probiotics. All eight of these systematic reviews received a ‘high’ AMSTAR quality rating. However, one systematic review (mother's own milk) found no trials. There was no systematic review in the last 3 years of 15 research questions (early initiation, responsive feeding, advancement, exclusive breastfeeding duration, kangaroo mother care, iron, zinc, vitamin D, vitamin A, calcium and phosphorus, multiple micronutrients, CPAP pressure source, methyl xanthines, family involvement and family support). The authors concluded that while they found high-quality systematic reviews of almost a third of their research, they found gaps in thermal care, feeding and family support interventions. Reference 1Edmond K, Strobel N. Evidence for global health care interventions for preterm or low birth weight infants: An overview of systematic reviews. Pediatrics 2022; 150(S1): e2022057092C. Reviewer: David Isaacs, david.isaacs@health.nsw.gov.au, Children's Hospital at Westmead, Sydney, New South Wales, Australia. Volume58, Issue9September 2022Pages 1702-1703 ReferencesRelatedInformation

Evidence for Global Health Care Interventions for Preterm or Low Birth Weight Infants: An Overview of Systematic Reviews.

Twenty-four research questions (framed as population, intervention, comparator, and outcomes) for global health care interventions for preterm and low birth weight (LBW) infants were identified at a World Health Organization guideline development group expert meeting in December 2020. To describe which systematic reviews had addressed these research questions in the last 3 years. Medline (Ovid); the Cochrane Database of Systematic Reviews; the Cochrane Database of Systematic Review Protocols; and the PROSPERO International prospective register of systematic reviews databases from January 1, 2019 to December 31, 2021 were used.Randomized controlled trials or observational studies. Two reviewers independently extracted data. We found 9 systematic reviews. Eight reviews of 121 studies and 25 465 preterm or LBW infants published in the last 36 months "fully" addressed 8 of our 24 research questions (donor human milk, multicomponent fortifier, formula milk, probiotics, emollients, continuous positive airways pressure [CPAP] any, CPAP early, CPAP prophylactic); and 1 systematic review found no trials (mother's own milk). All received a "high" AMSTAR quality rating. Fifteen research questions (kangaroo mother care, early initiation, responsive feeding, advancement, exclusive breastfeeding duration, iron, zinc, vitamin D, vitamin A, calcium and phosphorous, multiple micronutrients, CPAP pressure source, methyl xanthines, family involvement, and family support) had no systematic review. Limitations include that we restricted our search to those interventions identified as a priority at a World Health Organization scoping meeting. Other interventions that may be of importance to preterm or LBW infants were not able to be considered. Almost a third of our research questions were addressed by high quality systematic reviews. We found gaps in thermal care, feeding, and familysupport interventions, which need to be addressed.

Novel ADM Ceylon Standardized Extract With Antioxidant and Antimicrobial Effects Evaluated in Caenorhabditis elegans Model

ObjectivesThe main objective is to develop a novel powdered extract from Ceylon tea, standardized to gallic acid, flavanols and xanthines, and to evaluate “in vivo” its functional properties. MethodsCeylon tea leaves and corresponding powdered extracts were obtained at laboratory and industrial scales. To analyze individual antioxidants, High Performance Liquid Chromatography (J. Chromatogr. A, 2000,881, 439–447) and Gas Chromatography (ACS Food Sci. Technol., 2021, 1, 4,596–604). Oxidative stress resistance (J. Agric. Food Chem., 2011, 59,2077–2085). C. elegans nematodes were egg-synchronized in NGM plates (control medium) and NGM plates containing Ceylon extract (0.1 to 2 mg/mL). Nematode viability was assessed after oxidative stress (2 mM H2O2). Vitamin C (10 μg/mL) was used as positive control. Experiments were carried out in duplicate. Infection assays (Antioxidants 2021, 10,536). Nematodes were age-synchronized by recovering the eggs from adults in agar plates, already seeded with E. coli OP50 (NGM), and NGM plates containing three different doses of Ceylon (0.1 to 1 mg/mL). The pathogen strain Staphylococcus aureus (ATCC25923) was used for infections. Nematodes were incubated at 25 °C and scored for survival during 5–10 days. ResultsChromatographic analyses Industrial scale Ceylon extracts was standardized to gallic acid (1.8 ± 0.0%), monomeric, oligomeric flavanols and methyl xanthines, respectively 2.1 ± 0.1%, 0.2 ± 0.0%, & 4.2 ± 0.1%. The volatile composition showed characteristic profile of Camellia sinensis, with higher relative proportion of trans-2-hexenal (1.9 ± 0.1%), linalool (3.1 ± 0.3%) and benzaldehyde (3.5 ± 0.2%), together with limonene (12.0 ± 1.3%) and eugenol (13.0 ± 0.0%). Antioxidant activity and pathogen protection ADM® Ceylon extract showed significant protection both upon acute oxidative stress and S. aureus infection in the model of C. elegans. Thus, nematodes feeding 1 mg/mL of Ceylon extract, significantly increased their survival compared with control fed population (48% versus 28%). The extract (1 mg/mL) increased 20% survival vs control infected population. ConclusionsADM® Ceylon powdered extract is a novel standardized functional extract with potential antioxidant and protective effects against pathogens. Funding SourcesThanks to ADM® for funding this research work.

Methylxanthines Induce a Change in the AD/Neurodegeneration-Linked Lipid Profile in Neuroblastoma Cells.

Alzheimer’s disease (AD) is characterized by an increased plaque burden and tangle accumulation in the brain accompanied by extensive lipid alterations. Methylxanthines (MTXs) are alkaloids frequently consumed by dietary intake known to interfere with the molecular mechanisms leading to AD. Besides the fact that MTX consumption is associated with changes in triglycerides and cholesterol in serum and liver, little is known about the effect of MTXs on other lipid classes, which raises the question of whether MTX can alter lipids in a way that may be relevant in AD. Here we have analyzed naturally occurring MTXs caffeine, theobromine, theophylline, and the synthetic MTXs pentoxifylline and propentofylline also used as drugs in different neuroblastoma cell lines. Our results show that lipid alterations are not limited to triglycerides and cholesterol in the liver and serum, but also include changes in sphingomyelins, ceramides, phosphatidylcholine, and plasmalogens in neuroblastoma cells. These changes comprise alterations known to be beneficial, but also adverse effects regarding AD were observed. Our results give an additional perspective of the complex link between MTX and AD, and suggest combining MTX with a lipid-altering diet compensating the adverse effects of MTX rather than using MTX alone to prevent or treat AD.

Atividade da Metilxantina em pó aplicada na cama de frango sobre adultos de Alphitobius diaperinus (Panzer, 1797) (Coleoptera: Tenebrionidae)

Abstract One of the pests that most affect and compromise poultry production worldwide is the insect Alphitobius diaperinus, known as the lesser mealworm. This insect is a vector of diseases that compromise not only chicken production but also human health. This study proposes to examine the efficacy and determine the appropriate rate of methylxanthine (MTX), a natural insecticide extracted from cafeine, for the control of an adult population of lesser mealworms in poultry litter. A total of 2,500 adult mealworms were distributed into five treatments in a completely randomized design using 10 replications with 50 insects per replication. The treatments consisted of a control group and four concentrations of MTX (14, 16, 18, and 20 g/m2) spread in plastic boxes containing reused poultry litter and feed, allocated in a broiler shed, to simulate the farm condition. The experimental period was 18 days, and five readings were performed on days 2, 4, 6, 10, and 18. Methylxanthine affected (P<0.05) the mealworms’ cumulative mortality rate, with the groups of insects housed in boxes treated with 16 g /m2 MTX showing the highest cumulative mortality (86.6%) at the end of the experimental period. In conclusion, MTX has insecticidal action on adults of lesser mealworm and can be used on chicken litter to control the population of this insect in poultry sheds. The MTX concentration of 16 g/m2 showed the greatest effectiveness.

Cyclic adenosine monophosphate modulator supplementation on in vitro maturation of bovine oocytes

Study evaluated the role of cAMP modulator (Forskolin and 3-isobutyl-1- methyl xanthine) supplementation on developmental competence of bovine oocytes. Cumulus oocyte complexes recovered from bovine ovaries of unknown reproductive status were used for the study. Oocytes retrieved by aspiration method were graded based on cumulus cell distribution and culture grade oocytes were selected for the study. A total of 414 culture grade oocytes were taken and divided into two groups. Group I constituted of 201 oocytes in which pre-maturation was carried out for a period of 2 h. In group II, 213 oocytes were selected in which normal maturation was carried out. Maturation was assessed after 24h of culture in CO2 incubator maintained at 38.5o C in 95 per cent humidified atmosphere of 5 per cent CO2 . Fertilisation was carried out using frozen thawed semen and the presumptive zygotes were then transferred to culture media and cleavage was assessed 48 h after insemination. A significantly higher maturation rate (p ?0.05) was observed in group I compared to group II (86.85 ± 1.19 vs 79.88 ± 2.67). There was a highly significant increase (p ?0.01) in cleavage rate in group I (65.92 ± 1.23) compared to group II (59.29 ± 1.50). A higher fertilisation rate was observed in group I (75.35 ± 1.19) than group II (71.88 ± 2.56). It could be concluded that pre-maturation with cAMP modulators improved the developmental competence of bovine oocytes.

Analysis of Consumer Products: Demonstrating the Power of LC-MS/MS for the Simultaneous Analysis of Caffeine and Other Methylxanthines in Guaraná Fruit Powder Extract

Dilute guaraná (Paullinia cupana) powder aqueous extract is a soft drink that contains three structurally related methylxanthines (MXs), caffeine (CF), theobromine (TB), and theophylline (TP); CF is present in a large excess. Literature data show that values of λmax and εmax of these three MXs are very close. Consequently, quantitative analysis using a single technique (UV–vis) is difficult, at best. We asked our students how to determine the three MXs simultaneously. They suggested use of chromatographic separation followed by mass spectrometry (MS) detection. Use of electrospray ionization solved the MX structure identification problem only partially because TB and TP have the same molar mass. Using LC-MS/MS solved this problem, as TB and TP have distinct retention times and fragmentation patterns. This is an important everyday situation (analysis of foods and drinks) because of the popularity of CF-containing drinks (guarana, coffee, tea, cacao) and health concerns about abuse of CF consumption.

A Randomized Controlled Trial Comparing Two Doses of Caffeine for Apnoea in Prematurity.

Caffeine is the most commonly used methyl xanthine for the prevention of apnoea in prematurity, but the ideal dose was uncertain, until now. This study compared two doses of caffeine for the prevention of apnoea in prematurity. A clinical trial was conducted on 78 preterm infants ≤32 weeks in Neonatal Intensive Care Unit. They were randomly allocated to receive the intervention (loading 40 mg/kg/day and maintenance of 20 mg/kg/day) or the control (loading 20 mg/kg/day and maintenance of 10 mg/kg/day) dose of caffeine. The primary outcome of the study was the frequency and total days of apnoea per duration of treatment for both groups. The frequency of apnoea ranged from zero to fourteen in the intervention group and zero to twelve in the control group. There was no statistically significant difference between the groups, with a p-value of 0.839. The number of days of apnoea was also similar between both groups, with a p-value of 0.928. There was also no significant difference in adverse events between both regimens. This study did not support the use of higher doses of caffeine as a prevention for apnoea in prematurity.

Thyroid Pathological Consequences Induced by Caffeine in Female Rats

Objective: this study was designed to investigate the histopathological changes induced by caffeine onthyroid, liver and kidneys in female rats. Caffeine is a central nervous stimulant of methyl xanthine class ofdrugs, it has many hormonal and metabolic effects.Method: twenty-four adult female rats was split in to four equal categories of 6 rats in each group as thefollowing: Group1,control group received distilled water only by oral gavage. Group2, received 35mg\kg ofcaffeine solution. Group3, received 75mg\kg of caffeine and Group4, received 150mg\kg of caffeine. Theexperiment continued for 40 days. After 24 hours of the end of experiment, the animals were sacrificed andblood has been withdrawn from vena cava to prepare serum for hormonal analysis, whereas liver, kidneysand thyroid were excised and fixed in formalin solution for histopathological processing.Results: caffeine ingestion cause significant reduction in thyroid function (reduction in T3, T4 and TSH)in all treated groups compared to control group in addition histopathological study show enlargement ofthyroid follicle with thinning of lining epithelium of acini, vacuolation of both renal tubules, hepatocytesand vascular congestion of these organs.Conclusion: Caffeine consumption in high doses causes many histologic and hormonal effects in the studiedorgans.

Methylxanthines and Neurodegenerative Diseases: An Update.

Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson’s disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.

Validation of a high-throughput method for the quantification of flavanol and procyanidin biomarkers and methylxanthines in plasma by UPLC-MS.

Nutritional biomarkers are critical tools to objectively assess intake of nutrients and other compounds from the diet. In this context, it is essential that suitable analytical methods are available for the accurate quantification of biomarkers in large scale studies. Recently, structurally-related (-)-epicatechin metabolites (SREMs) and 5-(3',4'-dihydroxyphenyl)-γ-valerolactone metabolites (gVLMs) were identified as biomarkers of intake of flavanols and procyanidins, a group of polyphenol bioactives. This study aimed at validating a high throughput method for the quantification of SREMs and gVLMs in plasma along with methylxanthines (MXs), dietary compounds known to interact with flavanol and procyanidin effects. To accomplish this, a full set of authentic analytical standards were used to optimize a micro solid phase extraction method for sample preparation coupled to HPLC-MS detection. Isotopically-labelled standards for all analytes were included to correct potential matrix effects on quantification. Average accuracies of 101%, 93% and 103% were obtained, respectively, for SREMs, gVLMs and MXs. Intra- and inter-day repeatability values were <15%. The method showed linear responses for all analytes (>0.993). Most SREMs and gVLMs had limits of quantifications <5 nM while limits of quantification of MXs were 0.2 μM. All analytes were stable under different tested processing conditions. Finally, the method proved to be suitable to assess SREMs, gVLMs and MXs in plasma collected after single acute and daily intake of cocoa-derived test materials. Overall, this method proved to be a valid analytical tool for high throughput quantification of flavanol and procyanidin biomarkers and methylxanthines in plasma.

SERS multiplexing of methylxanthine drug isomers via host–guest size matching and machine learning

Simultaneous quantification of drug isomers, methylxanthines (MeX), by SERS via self-assembly of gold nanoparticles (Au NPs) mediated by cucurbit[n]urils (CBs).

Effect of pentoxifylline administration on an experimental rat model of intraperitoneal adhesion

Aim: Intraabdominal adhesions are the pathological structures that form between the peritoneal surfaces throughout the healing of the peritoneal surface defects with scar formation. Adhesions are a significant problem because they affect the quality of life, lead to morbidity and mortality, and increase health expenses. We have investigated the effectiveness of pentoxifylline (PTX), which is a methyl xanthine derivative, on the development of experimentally generated intraperitoneal adhesions in rats.Materials and Methods: In our study, 30 Wistar Albino rats, each weighing an average of 200-250 grams, were used. In this study, 3 groups of 10 rats were formed. As the adhesion model, cecotomy method was preferred and applied. Groups were classified as; the sham group, control group and PTX group. In the Sham group, merely laparotomy was applied, the control group was intraperitoneal 5 cc isotonic after the cecotomy, and the PTX group was intraperitoneal 100 mg / kg after the cecotomy. Rats were sacrificed on the 15 th day. Macroscopic, microscopic adhesion and adhesion tissues were evaluated with regard to hydroxyproline levels.Results: In the comparison of the groups from the macroscopic point of view, there was a noteworthy difference in adhesion between the sham group and the PTX group (p = 0.027) and between the control group and the PTX group (p = 0.001).Conclusion: In this study, it was observed that PTX can reduce intraabdominal adhesion and increase the level of hydroxyproline after surgery.

Review Effect of Caffeine Overdose

Background: Caffeine is from methyl xanthine class which mainly stimulates the central nervous system. Caffeine is one of the most widely used psychoactive drugs in the world. It is commonly found in beverages, chocolates, cocoa containing products and in medications. Caffeine is recognized as legal and its consumption is unregulated all over of the world.&#x0D; Objectives: The objective of this study is to summarize the impact of caffeine on behavioral and health alterations, in both controlled and overdose conditions. Moreover, the specifics of caffeine withdrawal and a number of guidelines on how to handle reducing or quitting caffeine intake altogether is also highlighted.&#x0D; Methodology: To compose this review, more than seventy research and review articles were overviewed that were published over a period of last twenty years, using Google Scholar search engines.&#x0D; Results: Caffeine regular use causes physical dependence which may become the caffeine withdrawal sign that can consequently harm normal working. The most important function of caffeine is that it can reversibly blocks the adenosine performance on its receptor and as a result which prevent the beginning of drowsiness encouraged by adenosine. Caffeine also stimulates certain portions of the autonomic nervous system symptom including fatigue, drowsiness, depressed mood, headache, difficulty concentrating, decreased energy, decreased contentedness, decreased alertness, irritability and unclear headed.&#x0D; Conclusion: It is concluded that utilization of caffeine in a prescribed dose can have good impact on health and may decrease addictive symptoms. Additionally, reducing caffeine dosage over a six-week period guides to successful, long-term caffeine cessation with very few side effects.

Theophylline enhances melanogenesis in B16F10 murine melanoma cells through the activation of the MEK 1/2, and Wnt/β-catenin signaling pathways

Theophylline is a kind of methyl xanthine, which has been suggested to inhibit the activity of phosphodiesterase and increase the intracellular level of cyclic adenine monophosphate (cAMP). Theophylline has also been reported to increase the length and complexity of the dendritic process in melanocytes. However, the mode of action of theophylline in melanogenesis has never been reported. In this study, the effects of theophylline on melanogenesis were evaluated spectrophotometrically by the mushroom tyrosinase activity assay and by the determination of the intracellular tyrosinase activity and melanin content. The expression levels of melanogenesis-related proteins were analyzed by Western blot. The results indicated that theophylline (100–500 μM) effectively enhanced melanogenesis in the B16F10 murine melanoma cells. Moreover, theophylline increased the protein expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein 1 (TRP-1), and the level of phosphorylated extracellular regulated protein kinase (p-ERK) and phosphorylated glycogen synthase kinase-3β (p-GSK3β) were also increased. In summary, the results revealed that theophylline promoted melanogenesis in B16F10 cells by upregulating the mitogen-activated protein kinase kinase 1 (MEK 1/2) and Wnt/β-catenin signaling pathways.