Search

Objective: Erythema, characterized by the redness of the skin, is a common skin reaction triggered by various endogenous and exogenous factors. This response is often a result of the activation of underlying inflammatory mechanisms within the skin. The objective of this study is to investigate the potential benefits of applying a combination of skincare ingredients, namely allantoin, bisabolol, D-panthenol and dipotassium glycyrrhizinate (AB5D), in the modulation of inflammatory factors associated with erythema. Additionally, the study aims to elucidate the mechanisms by which these ingredients exert their combined actions to alleviate erythema-associated inflammation., Methods: Human epidermal keratinocytes were exposed to UVB and subsequently treated with AB5D. Transcriptomics profiling was performed to analyse the dose-response effect of AB5D treatment on keratinocytes. The quantitation of inflammatory mediators, including PGE 2 , IL-1α, IL-6, IL-8, IL-1RA and TNFα, was performed on cultured media. Additionally, the oxygen radical absorbance capacity (ORAC) assay was carried out to evaluate the total antioxidant capacity of both individual ingredients and the AB5D combination. To assess the in-vitro antioxidant effects of AB5D against UVB-induced oxidative stress in hTERT keratinocytes, real-time quantitation of mitochondrial superoxide was measured through live-cell imaging., Results: The application of AB5D to UVB-exposed keratinocytes downregulated gene sets associated with inflammatory responses, highlighting the anti-inflammatory properties of AB5D. Specifically, AB5D effectively reduced the production of PGE 2 , leading to the downregulation of inflammatory cytokines. Moreover, our findings indicate that AB5D exhibits antioxidative capabilities, functioning as both an antioxidant agent and a regulator of antioxidant enzyme expression to counteract the detrimental effects of cellular oxidative stress., Conclusion: We demonstrated that AB5D can reduce UVB-induced PGE 2 , IL-1α, IL-6, IL-8, IL-1RA and TNFα as well as mitochondrial superoxide. These findings suggest that AB5D may alleviate erythema by modulating inflammation via PGE 2 and through antioxidation mechanisms., (© 2024 Procter & Gamble. International Journal of Cosmetic Science published by John Wiley & Sons Ltd on behalf of Society of Cosmetic Scientists and Societe Francaise de Cosmetologie.)

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that often occurs in older people. Neuroinflammation and oxidative stress are important factors in the development of PD. Gastrointestinal dysfunction is the most common non-motor symptom, and inflammation of the gut, which activates the gut-brain axis, maybe a pathogenic factor. Previous studies have attributed anti-inflammatory and antioxidant effects to Allantoin, but its function and mechanism of action in PD are unclear. This study aimed to investigate the effect and mechanism of Allantoin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice. Our results showed that Allantoin administration ameliorated motor dysfunction and neuronal damage in mice injected with MPTP by inhibiting neuroinflammation and oxidative damage. Mechanistic studies showed that Allantoin suppresses inflammatory responses by inhibiting the overactivation of the NF-κB and MAPK signaling pathways, as well as oxidative stress by regulating the AKT/Nrf2/HO-1 signaling pathway. Notably, Allantoin also restored intestinal barrier function by modulating the gut microbiota and improving antioxidant and anti-inflammatory capacities to alleviate MPTP-induced motor deficits. In conclusion, the present study shows that the administration of Allantoin attenuated neurodegeneration in mice injected with MPTP by inhibiting neuroinflammation and oxidative stress and modulating the composition of the gut microbiome.

Wound healing requires diverse functionalities in dressings, and conventional materials often fall short in water absorption and moisture regulation. Natural sodium alginate is popular in wound dressings due to its excellent film-forming ability, biocompatibility, ionic crosslinking, and pH responsiveness. However, it has limitations in physical stability and solubility in aqueous environments. This study enhanced alginate dressings by incorporating allantoin and treating with calcium chloride and citric acid to improve physicochemical properties and mechanical performance. Treatments for S2 to S5 prevented dissociation and maintained integrity, with suitable water absorption (363 %-442 %) and water vapor transmission rates (612.53-715.39 g × m 2  × day -1 ). The treatments also improved tensile strength (44.90-55.19 MPa). S2 had the highest migration ratio (52.71 %) of L929 cells and wound healing rates for mice skin (86.6 %), indicating that calcium chloride treatment is beneficial. All dressings (S1 to S5) exhibited low cytotoxicity against L929 cells and low hemolysis ratios, indicating good biocompatibility. Higher allantoin content improved wound healing efficacy. This study provides valuable insights for the design and development of alginate dressings in wound repair, expanding allantoin's application in wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rosmarinic acid is a well-known natural antioxidant and anti-inflammatory compound, and it is one of the polyphenolic compounds found in comfrey plants. Comfrey root also contains allantoin, which helps with new skin regeneration. This study aimed to investigate the healing and skin regeneration process of skin wounds in Wistar rats using creams based on comfrey extract and to correlate the results with active compounds in the extract. The obtained results showed that comfrey root is rich in bioactive compounds, including allantoin, salvianolic acid, and rosmarinic acid, which are known for their great free radical scavenging activity, and the high antioxidant activity of the extract may be mainly due to these compounds. The obtained extract has an antimicrobial effect on Staphylococcus aureus (1530.76/382.69), Escherichia coli (6123.01/6123.01), and Pseudomonas aeruginosa (6123.01/6123.01). The macroscopic evaluation and the histological analysis of the skin defects 14 days after the intervention showed faster healing and complete healing in the skin excisions treated with oil-in-water cream with 20% extract of comfrey as the active ingredient.

Allantoin is an abundant component of yams and has been known as a skin protectant due to its pharmacological activities. In previous methods for allantoin determination using high-performance liquid chromatography (HPLC), the separation was unsatisfactory. We herein developed a 1 H quantitative nuclear magnetic resonance (qNMR) method for quantification of allantoin in the flesh and peel of yams. The method was carried out based on the relative ratio of signals integration of allantoin to a certain amount of the internal standard dimethyl sulfone (DMSO 2 ) and validated in terms of specificity, linearity (range 62.5-2000 μg/ml), sensitivity (limit of detection (LOD) and quantification (LOQ) 4.63 and 14.03 μg/ml, respectively), precision (RSD% 0.02-0.26), and recovery (86.35-92.11%). The method was then applied for the evaluation of allantoin in flesh and peel extracts of four different yams cultivated in Korea.

This work describes a liquid allantoin-enriched pectin hydrogel with hydrophilic behavior that is supported by the presence of functional groups related to healing efficacy. A topical study shows the effect of the hydrogel application on surgically induced skin wound healing in a rat model. Contact angle measurements confirm hydrophilic behavior (11.37°), while Fourier-transform infrared spectroscopy indicates the presence of functional groups related to the healing effectiveness (carboxylic acid and amine groups). Allantoin is distributed on the surface and inside the amorphous pectin hydrogel surrounded by a heterogeneous distribution of pores. This promotes wound drying with better interaction between the hydrogel and cells involved in the wound healing process. An experimental study with female Wistar rats indicates that the hydrogel improves wound contraction, reducing around 71.43% of the total healing time and reaching total wound closure in 15 days.

Drought is a misfortune for agriculture and human beings. The annual crop yield reduction caused by drought exceeds the sum of all pathogens. As one of the gatekeepers of China's "granary", rice is the most important to reveal the key drought tolerance factors in rice. Rice seedlings of Nipponbare ( Oryza sativa L. ssp. Japonica ) were subjected to simulated drought stress, and their root systems were analyzed for the non-targeted metabolome and strand-specific transcriptome. We found that both DEGs and metabolites were enriched in purine metabolism, and allantoin accumulated significantly in roots under drought stress. However, few studies on drought tolerance of exogenous allantoin in rice have been reported. We aimed to further determine whether allantoin can improve the drought tolerance of rice. Under the treatment of exogenous allantoin at different concentrations, the drought resistant metabolites of plants accumulated significantly, including proline and soluble sugar, and reactive oxygen species (ROS) decreased and reached a significant level in 100 μmol L -1 . To this end, a follow-up study was identified in 100 μmol L -1 exogenous allantoin and found that exogenous allantoin improved the drought resistance of rice. At the gene level, under allantoin drought treatment, we found that genes of scavenge reactive oxygen species were significantly expressed, including peroxidase (POD), catalase (CATA), ascorbate peroxidase 8 (APX8) and respiratory burst oxidase homolog protein F (RbohF). This indicates that plants treated by allantoin have better ability to scavenge reactive oxygen species to resist drought. Alternative splicing analysis revealed a total of 427 differentially expressed alternative splicing events across 320 genes. The analysis of splicing factors showed that gene alternative splicing could be divided into many different subgroups and play a regulatory role in many aspects. Through further analysis, we restated the key genes and enzymes in the allantoin synthesis and catabolism pathway, and found that the expression of synthetase and hydrolase showed a downward trend. The pathway of uric acid to allantoin is completed by uric acid oxidase (UOX). To find out the key transcription factors that regulate the expression of this gene, we identified two highly related transcription factors OsERF059 and ONAC007 through correlation analysis. They may be the key for allantoin to enhance the drought resistance of rice.

Herein, the isolation of secondary metabolites from the aerial parts of Justicia aequilabris guided by HPLC-MS n and molecular networking analyses is reported. Twenty-two known compounds were dereplicated. Three new lignans (aequilabrines A-C ( 1 - 3 )) and three known compounds (lariciresinol-4'- O- β-glucose ( 4 ), roseoside ( 5 ), and allantoin ( 6 )) were obtained. The anti-inflammatory activity of compounds 1 - 3 was evaluated in vitro by inhibiting the nitric oxide production (NO) and pro-inflammatory activity on the cytokine IL-1β. Compounds 2 and 3 showed significant inhibitory activity against NO production, with IC 50 values of 9.1 and 7.3 μM, respectively. The maximum inhibition of IL-1β production was 23.5% ( 1 ), 27.3% ( 2 ), and 32.5% ( 3 ).

Alzheimer's disease (AD) is a brain disease that causes problems in memory, thinking, and behavior. Allantoin has been shown to have antioxidant, anti-inflammatory, and neuroprotective effects. In this study, we aimed to investigate the effect and mechanism of action of allantoin on AD-related memory impairment. We investigated the effect of allantoin on an amyloid β 1-42 peptide (Aβ 1-42 )-induced AD model in rats and evaluated its memory-enhancing effect using the Morris water maze test. Pathological changes in the hippocampus and cortex were examined by hematoxylin-eosin staining. The expression of the phosphorylated Tau protein and PI3K/Akt/GSK-3β signaling pathway was analyzed by western blotting. The results of the water maze test showed that after treatment with allantoin, the rats could reduce their swimming time and travel distances to find the platform. Allantoin treatment also increased the time spent in the quadrant in which the platform was located. Histological assessment showed that Aβ 1-42 could cause morphological alterations in nerve cells in the hippocampal CA1 region, and that allantoin could repair the damage to these cells. Western blotting revealed that allantoin treatment increased the expression of p-PI3K, p-Akt, and p-GSK-3β and decreased p-Tau in the hippocampus and cortex of rats. These effects were inhibited by LY294002. These findings showed that allantoin could improve cognitive impairment in Aβ 1-42 -induced rats by activating the PI3K/Akt/GSK-3β signaling pathway to reduce abnormal hyperphosphorylation of Tau. Thus, allantoin may be a potential therapeutic agent for neurodegenerative diseases., Competing Interests: Conflict of interest statement The authors declare that there are no conflicts of interests., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The aln-3 mutant overaccumulating allantoin and respective wild type (WT) strain of Arabidopsis thaliana were exposed to cadmium (Cd) or mercury (Hg) with or without nitric oxide (NO) donor (sodium nitroprusside, SNP) to study cross-talk, metabolic and oxidative changes between these nitrogen sources (organic vs. inorganic). The aln-3 accumulated over 10-fold more allantoin than WT with the effect of Cd and Hg differing in leaf and root tissue: aln-3 contained more ascorbic acid and phytochelatins when treated with Cd or Hg and more Cd in both organs. SNP depleted leaf Cd and root Hg accumulation in aln3 but had a positive impact on the amount of metabolites typically in WT plants, indicating potentially negative relation between allantoin and NO. In agreement, aln-3 roots showed lower NO signals in control or metal treatments, but higher ROS signal, and SNP had more pronounced impact in WT roots. Flavonol glycosides were more abundant in aln-3 and were affected more by metals than by SNP. Malate was the most affected Krebs acid with strong reaction to SNP and Hg treatment. Data indicate that allantoin overaccumulation influences the accumulation of specific metabolites but nitric oxide has a greater impact on the metabolite profile in WT., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Copper stress in the presence of exogenous methyl jasmonate and Serratia plymuthica in a complete trifactorial design with copper (0, 50 µM), methyl jasmonate (0, 1, 10 µM) and Serratia plymuthica (without and with inoculation) was studied on the physiological parameters of Phaseolus coccineus. Copper application reduced biomass and allantoin content, but increased chlorophyll and carotenoids contents as well as catalase and peroxidases activities. Jasmonate did not modify biomass and organic acids levels under copper treatment, but additional inoculation elevated biomass and content of tartrate, malate and succinate. Jasmonate used alone or in combination with bacteria increased superoxide dismutase activity in copper application. With copper, allantoin content elevated at lower jasmonate concentration, but with additional inoculation - at higher jasmonate concentration. Under copper stress, inoculation resulted in higher accumulation of tartrate, malate and citrate contents in roots, which corresponded with lower allantoin concentration in roots. Combined with copper, inoculation reduced catalase and guaiacol peroxidase activities, whereas organic acids content was higher. Under metal stress, with bacteria, jasmonate reduced phenolics content, elevated superoxide dismutase and guaiacol peroxidase activities. The data indicate that jasmonate and S. plymuthica affected most physiological parameters of P. coccineus grown with copper and revealed some effect on biomass., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: Following peripheral nerve injury, in addition to axonal and myelin degeneration, a sharp increase is observed in cell numbers, especially Schwann cells, in the distal part of the injury. This study investigated the effect of allantoin, involved in purine catabolism, on the reactions occurring in the lesion area., Material and Method: An experimental sciatic nerve injury model was established with the application of pressure at 50 Newtons for 5 s to the right sciatic nerves of experimental animals following visualization with the help of pliers. Allantoin was administered to the test groups via the intraperitoneal (i.p.) route (10 mg/kg), at the same time every day for 30 days. The animals were sacrificed at the end of 30 days, following electromyography and Sciatic Function Index tests. Myelinated/unmyelinated axon numbers were evaluated stereologically. Myelin sheath thickness, axon diameter, mitotic activity, and functional improvement in muscles in this peripheral nerve degeneration model were investigated. The test results were then subjected to statistical analysis., Results: Allantoin was observed to exhibit curative effects in terms of function, although stereological tests revealed no morphological differences., Conclusion: The i.p. administration of allantoin may have a beneficial effect on nerve healing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: This study aimed to investigate the effectiveness of topical allantoin application on wound healing in a rat chronic tympanic membrane perforation (TMP) model., Methods: A chronic TMP model was established with 25 healthy, female, 6-month-old, Sprague Dawley rats with chemical damage (trichloroacetic acid 50%). The rats were randomly assigned into 3 groups as follows: Group 1 (10 rats, 20 ears) was administered intratympanic (IT) 20 μL/day 0.57% allantoin solution 7 times, every other day; Group 2 (5 rats, 10 ears) received no substance; Group 3 (10 rats, 20 ears) received IT 20 μl/day distilled water 7 times, every other day. After tympanic membrane (TM) examination with an otoendoscope, histopathological examination of the TM was performed to evaluate neutrophil activity, chronicity, histiocytes, keratin accumulation, subepithelial edema, congestion, fibroblast proliferation, neovascularization, and tympanic membrane thickness., Results: Two TM perforations, 1 in Group 1 and 1 in Group 3, were not healed whereas TM perforations in 48 ears demonstrated closure at the end of the study. According to the histopathological examination, neutrophil activity and fibroblast proliferation were significantly higher in Group 1. There was no significant difference between the groups in terms of other histopathological parameters., Conclusion: To the best of our knowledge, this is the first study investigating the effect of allantoin in an experimental chronic TMP model. According to the histopathological findings, allantoin may have positive effects on the wound healing process of chronic TMP.

Allantoin (ALL) is a phytochemical possessing an impressive array of biological activities. Nonetheless, developing a nanostructured delivery system targeted to augment the gastric antiulcerogenic activity of ALL has not been so far investigated. Consequently, in this survey, ALL-loaded chitosan/sodium tripolyphosphate nanoparticles (ALL-loaded CS/STPP NPs) were prepared by ionotropic gelation technique and thoroughly characterized. A full 2 4 factorial design was adopted using four independently controlled parameters (ICPs). Comprehensive characterization, in vitro evaluations as well as antiulcerogenic activity study against ethanol-induced gastric ulcer in rats of the optimized NPs formula were conducted. The optimized NPs formula, (CS (1.5% w/v), STPP (0.3% w/v), CS:STPP volume ratio (5:1), ALL amount (13 mg)), was the most convenient one with drug content of 6.26 mg, drug entrapment efficiency % of 48.12%, particle size of 508.3 nm, polydispersity index 0.29 and ζ-potential of + 35.70 mV. It displayed a sustained in vitro release profile and mucoadhesive strength of 45.55%. ALL-loaded CS/STPP NPs (F-9) provoked remarkable antiulcerogenic activity against ethanol-induced gastric ulceration in rats, which was accentuated by histopathological, immunohistochemical (IHC) and biochemical studies. In conclusion, the prepared ALL-loaded CS/STPP NPs could be presented to the phytomedicine field as an auspicious oral delivery system for gastric ulceration management.

Introduction: In our days, several approaches reported the use of natural compounds in medical applications. Among them, pectin and allantoin are nontoxic, biocompatible, and biodegradable; however, its use for possible wound healing therapeutics is still limited. Pectin and allantoin have been applied in pharmaceutical industry and beauty cosmetic and could be also applied as scaffolds for tissue regeneration, wound healing, and so on. The aim of this study was to combine by the first time two natural ingredients to develop a new biomaterial to treat skin injuries in a rat model., Methods: For the hydrogel development, new synthesis parameters were established for the obtaining of the film such as temperature, mixing velocity and time, and drying temperatures as well. To enrich the film, the allantoin concentrations were set at 90 wt% and 100 wt% of pectin used. By in vivo assay, films were tested in wound healing in female Wistar rats, 190 ± 10 g in weight and 2 months aged., Results: The obtained films comprise 2 well-differentiated layers, one layer rich in allantoin, which will be the regenerative layer, and one rich in pectin, which will work as an antimicrobial and protective layer to the wound. These were characterized by swelling kinetics, Fourier transform of the infrared spectrum of absorption (FTIR) spectroscopy, and contact angle. The morphology and topography were determined by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). In vivo assay showed remarkable reduce in a time period in a wound healing process when the film was used. The results show that the use of PA (Pectin-Allantoin) hydrogel reduces the total healing time by 25% approximately., Conclusions: Pectin-Allantoin (PA) film has potential use in medical applications as wound healing material promoting healthy tissue renewal., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Karen Zulema Meza Valle et al.)

Aim/background: Although many agents have been tested as treatment options for caustic esophageal burn (CEB), none have successfully suppressed the formation of strictures. Thus,the purpose of this study was to determine the efficacy of Contractubex® gel (10% onion extract, 50 U/gr heparin, and 1% allantoin) in stricture preventing after CEB., Methods: In this study, 24 Wistar-albino rats were divided into 4 groups. CEB was initiated with an instillation of 1 mL of 10% NaOH solution into the an isolated esophageal segment for 3 min. Group C (control) was uninjured and untreated. In Group CEB, was initiated but no treatment was given. In Groups CTX 1 and CTX 2 , the animals received 100 and 200 mg/kg/d, respectively, of Contractubex® for 4 weeks via gavage after CEB was initiated. The stenosis indices (SI), histopathologic damage scores, tissue hydroxyproline (HP) levels, and weights of the rats were taken before the experiment and 4 weeks after the experiment., Results: The Mean SI levels, HP levels, and histopathologic damage scores were statistically lower in Groups CTX 1 and CTX 2 when compared with Group CEB (p <0.05). The treatment groups increased in weight when compared to Group CEB. The results were similar between Group CTX 1 and Group CTX 2 (p >0,05); the efficacy of the treatment was not dose-dependent., Conclusion: For the first time, Contractubex® was used for its antifibrotic, antioxidant, anti-inflammatory, and wound healing effects to treat caustic esophageal burn in rats. It was effective in reducing stricture formation by decreasing the HP levels and histopathologic damage as well as preventing stenosis and weight gain in the treatment groups., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Anthocyanin accumulation in grape berry skin is a crucial determinant of red/black grape berry quality. Recently, viticulture has been hampered by the issue of global warming, which has led to loss of anthocyanin accumulation in berry skin. The objectives of this study were to investigate the effect of allantoin on anthocyanin accumulation in berry skins of field-grown grapevines and to elucidate the molecular mechanism of the allantoin-induced anthocyanin accumulation in the berry skins. Allantoin enhanced anthocyanin accumulation in grape cultured cells and berry skins from field-grown grapevines at the early stage of ripening. MybA1 and UFGT, which encode the key transcription factor and enzyme in anthocyanin biosynthesis, were upregulated in allantoin-treated berry skins. Allantoin seems to increase the contents of delphinidin-based anthocyanin 3-glucosides in berry skins through the upregulation of F3'5'H gene that drives the synthesis of delphinidin-based anthocyanin 3-glucosides, compared with control berry skins. Allantoin increased soluble sugar contents in berries 10 days after treatment and upregulated abscisic acid (ABA)-responsible HT6 gene that encodes a key hexose transporter in sugar accumulation during ripening, in berry skins. These results suggested that physiological changes in allantoin-treated grape berries occurred in an ABA-dependent manner. Allantoin produced bioactive ABA through the β-glucosidase-catalyzed hydrolysis of glucose-conjugated ABA but not through the ABA biosynthesis by NCED, a key enzyme in ABA biosynthesis, in berry skins. Allantoin application in viticulture under global warming conditions is expected to contribute to mitigating loss of red/black berry skin color., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Ethnopharmacological Relevance: Dysfunction of glucose metabolism is associated with the occurrence of metabolic syndromes, including type 2 diabetes mellitus (T2DM). In this study, we investigated the anti-diabetic effects of yam aqueous extract and allantoin in high-fat-diet (HFD) and streptozotocin (STZ)-induced diabetic mice and the mechanism of action on the dysfunction of the liver, pancreas, and skeletal muscle., Materials and Methods: Male C57BL/6 mice were induced into a diabetic condition by HFD for 16 weeks and a single injection of STZ (120 mg/kg) and then orally administered yam aqueous extract (500 and 1000 mg/kg) or allantoin (20 and 50 mg/kg) once daily for 4 weeks. The changes in physiological parameters, serological parameters, and morphology of tissues were investigated. The expression levels of antioxidant enzymes, biogenetic proteins, and myogenetic proteins were determined in the liver, pancreas and skeletal muscle tissues of mice., Results: The administration of yam aqueous extract and allantoin at high doses in HFD/STZ-induced diabetic mice compared with the control group significantly decreased the increase in body weight, caloric intake, and water intake. Yam aqueous extract and allantoin significantly decreased high glucose and leptin, total cholesterol, triglyceride, low-density lipoprotein-cholesterol, aspartate transaminase, alanine aminotransferase levels and increased insulin and albumin levels in the plasma of mice. Yam aqueous extract and allantoin inhibited the structural damage of the liver with regard to fat accumulation, the pancreas with atrophy of Langerhans' islets, and skeletal muscle with regard to atrophy and significantly increased the expression of antioxidant enzymes and mitochondria-mediated biogenetic factors in the liver, pancreas, and muscle tissues. In addition, Yam aqueous extract and allantoin significantly increased the expression of myogenetic proteins in skeletal muscle tissues., Conclusion: Our results indicated that Yam aqueous extract and allantoin improve diabetic symptoms through the regulation of oxidation and glucose imbalance in liver, pancreas, and skeletal muscle tissues in mice. These findings suggest that Yam aqueous extract and allantoin can be used as antidiabetic factors in supplementary foods and medications for T2DM patients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Allantoin as a nitrogen metabolite can improve the salt tolerance in plants, but its mechanism of action remain elusive. Herein, the effects of pretreatment with exogenous allantoin in salt tolerance were investigated in sugar beet. The seedlings were subjected to salt stress (300 mM Na + ) without or with different allantoin concentrations (0.01, 0.1, and 1 mM). The effects of allantoin on plant growth, homeostasis, oxidative damage, osmoregulation, and polyamine metabolism were studied. The results showed that salt stress inhibited the net photosynthetic rate and plant growth, and caused oxidative damage. However, these adverse effects were mitigated by exogenous allantoin in a dose-dependent manner, especially at 0.1 mM. Allantoin reduced the accumulation of ROS by increasing the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ascorbate peroxidase (APX), and AsA content. Under salt stress, allantoin reduced the root concentrations of free putrescine (Put) but increased the free spermine (Spm) in leaves and roots. Furthermore, allantoin decreased the Na + /K + ratio and promoted the accumulation of betaine and soluble sugars in leaves and roots. Under salinity conditions, allantoin may enhance the antioxidant system and improve ion homeostasis by enhancing putrescine and/or spermine accumulation. In addition, Pearson's correlation and principal component analysis (PCA) established correlations between physiological parameters, and significant differences between different concentrations of allantoin were observed. In total, exogenous allantoin effectively reduced the oxidative damage and ion toxicity in sugar beet, caused by salinity, this finding would be helpful in improving salt tolerance in plant., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

This study aimed to evaluate the effect of probiotic administration on obese and ageing models. Sprague Dawley rats were subjected to high-fat diet (HFD) and injected with D-galactose to induce premature ageing. Upon 12 weeks of treatment, the faecal samples were collected and subjected to gas chromatography-mass spectrophotometry (GC-MS) analysis for metabolite detection. The sparse partial least squares discriminant analysis (sPLS-DA) showed a distinct clustering pattern of metabolite profile in the aged and obese rats administered with probiotics Lactobacillus plantarum DR7 and L. reuteri 8513d, particularly with a significantly higher concentration of allantoin. Molecular docking simulation showed that allantoin promoted the phosphorylation (activation) of adenosine monophosphate-activated kinase (AMPK) by lowering the substrate free energy of binding (FEB) and induced the formation of an additional hydrogen bond between Val184 and the substrate AMP. Allantoin also suppressed cholesterol biosynthesis by either inducing enzyme inhibition, occupying or blocking the putative binding site to result in non-spontaneous substrate binding, as in the cases of 3-hydroxy-methylglutaryl-coA reductase (HMGCR), mevalonate kinase (MVK) and lanosterol demethylase (LDM) where positive FEBs were reported. These results demonstrated the potential of allantoin to alleviate age-related hypercholesterolaemia by upregulating AMPK and downregulating cholesterol biosynthesis via the mevalonate pathway and Bloch pathway.

Massive lysis of tumor mass in cancer patients under chemotherapy regimens generates high levels of uric acid, leading to what is known as tumor lysis syndrome (TLS). Rasburicase, a recombinant urate oxidase, converts urate to allantoin, which is readily excreted by the kidneys. Even though there is a high production of allantoin from urate in cancer patients following rasburicase treatment, there are no studies on how allantoin excess could interfere with chemotherapy. We have evaluated allantoin interference with cisplatin efficiency on the lung cancer cell line H460 in vitro. The cells were treated with cisplatin (33 µM), with or without allantoin, for 48 h, in the presence or absence of UV light, and N-acetyl-L-cysteine (NAC) for 24 h. Cell viability, cell cycle, ROS production, apoptosis and immunoblot assays were performed. We showed that allantoin reduced the apoptosis induced by cisplatin in the H460 cell line. However, the activity of carboplatin and oxaliplatin, betulinic acid, TIBA, UV and H 2 O 2 was not affected by allantoin. NMR spectroscopy showed that allantoin reduces cisplatin activity through direct interaction with cisplatin.

Concentration-dependent responses of cucumber plants to cadmium (Cd, 5-15 µM) and/or allantoin (Alla, 10-1000 µM) have been investigated to detect a possible protective role of Alla under Cd excess. After 14 days of exposure, Alla often considerably reversed Cd-induced inhibition of growth and reduction of the content of photosynthetic pigments. Higher Alla doses depleted the Cd amount in shoots, which could be related to citric acid (increase in the shoots but depletion in the roots in Cd+Alla treatments) rather than to phytochelatins (Alla had a negative impact on the phytochelatin accumulation). An increase in the Alla concentration suppressed Cd-induced spatial H 2 O 2 appearance, which does not seem to be related to antioxidative enzymes (low impact of Alla on catalase, ascorbate peroxidase, and guaiacol peroxidase). On the contrary, shoot glutathione and mainly ascorbic acid accumulation strongly increased in Cd+Alla treatments, indicating their prominent role in Alla-induced amelioration of Cd-stimulated oxidative stress and growth retardation. Similarly, phenolic metabolites (total soluble phenols and flavonols) were slightly influenced by Alla and their antioxidative action was not expected. We conclude that Alla-mediated attenuation of Cd-induced toxicity relies on enhanced accumulation of glutathione and ascorbate in the shoot tissue mainly, rather than on elevated antioxidative enzyme activities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Allantoin, an important intermediate of ureide metabolism, has been the subject of investigation recently due to its dual function in nitrogen recycling and abiotic stress response in plants. Allantoin appears to be the dominant ureide accumulating in response to different abiotic stresses, and mutants containing elevated allantoin concentrations exhibit a stress-tolerant phenotype due to limited reactive oxygen species (ROS) generation. Here we describe the involvement of allantoin in stress response and attempt to explain the regulatory mechanism(s) underlying allantoin function in plants. Growth of wild type Col-0 seedlings in the presence of exogenous allantoin improved root elongation in response to Cd treatment. Allantoin treatment of Col-0 seeds increases superoxide dismutase activity causing an enhanced seed germination and seedling growth following Cd exposure. Additionally, allantoinase-overexpressed (ALNox) lines, with lower levels of allantoin, exhibited more susceptibility to Cd treatment than Col-0 Arabidopsis, implying that there is a positive correlation between allantoin concentration and Cd resistance in plants. Growing ABA-insensitive (abi) mutants on allantoin-containing media and comparison between abi mutants and their wild-type backgrounds demonstrated that the potential regulatory function of allantoin does not require ABA at germination but may be ABA-dependent at later stages of seedling growth, suggesting a potential crosstalk between allantoin-mediated stress response and ABA signalling pathway in plants., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Snail mucus is a mixture of active substances commonly thought to have healthy properties for the treatment of skin disorders. Although snail mucus is an ingredient of several cosmetic and para-pharmaceutic products, a comprehensive characterization of chemical composition and biological effects is still missing. Crude purified extracts from Helix aspersa muller mucus (HelixComplex) were prepared and, after chemical characterization, tested on in vitro experimental models. Differently from what expected, HelixComplex was characterized by the presence of small amounts of glycolic acid and allantoin. By using different in vitro assays on fibroblast cultures, we found that HelixComplex lacked of cytotoxicity, protected cells from apoptosis (p < 0.05) and, importantly, was able to significantly induce cell proliferation and migration through direct and indirect mechanisms. These effects were associated to morphological changes, cytoskeleton re-organization and release of cytokines. In conclusion, our findings suggest that snail mucus biological effects are attributable to cell proliferation and migration, and pave the way for further investigating snail mucus potential as therapeutic agent.

Purpose: Gastritis is found to be one of the most common gastrointestinal diseases worldwide. However, current therapeutic agents cause side effects, interaction, and recurrence. Allantoin has anti-inflammatory and wound healing properties. In this study, the therapeutic effect of allantoin has been assessed on the histopathological indices and gastric mucosal barrier of male rats., Methods: Male rats were equally divided into control, ethanol-induced gastritis, and allantoin groups. The therapeutic groups consisted of gastritis plus 12.5 mg/kg allantoin, gastritis plus 25 mg/kg allantoin, and gastritis plus 50 mg/kg allantoin groups. After 5 days of allantoin administration, the rats were sacrificed and a part of their gastric tissue was maintained at -70 °C for prostaglandin E2 (PGE2) and non-protein sulfhydryl (NP-SH) measurements. Another part was stained with hematoxylin and eosin and Masson's trichrome., Results: We found that Allantoin increased parietal and mucosal cell counts and mucosal thickness after gastritis induction. In addition, the number of leukocytes and vessels decreased in both of the mucosal and the submucosal layers. Allatoin improved gastric ulcer in all treatment groups. Gastric levels of PGE2 and NP-SH increased after allantoin treatment., Conclusion: This study indicated that allantoin had a considerable effect on gastritis treatment, which seems to result from the reinforcement of gastric mucosal barrier.

Background: Postoperative epidural adhesion is a frequent cause of failed back surgery syndrome, manifesting with back and leg pain or neurologic deficits. Development of preventive measures for epidural adhesion after laminectomy is critical to improve outcomes of lumbar surgery. We hypothesized that positive effects of topical application of Contractubex (CTX) gel and benzothiazole (BT) individually and in combination could aid in preventing epidural fibrosis in a rat laminectomy model., Methods: Rats were randomly assigned to 2 control and 5 experimental groups (n = 8 for each group). The control(-) group received no surgery, whereas the control(+) group underwent laminectomy without any drug administration. In experimental groups, study agents applied to dura mater after laminectomy were 100mgCTX, 2.5%BT, 5%BT; 100mgCTXplus2.5%BT, and 100mgCTXplus5%BT. Laminectomy was performed at the L3 level for all rats. The extent of epidural fibrosis was assessed 4 weeks later macroscopically and histopathologically. Hepatic and renal toxicity of study drugs was assessed histopathologically., Results: Topical CTX and BT individually and in combination reduced epidural fibrosis after laminectomy in rats. Although a meaningful decrease of epidural fibrosis with individual application of CTX and BT (2.5% or 5%) was obtained (P < 0.05), the effect of their combination was more pronounced without meaningful hepatic and renal toxicity (P < 0.05)., Conclusions: Combined use of topical CTX and BT could be a potential therapy for epidural fibrosis. Further research with this agents for the prevention of epidural fibrosis is warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

With the aging process, a loss of skeletal muscle mass and dysfunction related to metabolic syndrome is observed in older people. Yams are commonly use in functional foods and medications with various effects. The present study was conducted to investigate the effects of rhizome extract of Dioscorea batatas (Dioscoreae Rhizoma, Chinese yam) and its bioactive compound, allantoin, on myoblast differentiation and mitochondrial biogenesis in skeletal muscle cells. Yams were extracted in water and allantoin was analyzed by high performance liquid chromatography (HPLC). The expression of myosin heavy chain (MyHC) and mitochondrial biogenesis-regulating factors, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), sirtuin-1 (Sirt-1), nuclear respiratory factor-1 (NRF-1) and transcription factor A, mitochondrial (TFAM), and the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) were determined in C2C12 myotubes by reverse transcriptase (RT)-polymerase chain reaction (RT-PCR) or western blot. The glucose levels and total ATP contents were measured by glucose consumption, glucose uptake and ATP assays, respectively. Treatment with yam extract (1 mg/mL) and allantoin (0.2 and 0.5 mM) significantly increased MyHC expression compared with non-treated myotubes. Yam extract and allantoin significantly increased the expression of PGC-1α, Sirt-1, NRF-1 and TFAM, as well as the phosphorylation of AMPK and ACC in C2C12 myotubes. Furthermore, yam extract and allantoin significantly increased glucose uptake levels and ATP contents. Finally, HPLC analysis revealed that the yam water extract contained 1.53% of allantoin. Yam extract and allantoin stimulated myoblast differentiation into myotubes and increased energy production through the upregulation of mitochondrial biogenesis regulators. These findings indicate that yam extract and allantoin can help to prevent skeletal muscle dysfunction through the stimulation of the energy metabolism., Competing Interests: The authors no conflict of interest.

Cranial irradiation is the main therapeutic strategy for treating primary and metastatic brain tumors. However, radiation is well-known to induce several unexpected side effects including emotional disorders. Although radiation-induced depression may cause decreased quality of life after radiotherapy, investigations of its molecular mechanism and therapeutic strategies are still insufficient. In this study, we found that behavioral symptoms of depression on mice models with the decrease of BrdU/NeuN- and Dcx-positive populations and MAP-2 expression in hippocampus were induced by cranial irradiation, and transthyretin (TTR) was highly expressed in hippocampus after irradiation. It was shown that overexpression of TTR resulted in the inhibition of retinol-mediated neuritogenesis. PAK1 phosphorylation and MAP-2 expression were significantly reduced by TTR overexpression following irradiation. Moreover, we observed that treatment of allantoin and neferine, the active components of Nelumbo nucifera, interrupted irradiation-induced TTR overexpression, consequently leading to the increase of PAK1 phosphorylation, neurite extension, BrdU/NeuN- and Dcx-positive populations, and MAP-2 expression. Behavioral symptoms of depression following cranial irradiation were also relieved by treatment of allantoin and neferine. These findings demonstrate that TTR plays a critical role in neurogenesis after irradiation, and allantoin and neferine could be potential drug candidates for recovering the effects of radiation on neurogenesis and depression.

Gastric ulcer affects people worldwide, and its inefficacy and recurrence have fueled the search for new therapeutic strategies. Despite the well-known use of allantoin in medicines and cosmetic products, its effect has not yet been studied with regard to gastric ulcer. Hence, the aim of the present study was to explore the pharmaco-mechanistic efficacy of allantoin against commonly harmful agents that cause injuries to the stomach. Ethanol, indomethacin, and stress-induced gastric ulcer models were adopted, in addition to pylorus ligature, a quantification of vascular permeability, glutathione (GSH), gastric adhered mucus, prostaglandin (PGE 2 ), pro-inflammatory cytokines levels, myeloperoxidase (MPO), and catalase (CAT) activities. The gastric lesions were examined by gross, histological, and ultrastructural features. The results showed that treatment with allantoin (60mg/kg, per oral) reduced the gastric ulcer formation in all models. Furthermore, allantoin reduced the parameters of gastric acid secretion and attenuated both the vascular permeability and MPO activity. The levels of pro-inflammatory cytokines were also reduced, accompanied by a restoration of CAT activity and GSH levels. Notably, allantoin treatment preserved the gastric-adhered mucus and PGE 2 levels after ethanol administration. Microscopic and ultrastructural analysis revealed that allantoin maintained tissue integrity and prevented morphological changes in cells caused by ethanol. In summary, we demonstrated for the first time that allantoin possesses gastroprotective activity through anti-inflammatory, anti-oxidative, antisecretory, and cytoprotective mechanisms. The antisecretory and cytoprotective mechanisms are probably associated with an increase in PGE 2 levels., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Allantoin is a nitrogenous compound derived from purine catabolism that contributes to nitrogen recycling in plants. Accumulation of allantoin in plant tissues and a potential role in protection of plants from abiotic stress conditions has been identified. The present work shows that application of exogenous allantoin increased stress tolerance of Arabidopsis seedlings when germinated on, or subjected to the media containing NaCl. Allantoin-induced tolerance to NaCl stress was associated with decreased production of superoxide and hydrogen peroxide in seedlings. To understand the molecular mechanism, the effect of exogenous allantoin treatment on expression of several stress-related genes was investigated. Exogenous allantoin altered the expression of several antioxidant encoding genes and upregulated the expression of two genes involved in oxidative stress tolerance, SOS1 and RCD1, in the presence or absence of NaCl. Allantoin increased the NaCl tolerance of abscisic acid insensitive mutants, suggesting that it can function independently of abscisic acid signaling. These results provide additional evidence for the role of allantoin in enhancing plants tolerance to oxidative stress., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Allantoin is widely used as a skin care agent and readily forms crystals, which were recently shown to bind endotoxins and high molecular weight aggregates in cell culture harvests. Here, we have investigated the effects of allantoin on thermal stability and aggregation of protein using ribonuclease, bovine serum albumin and lysozyme using temperature-regulated circular dichroism (CD) and differential scanning microcalorimetry (DSC). Ribonuclease showed no change in thermal stability and aggregation by the addition of allantoin. While allantoin showed no effects on the thermal stability of bovine serum albumin, it enhanced aggregation. Similarly, allantoin showed no stabilizing effects on lysozyme, but it strongly suppressed aggregation. Such suppressed aggregation resulted in reversibility of thermal unfolding of lysozyme. These effects of allantoin were then compared with those of NaCl and arginine hydrochloride. Arginine was similar to allantoin at low concentrations, where both solvent additives can be compared due to limited solubility of allantoin., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ureides are nitrogen-rich compounds, derived from purine catabolism. A dual role for ureides, and for allantoin in particular, in both nitrogen recycling and the abiotic stress response has been recently identified. Previous work on the effect of allantoin on cadmium (Cd)-exposed Arabidopsis revealed that high concentration of allantoin in allantoinase-negative mutant (aln-3) leaves alleviates Cd toxicity via inducing antioxidant mechanisms in these plants. In the present study, we evaluate whether allantoin has a similar protective role in roots. Both wild type and aln-3 roots contain higher amounts of internal Cd compared to leaves. Likewise, aln-3 roots are more resistant to Cd, reflected in fresh and dry weight, and stimulated antioxidant enzyme activity, including superoxide dismutase (SOD) and catalase (CAT), resulting in lower reactive oxygen species concentration. In contrast with wild-type leaves, high levels of Cd in Col-0 roots reduces transcript abundance of uricase, leading to a significant decline in allantoin level of treated roots at 1000 and 1500 μM CdCl 2 . This metabolite change is also accompanied by decreasing the activity of antioxidant enzymes (SOD and CAT). Additionally, contrary to wild-type leaves, root genotype has a significant effect on CAT activity under Cd treatment, suggesting the possible different sources of damage and oxidative stress response in these two tissues., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

While the importance of cell type specificity in plant adaptive responses is widely accepted, only a limited number of studies have addressed this issue at the functional level. We have combined electrophysiological, imaging, and biochemical techniques to reveal the physiological mechanisms conferring higher sensitivity of apical root cells to salinity in barley (Hordeum vulgare). We show that salinity application to the root apex arrests root growth in a highly tissue- and treatment-specific manner. Although salinity-induced transient net Na + uptake was about 4-fold higher in the root apex compared with the mature zone, mature root cells accumulated more cytosolic and vacuolar Na + , suggesting that the higher sensitivity of apical cells to salt is not related to either enhanced Na + exclusion or sequestration inside the root. Rather, the above differential sensitivity between the two zones originates from a 10-fold difference in K + efflux between the mature zone and the apical region (much poorer in the root apex) of the root. Major factors contributing to this poor K + retention ability are (1) an intrinsically lower H + -ATPase activity in the root apex, (2) greater salt-induced membrane depolarization, and (3) a higher reactive oxygen species production under NaCl and a larger density of reactive oxygen species-activated cation currents in the apex. Salinity treatment increased (2- to 5-fold) the content of 10 (out of 25 detected) amino acids in the root apex but not in the mature zone and changed the organic acid and sugar contents. The causal link between the observed changes in the root metabolic profile and the regulation of transporter activity is discussed., (© 2016 American Society of Plant Biologists. All Rights Reserved.)

The aims of this study are to investigate the antioxidant and antitumor activities of the water and ethanol extracts isolated from Chinese yam (Dioscorea opposite Thunb.) flesh (CYF) and peel (CYP) and the effective compounds. It was found that all peel portions have a better effect on reactive oxygen (ROS) scavenging assay than meat portions, especially for the water extract of Chinese yam peel (CYP-W). Its IC50 values for hydroxyl radical (OH•) scavenging assay (744.25 ± 3.46 μg/mL) and for 1,1-diphenyl-2-picrylhydrazyl scavenging assay (374.85 ± 6.78 μg/mL) were both lower than that of yam flesh (CYF-W). Furthermore, the antitumor property of yam peel was more effective than that of yam flesh (CYF-W) on mouse models, with tumor inhibition rates were 47.92% and 27.41% for Ehrlich Ascites Tumor (EAC) model and 40.44% and 24.22% for H22 hepatocarcinoma tumor (H22) model. Meanwhile, extracts of peel showed higher allantoin, total flavonoids, and total phenolics contents than extracts of flesh. In conclusion, this study demonstrated that CYP-W exerted better antitumor activity than flesh extracts and the scavenging ROS effects were also significantly higher in the CYP-W in vitro. Moreover, the data indicated that allantoin may play an important role on antioxidative and antitumor capacity in yam peel., (© 2016 Institute of Food Technologists®)

Caloric restriction (CR), a reduction in calorie intake without malnutrition, retards aging in several animal models from worms to mammals. Developing CR mimetics, compounds that reproduce the longevity benefits of CR without its side effects, is of widespread interest. Here, we employed the Connectivity Map to identify drugs with overlapping gene expression profiles with CR. Eleven statistically significant compounds were predicted as CR mimetics using this bioinformatics approach. We then tested rapamycin, allantoin, trichostatin A, LY-294002 and geldanamycin in Caenorhabditis elegans. An increase in lifespan and healthspan was observed for all drugs except geldanamycin when fed to wild-type worms, but no lifespan effects were observed in eat-2 mutant worms, a genetic model of CR, suggesting that life-extending effects may be acting via CR-related mechanisms. We also treated daf-16 worms with rapamycin, allantoin or trichostatin A, and a lifespan extension was observed, suggesting that these drugs act via DAF-16-independent mechanisms, as would be expected from CR mimetics. Supporting this idea, an analysis of predictive targets of the drugs extending lifespan indicates various genes within CR and longevity networks. We also assessed the transcriptional profile of worms treated with either rapamycin or allantoin and found that both drugs use several specific pathways that do not overlap, indicating different modes of action for each compound. The current work validates the capabilities of this bioinformatic drug repositioning method in the context of longevity and reveals new putative CR mimetics that warrant further studies., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Allantoin is a metabolic intermediate of purine catabolism that often accumulates in stressed plants. Recently, we used Arabidopsis knockout mutants (aln) of ALLANTOINASE to show that this purine metabolite activates abscisic acid (ABA) production, thereby stimulating stress-related gene expression and enhancing seedling tolerance to abiotic stress. A detailed re-examination of the microarray data of an aln mutant (aln-1) confirmed the increased expression of ABA-related genes and also revealed altered expression of genes involved in jasmonic acid (JA) responses, probably under the control of MYC2, a master switch in the JA signaling pathway. Consistent with the transcriptome profiles, the aln-1 mutant displayed increased JA levels and enhanced responses to mechanical wounding and exogenous JA. Moreover, aln mutants demonstrated modestly increased susceptibility to Pseudomonas syringae and Pectobacterium carotovorum, probably reflecting the antagonistic action of MYC2 on the defense against these bacterial phytopathogens. Exogenously administered allantoin elicited the expression of JA-responsive genes, including MYC2, in wild-type plants, supporting the idea that allantoin might be responsible for the observed JA-related phenotypes of aln mutants. However, mutants deficient in bioactive JA (jar1-1), insensitive to JA (myc2-3), or deficient in ABA (aba2-1 and bglu18) suppressed the effect of exogenous allantoin. The suppression was further confirmed in aln-1 jar1-1 and aln-1 bglu18 double mutants. These results indicate that allantoin can activate the MYC2-regulated JA signaling pathway through ABA production. Overall, this study suggests a possible connection of purine catabolism with stress hormone homeostasis and signaling, and highlights the potential importance of allantoin in these interactions., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Delayed gastric emptying and impaired gastric accommodation (decreased gastric compliance) play important roles in functional dyspepsia (FD). Here we screen for a clinically used drug with an ability to improve delayed gastric emptying in rats. Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying. Administration of allantoin, but not aluminium hydroxide, restored the gastric emptying. Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity. Aldioxa or aluminium hydroxide but not allantoin restored gastric compliance with restraint stress, suggesting that aluminium hydroxide moiety is involved in this restoration. We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

The objective of this study was to investigate the therapeutic efficacies of crude yam (Dioscorea batatas) powder (PY), water extract of yam (EY), and allantoin (the active constituent of yam) in streptozotocin (STZ)-induced diabetic rats with respect to glucose, insulin, glucagon-like peptide-1 (GLP-1), C-peptide, glycated hemoglobin (HbAlc), lipid metabolism, and oxidative stress. For this purpose, 50 rats were divided into five groups: normal control (NC), diabetic control (STZ), and STZ plus treatment groups (STZ + PY, STZ + EY, and STZ + allantoin). After treatment for one-month, there was a decrease in blood glucose: 385 ± 7 in STZ, 231 ± 3 in STZ + PY, 214 ± 11 in STZ + EY, and 243 ± 6 mg/dL in STZ + allantoin, respectively. There were significant statistical differences (p < 0.001) compared to STZ (100%): 60% in STZ + PY, 55% in STZ + EY, and 63% in STZ + allantoin. With groups in the same order, there were significant decreases (p < 0.001) in HbAlc (100% as 24.4 ± 0.6 ng/mL, 78%, 75%, and 77%), total cholesterol (100% as 122 ± 3 mg/dL, 70%, 67%, and 69%), and low-density lipoprotein (100% as 29 ± 1 mg/dL, 45%, 48%, and 38%). There were also significant increases (p < 0.001) in insulin (100% as 0.22 ± 0.00 ng/mL, 173%, 209%, and 177%), GLP-1 (100% as 18.4 ± 0.7 pmol/mL, 160%, 166%, and 162%), and C-peptide (100% as 2.56 ± 0.10 ng/mL, 129%, 132%, and 130%). The treatment effectively ameliorated antioxidant stress as shown by a significant decrease (p < 0.001) in malondialdehyde (100% as 7.25 ± 0.11 nmol/mL, 87%, 86%, and 85%) together with increases (p < 0.01) in superoxide dismutase (100% as 167 ± 6 IU/mL, 147%, 159%, and 145%) and reduced glutathione (100% as 167 ± 6 nmol/mL, 123%, 141%, and 140%). The results indicate that yam and allantoin have antidiabetic effects by modulating antioxidant activities, lipid profiles and by promoting the release of GLP-1, thereby improving the function of β-cells maintaining normal insulin and glucose levels.

This study investigates the biological activity of pure allantoin (PA) and aqueous extract of the comfrey (Symphytum officinale L.) root (AECR) standardized to the allantoin content. Cell viability and proliferation of epithelial (MDCK) and fibroblastic (L929) cell line were studied by using MTT test. Anti-irritant potential was determined by measuring electrical capacitance, erythema index (EI) and transepidermal water loss of artificially irritated skin of young healthy volunteers, 3 and 7 days after application of creams and gels with PA or AECR. Pure allantoin showed mild inhibitory effect on proliferation of both cell lines at concentrations 40 and 100 µg/ml, but more pronounced on MDCK cells. Aqueous extract of the comfrey root effect on cell proliferation in concentrations higher than 40 µg/ml was significantly stimulatory for L929 but inhibitory for MDCK cells. Pharmaceutical preparations that contained AECR showed better anti-irritant potential compared with PA. Creams showed better effect on hydration and EI compared with the gels that contained the same components. Our results indicate that the biological activity of the comfrey root extract cannot be attributed only to allantoin but is also likely the result of the interaction of different compounds present in AECR. Topical preparations that contain comfrey extract may have a great application in the treatment of skin irritation., (Copyright © 2015 John Wiley & Sons, Ltd.)

The immunosuppressive properties of Benzophenone-4, an UV-filter and three ingredients, Allantoin, Bisabolol and Enoxolon used in sunscreen formulation, previously characterized as anti-inflammatory compounds, are studied. The results of this study demonstrate that four tested molecules have effects on DCs and T cells which are the most important cells of the immune system. The impact is also visible on keratinocyte cells which are in the direct contact with skin sunscreens. Each ingredient should be used with caution at reduced doses or even removed from some cosmetic preparations, such as sunscreens.

The aim of this work was to develop solid lipid nanoparticles (SLN) containing copaiba oil with and without allantoin (NCOA, NCO, respectively) and to evaluate their antifungal activity. Nanoparticle suspensions were prepared using a high homogenisation technique and characterised by dynamic light scattering, laser diffraction, nanoparticle tracking analysis, multiple light scattering analysis, high-pressure liquid chromatography, pH and rheology. The antifungal activities of the formulations were tested in vitro against the emergent yeasts Candida krusei and Candida parapsilosis, and the fungal pathogens of human skin Trichophyton rubrum and Microsporum canis. The dynamic light scattering analysis showed z-average diameters (intensity) between 118.63 ± 8.89 nm for the nanoparticles with both copaiba oil and allantoin and 126.06 ± 9.84nm for the nanoparticles with just copaiba oil. The D[4,3] determined by laser diffraction showed similar results of 123 ± 1.73 nm for the nanoparticles with copaiba oil and allantoin and 130 ± 3.6 nm for the nanoparticles with copaiba oil alone. Nanoparticle tracking analysis demonstrated that both suspensions had monomodal profiles and consequently, the nanoparticle populations were homogeneous. This analysis also corroborated the results of dynamic light scattering and laser diffraction, exhibiting a smaller mean diameter for the nanoparticles with copaiba oil and allantoin (143 nm) than for the nanoparticles with copaiba oil (204 nm). The physicochemical properties indicated that the dispersions were stable overtime. Rheology evidenced Newtonian behaviour for both suspensions. Antifungal susceptibility showed a MIC90 of 125 μg/mL (nanoparticles with copaiba oil) and 7.8 μg/mL (nanoparticles with copaiba oil and allantoin) against C. parapsilosis. The nanoparticles with copaiba oil and the nanoparticles with copaiba oil and allantoin presented a MIC90 of 500 μg/mL and 250 μg/mL, respectively, against C. krusei. The MIC90 values were 500 μg/mL (nanoparticles with copaiba oil) and 1.95 μg/mL (nanoparticles with copaiba oil and allantoin) against T. rubrum. Against M. canis, the nanoparticles with copaiba oil and allantoin had a MIC9 of 1.95 μg/mL. In conclusion, nanoencapsulation improved the antifungal activity of copaiba oil, which was enhanced by the presence of allantoin. The MICs obtained are comparable to those of commercial products and can represent promising therapeutics for cutaneous infections caused by yeasts and dermatophytes.

Purine catabolism is regarded as a housekeeping function that remobilizes nitrogen for plant growth and development. However, emerging evidence suggests that certain purine metabolites might contribute to stress protection of plants. Here, we show that in Arabidopsis, the intermediary metabolite allantoin plays a role in abiotic stress tolerance via activation of abscisic acid (ABA) metabolism. The aln loss-of-function of ALN, encoding allantoinase, results in increased allantoin accumulation, genome-wide up-regulation of stress-related genes and enhanced tolerance to drought-shock and osmotic stress in aln mutant seedlings. This phenotype is not caused by a general response to purine catabolism inhibition, but rather results from a specific effect of allantoin. Allantoin activates ABA production both through increased transcription of NCED3, encoding a key enzyme in ABA biosynthesis, and through post-translational activation via high-molecular-weight complex formation of BG1, a β-glucosidase hydrolysing glucose-conjugated ABA. Exogenous application of allantoin to wild-type plants also activates the two ABA-producing pathways that lead to ABA accumulation and stress-responsive gene expression, but this effect is abrogated in ABA-deficient and BG1-knockout mutants. We propose that purine catabolism functions not only in nitrogen metabolism, but also in stress tolerance by influencing ABA production, which is mediated by the possible regulatory action of allantoin., (© 2013 John Wiley & Sons Ltd.)

Allantoin is contained in Nelumbo nucifera (lotus) and a well-known cosmetic ingredient reported to have anti-oxidative and anti-inflammatory activities. In the present study, we investigated whether allantoin affects cognitive function in mice. The subchronic administration of allantoin (1, 3 or 10 mg/kg, for 7 days) significantly increased the latency time measured during the passive avoidance task in scopolamine-induced cholinergic blockade and normal naïve mice. Allantoin treatment (3 or 10 mg/kg, for 7 days) also increased the expression levels of phosphorylated phosphatidylinositide 3-kinase (PI3K), phosphorylated protein kinase B (Akt) and phosphorylated glycogen synthase kinase-3β (GSK-3β). Doublecortin and 5-bromo-2-deoxyuridine immunostaining revealed that allantoin significantly increased the neuronal cell proliferation of immature neurons in the hippocampal dentate gyrus region. In conclusion, allantoin has memory-enhancing effects, and these effects may be partly mediated by the PI3K-Akt-GSK-3β signal pathway. These findings suggest that allantoin has therapeutic potential for the cognitive dysfunctions observed in Alzheimer's disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The agonists of imidazoline I-1 receptors (I-1R) are widely used to lower blood pressure. It has been indicated that guanidinium derivatives show an ability to activate imidazoline receptors. Also, allantoin has a chemical stricture similar to guanidinium derivatives. Thus, it is of special interest to characterize the effect of allantoin on I-1R. In conscious male spontaneous hypertensive rats (SHRs), mean blood pressure (MBP) was recorded using the tail-cuff method. Furthermore, the hemodynamic analyses in catheterized rats were applied to measure the actions of allantoin in vivo. Allantoin decreased blood pressures in SHRs at 30 minutes, as the most effective time. Also, this antihypertensive action was shown in a dose-dependent manner from SHRs treated with allantoin. Moreover, in anesthetized rats, allantoin inhibited cardiac contractility and heart rate as showing in hemodynamic dP/dt max significantly. Also, the peripheral blood flow was markedly increased by allantoin. Both actions were diminished by efaroxan at the dose sufficient to block I-1R. Thus, we suggest that allantoin, as I-1R agonist, has the potential to develop as a new therapeutic agent for hypertension in the future.

When determined in vitro, the SPF of certain commercial sunscreen products can be lower than the SPF indicated on the label. The study of the composition of this type of product enabled us to note that the majority contained substances reputed to have anti-inflammatory properties. This effect is shown by inhibiting the erythema, without protecting the skin, which constitutes a serious public health problem. The anti-inflammatory effects of αbisabolol-, allantoin- and 18-β-glycyrrhetinic acid-based emulsions, as well as commercial sun products containing any one of these molecules, have been tested with phorbol myristate acetate on mice. The effectiveness of these sunscreens products is quantified using two indicators: SPF (sun protection factor) and PF-UVA (protection factor-UVA) by in vitro method. We were thus able to show that certain sun products have an anti-inflammatory effect, which in turn causes the SPF value shown on the product to be overestimated, indeed sometimes by considerably large margins.

Allantoin is known as the agonist of imidazoline receptor, especially the I₂ subtype. Effect of allantoin on imidazoline I₁ receptor (I₁R) relating to reduction of blood pressure and its merit in steatosis are still obscure. Also, farnesoid X receptor (FXR) plays an important role in lipid homeostasis related to I₁R activation. Thus, we administered allantoin into high fat diet (HFD)-fed mice showing hypertriglyceridemia and hypercholesterolemia. Allantoin significantly improved hyperlipidemia in HFD mice after 4 weeks of administration. Pretreatment with efaroxan, at a dose sufficient to inhibit I₁R activation, attenuated the action of allantoin. In addition, in cultured HepG2 cells, allantoin increased the expression of farnesoid X receptor (FXR). The allantoin-induced FXR expression was blocked by efaroxan. Similar changes were observed in the expressions of FXR-targeted genes. Otherwise, allantoin also lowered systolic blood pressure (SBP) in HFD mice that can be blocked by efaroxan. Taken together, allantoin has an ability to activate I₁R for improvement of metabolic disorders., (© Georg Thieme Verlag KG Stuttgart · New York.)

In this study, we evaluated the effects of silicone-based gel on the healing of hypertrophic scars in the rabbit ear model. After 4-week application of silicone-based gel containing allantoin, dexpanthenol and heparin (Noscarna™) to scars in a rabbit ear model of hypertrophic scarring, significant improvements in hypertrophic scar healing and a great loss of skin pigment were observed compared to the non-treated control, base or silicone control-treated scars. Furthermore, histological analysis of Noscarna™-treated scars revealed a significant reduction in scar elevation index (SEI), anterior skin and epithelial thicknesses, inflammatory cells, vessels, collagen disorganization and fibroblasts compared to all control hypertrophic scars. Furthermore, Noscarna™ showed more favorable effects on hypertrophic scars than a commercial product, Contractubex®. Therefore, these results clearly demonstrated that the newly developed silicone-based gel, Noscarna™, could be a promising formulation as an effective therapeutic agent for hypertrophic scars.

Comfrey has a centuries-old tradition as a medicinal plant. Today, multiple randomized controlled trials have demonstrated the efficacy and safety of comfrey preparations for the topical treatment of pain, inflammation and swelling of muscles and joints in degenerative arthritis, acute myalgia in the back, sprains, contusions and strains after sports injuries and accidents, also in children aged 3 or 4 and over. This paper provides information on clinical trials and non-interventional studies published on comfrey to date and further literature, substantiating the fact that topical comfrey preparations are a valuable therapy option for the treatment of painful muscle and joint complaints., (Copyright © 2012 John Wiley & Sons, Ltd.)

The present work evaluates wound healing activity of leaves extracts of Symphytum officinale L. (comfrey) incorporated in three pharmaceutical formulations. Wound healing activity of comfrey was determined by qualitative and quantitative histological analysis of open wound in rat model, using allantoin as positive control. Three topical formulations, carbomer gel, glycero-alcoholic solution and O/W emulsion (soft lotion) were compared. The histological analysis of the healing process shows significant differences in treatment, particularly on its intensity and rate. The results indicate that emulsion containing both extracts, commercial and prepared, induced the largest and furthest repair of damaged tissue. This could be evidenced from day 3 to 28 by increase in collagen deposition from 40% to 240% and reduction on cellular inflammatory infiltrate from 3% to 46%. However, 8% prepared extract in emulsion presented the best efficacy. This work clearly demonstrates that comfrey leaves have a wound healing activity. The O/W emulsion showed to be the vehicle most effective to induce healing activity, particularly with extracts obtained from comfrey leaves collected in Minas Gerais state in Brazil. It shows the best efficacy to control the inflammatory process and to induce collagen deposition at 8% concentration.

Allantoin, an active principle of the yam, belongs to the group of guanidinium derivatives and has been reported to lower plasma glucose in diabetic animals. Recent evidence indicates that activation of the imidazoline I(2B) receptor (I(2B)R) by guanidinium derivatives also increases glucose uptake; however, the effect of allantoin on I(2B)R is still unknown. Glucose uptake into cultured C₂C₁₂ cells was determined using 2-[¹⁴C]-deoxy-D-glucose as a tracer. The changes in 5'-AMP-activated protein kinase (AMPK) expression were also identified by Western blotting analysis. The allantoin-induced glucose uptake action was dose-dependently blocked by BU224, a specific I₂R antagonist, in C₂C₁₂ cells. Moreover, AMPK phosphorylation by allantoin was found to be dose-dependently increased in C₂C₁₂ cells using AICAR treatment as a reference. In addition, both actions of allantoin, the increases in glucose uptake and AMPK phosphorylation, were dose-dependently attenuated by amiloride in C₂C₁₂ cells. Moreover, compound C at concentrations sufficient to inhibit AMPK blocked the allantoin-induced glucose uptake and AMPK phosphorylation. Thus, we suggest that allantoin can activate I(2B)R to increase glucose uptake into cells, and propose I(2B)R as a new target for diabetic therapy., (© Georg Thieme Verlag KG Stuttgart · New York.)