Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.

Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.

A Primeval Mechanism of Tolerance to Desiccation Based on Glycolic Acid Saves Neurons in Mammals from Ischemia by Reducing Intracellular Calcium-Mediated Excitotoxicity.

Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, reopen occluded arteries but do not protect against ischemia-induced damage that occurs before reperfusion or neuronal damage induced by ischemia/reperfusion. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in Caenorhabditis elegans dauer larva and that GA itself can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study, the protective effect of GA is tested in different ischemia models, i.e., in commonly used stroke models in mice and swine. The results show that GA, given during reperfusion, strongly protects against ischemic damage and improves functional outcome. Evidence that GA exerts its effect by counteracting the glutamate-dependent increase in intracellular calcium during excitotoxicity is provided. These results suggest that GA treatment has the potential to reduce mortality and disability in stroke patients.

Effect of glycolic acid and EDTA on dentin mechanical properties.

The aim of this study was to evaluate the effect of glycolic acid (GA) and EDTA on dentin mechanical properties. For the cohesive strength, flexural strength and fracture strength tests, the hourglass of root dentin, dentin sticks and roots standardised to 1 mm thickness were used respectively. ANOVA and Tukey tests were used for statistical analysis (P < 0.05). The results showed that EDTA and GA 17% reduced the cohesive strength values when compared to distilled water (control; P = 0.0022 and P = 0.0016 respectively), whereas the values for GA 10% group were similar to those of the control group (P = 0.093). No statistically significant difference was found among the groups for the flexural strength test (P = 0.1974). Fracture strength test showed that EDTA and GA 17% were statistically similar to each other (P = 0.7694) and statistically inferior to GA 10% (P = 0.0007 and P = 0.0004 respectively). It was concluded that 10% GA showed fewer negative effects on dentin mechanical properties.

Phencynonate hydrochloride exerts antidepressant effects by regulating the dendritic spine density and altering glutamate receptor expression.

Phencynonate hydrochloride (PCH) is a drug that crosses the blood-brain barrier. Cellular experiments confirmed that PCH protects against glutamate toxicity and causes only weak central inhibition and limited side effects. As shown in our previous studies, PCH alleviates depression-like behaviours induced by chronic unpredictable mild stress (CUMS). Here we administered PCH at three different doses (4, 8 and 16 mg/kg) to male rats for two continuous days after CUMS and conducted behavioural tests to assess the dose-dependent antidepressant effects of PCH and its effects on the neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC). Meanwhile, we measured the spine density and expression of related proteins to illustrate the mechanism of PCH. PCH treatment (8 mg/kg) significantly alleviated depression-like behaviours induced by CUMS. All doses of PCH treatment reversed the spine loss in prelimbic and CA3 regions induced by CUMS. Kalirin-7 expression was decreased in the hippocampus and mPFC of the CUMS group. The expression of the NR1 and NR2B subunits in the hippocampus, and NR2B in mPFC are increased by CUMS. PCH treatment (8 and 16 mg/kg) reversed all of these changes of Kalirin-7 in PFC and hippocampus, as well as NR1 and NR2B expression in the hippocampus. PCH is expected to be developed as a new type of rapid antidepressant. Its antidepressant effect may be closely related to the modulation of dendritic spine density in the prelimbic and CA3 regions and the regulation of Kalilin-7 and N-methyl-D-aspartic acid receptor levels in the hippocampus.

Theoretical Study of Retinol, Niacinamide and Glycolic Acid with Halloysite Clay Mineral as Active Ingredients for Topical Skin Care Formulations.

The adsorption of retinol, niacinamide and glycolic acid active ingredients on the internal surface of halloysite in an aqueous environment was explored at the molecular level by means of calculations based on quantum mechanics and force fields from empirical interatomic potentials. These active ingredients are stably adsorbed on the internal surface of halloysite forming hydrogen bonds between the hydrogen, oxygen and nitrogen atoms with the hydroxyl groups of the inner surface of the halloysite. In addition, electrostatic interaction between these active ingredients with the water molecules was observed. Therefore, the theoretical results indicate that the adsorption of these active principles is favourable in the halloysite nanotube, which allows directing future experimental investigations for the development and design of retinol, niacinamide and glycolic acid with halloysite nanotubes systems, which may be topical formulations for skincare.

Design, synthesis and biological evaluation of glycolamide, glycinamide, and ß-amino carbonyl 1,2,4-triazole derivatives as DPP-4 inhibitors.

Through modification of the skeleton of Sitagliptin and Vildagliptin, we successfully synthesized and built-up four series of 1,2,4-triazole derivatives, containing N,O-disubstituted glycolamide, N,N'-disubstituted glycinamide, ß-amino ester, and ß-amino amide as linkers, for the development of new dipeptidyl peptidase 4 (DPP-4) inhibitors. The synthetic strategy for glycolamides or glycinamides involved convenient two-steps reaction: functionalized transformation of 2-chloro-N-(2,4,5-triflurophenyl)acetamide 9 (hydroxylation or amination) and esterification or amidation of 1,2,4-triazole-3-carboxylic acid. On the other hand, the one-pot synthesis procedure, including substitution and deprotection, was developed for the preparation of ß-amino carbonyl 1,2,4-triazoles from (1H-1,2,4-triazol-3-yl)methanol 12 or (1H-1,2,4-triazol-3-yl)methanamine 13 and Boc-(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid 14. All of glycolamides, glycinamides, and ß-amino carbonyl 1,2,4-triazoles were also evaluated against DPP-4 inhibitory activity. Based on the SAR study of DPP-4 inhibitory capacity, ß-amino ester 5n and ß-amino amide 1,2,4-triazoles 6d and 6p possessed the significant inhibition of DPP-4 (IC50 < 51.0 nM), particularly for compound 6d (IC50 = 34.4 nM). The selectivity evaluation indicated compound 5n and 6p had excellent selectivity over QPP, DPP-8, and DPP-9. In addition, the docking results revealed compounds 5n and 6p provided stronger π-π stacking interaction with residue Phe357 than 1,5-disubstituted 1,2,4-triazole 6d and Sitagliptin 1. In summary, compounds 5n and 6p could be promising lead compounds for further development of DPP-4 inhibitor.

Indole-3-Acetic Acid Is Synthesized by the Endophyte Cyanodermella asteris via a Tryptophan-Dependent and -Independent Way and Mediates the Interaction with a Non-Host Plant.

The plant hormone indole-3-acetic acid (IAA) is one of the main signals playing a role in the communication between host and endophytes. Endophytes can synthesize IAA de novo to influence the IAA homeostasis in plants. Although much is known about IAA biosynthesis in microorganisms, there is still less known about the pathway by which IAA is synthesized in fungal endophytes. The aim of this study is to examine a possible IAA biosynthesis pathway in Cyanodermella asteris. In vitro cultures of C. asteris were incubated with the IAA precursors tryptophan (Trp) and indole, as well as possible intermediates, and they were additionally treated with IAA biosynthesis inhibitors (2-mercaptobenzimidazole and yucasin DF) to elucidate possible IAA biosynthesis pathways. It was shown that (a) C. asteris synthesized IAA without adding precursors; (b) indole-3-acetonitrile (IAN), indole-3-acetamide (IAM), and indole-3-acetaldehyde (IAD) increased IAA biosynthesis; and (c) C. asteris synthesized IAA also by a Trp-independent pathway. Together with the genome information of C. asteris, the possible IAA biosynthesis pathways found can improve the understanding of IAA biosynthesis in fungal endophytes. The uptake of fungal IAA into Arabidopsis thaliana is necessary for the induction of lateral roots and other fungus-related growth phenotypes, since the application of the influx inhibitor 2-naphthoxyacetic acid (NOA) but not the efflux inhibitor N-1-naphtylphthalamic acid (NPA) were altering these parameters. In addition, the root phenotype of the mutation in an influx carrier, aux1, was partially rescued by C. asteris.

Formulation of topical acidic products and acidification of the skin - Contribution of glycolic acid.

OBJECTIVE: The acidic skin pH is one of the regulating factors of skin barrier homeostasis. Topical products as extrinsic factors which influence skin pH could be used for acidification of the skin and consequent beneficial effect. To formulate stabile and safe topical emulsion product with low pH is on-going challenge and areas interesting to explore are related to the effect of acidic products on the skin pH together with development of protocols for these studies. Aim of our work was to investigate formulations of acidic topical products with glycolic acid (GA) stabilized with long chain alkyl polyglucoside emulsifier, in regard to the specific colloidal structure of the vehicle, together with effect of products with different concentration of acidic active on skin pH. METHODS: Investigated formulations were basic vehicle and two creams with glycolic acid (concentration 2 and 10 wt%). Microstructure was investigated by polarization microscopy, Raman spectral imaging, thermal analysis and rheological measurements. Effects on the skin were assessed by measurement of biophysical skin parameters in vivo studies (5-hour, 24-hour and 7-days). In vitro screening of antimicrobial activity was performed against bacteria Staphylococcus epidermidis. RESULTS: Polarization micrographs and Raman images have shown that GA does not disturb the specific colloidal structure. Together with rheological and thermal analysis obtained results have shown that GA in higher concentrations contributes to vehicles' lamellar structure. In 5-hour study the mean values of skin pH ranged from 3.98-4.25 and 3.89-4.10 after application of products with smaller and higher GA concentration. GA samples lowered skin surface pH to 5 and less in 24-hour and 7-day study, with stronger effect of sample with more GA. Sample with 10% of GA had significant inhibitory effect on growth of S. epidermidis in 1:1 concentration. CONCLUSIONS: Investigated APG emulsifier could be used as a stabilizer for acidic topical products with GA which are characterized by satisfactory safety profile. Topical products induce acidification of the skin after short- and long-term application without barrier impairment or sign of irritation. Acidification of the skin depends on presence of ingredients which are proton donors and their concentrations.

OBJECTIF: Le pH acide de la peau est l'un des facteurs de régulation de l'homéostasie de la barrière cutanée. Les produits topiques pourraient être utilisés en tant que facteurs extrinsèques d'influence du pH cutané pour permettre l'acidification de la peau et obtenir l'effet bénéfique qui en résulte. Formuler des émulsions topiques stables et sûres à faible pH représente un défi constant et les domaines d'étude dignes d'intérêt portent sur l'effet des produits acides sur le pH cutané et sur l'élaboration de protocoles pour ces études. L'objectif de notre travail était d'étudier des formulations de produits topiques acides à base d'acide glycolique (AG) stabilisé à l'aide d'un émulsionnant à base d'alkylpolyglucoside (APG) à longue chaîne, par rapport à la structure colloïdale spécifique de l'excipient, ainsi que l'effet des produits à différentes concentrations d'acide actif sur le pH cutané. MÉTHODES: Les formulations étudiées étaient un excipient de base et deux crèmes à base d'acide glycolique (concentration égale à 2 % et 10 % de la fraction massique). La microstructure a été étudiée par microscopie à polarisation, par spectroscopie Raman, par analyse thermique et par mesures rhéologiques. Les effets cutanés ont été évalués par la mesure des paramètres cutanés biophysiques dans des études in vivo (5 heures, 24 heures et 7 jours). Un dépistage in vitro de l'activité antimicrobienne a été effectué sur la bactérie Staphylococcus epidermidis. RÉSULTATS: Les micrographies après polarisation et les images obtenues par spectroscopie Raman ont montré que l'AG ne perturbe pas la structure colloïdale spécifique. Avec les analyses rhéologique et thermique, les résultats obtenus ont montré que l'AG à des concentrations plus élevées joue un rôle dans la structure lamellaire des excipients. Dans l'étude de 5 heures, les valeurs moyennes du pH cutané allaient de 3,98 à 4,25 et de 3,89 à 4,10 après l'application des produits présentant une concentration d'AG plus faible et plus élevée. Grâce aux échantillons d'AG, le pH de la surface cutanée a diminué, passant ainsi à une valeur de 5 et à des valeurs inférieures dans les études de 24 heures et de 7 jours, et l'échantillon contenant davantage d'AG a eu un effet plus important. L'échantillon contenant 10 % d'AG a eu un effet inhibiteur significatif sur la croissance de la bactérie S. epidermidis à une concentration de 1:1. CONCLUSION: L'émulsionnant à base d'APG étudié pourrait être utilisé comme stabilisateur pour les produits topiques acides à base d'AG caractérisés par un profil d'innocuité satisfaisant. Les produits topiques induisent une acidification de la peau après une application à court et à long terme sans altération de la barrière cutanée ou signe d'irritation. L'acidification de la peau dépend de la présence de donneurs de proton parmi les composants et de leurs concentrations.

Glycolate combats massive oxidative stress by restoring redox potential in Caenorhabditis elegans.

Upon exposure to excessive reactive oxygen species (ROS), organismal survival depends on the strength of the endogenous antioxidant defense barriers that prevent mitochondrial and cellular deterioration. Previously, we showed that glycolic acid can restore the mitochondrial membrane potential of C. elegans treated with paraquat, an oxidant that produces superoxide and other ROS species, including hydrogen peroxide. Here, we demonstrate that glycolate fully suppresses the deleterious effects of peroxide on mitochondrial activity and growth in worms. This endogenous compound acts by entering serine/glycine metabolism. In this way, conversion of glycolate into glycine and serine ameliorates the drastically decreased NADPH/NADP+ and GSH/GSSG ratios induced by H2O2 treatment. Our results reveal the central role of serine/glycine metabolism as a major provider of reducing equivalents to maintain cellular antioxidant systems and the fundamental function of glycolate as a natural antioxidant that improves cell fitness and survival.

pH-dependent delivery of chlorhexidine from PGA grafted mesoporous silica nanoparticles at resin-dentin interface.

BACKGROUND: A low pH environment is created due to the production of acids by oral biofilms that further leads to the dissolution of hydroxyapatite crystal in the tooth structure significantly altering the equilibrium. Although the overall bacterial counts may not be eradicated from the oral cavity, however, synthesis of engineered anti-bacterial materials are warranted to reduce the pathogenic impact of the oral biofilms. The purpose of this study was to synthesize and characterize chlorhexidine (CHX)-loaded mesoporous silica nanoparticles (MSN) grafted with poly-L-glycolic acid (PGA) and to test the in vitro drug release in various pH environments, cytotoxicity, and antimicrobial capacity. In addition, this study aimed to investigate the delivery of CHX-loaded/MSN-PGA nanoparticles through demineralized dentin tubules and how these nanoparticles interact with tooth dentin after mixing with commercial dentin adhesive for potential clinical application. RESULTS: Characterization using SEM/TEM and EDX confirmed the synthesis of CHX-loaded/MSN-PGA. An increase in the percentage of drug encapsulation efficiency from 81 to 85% in CHX loaded/MSN and 92-95% in CHX loaded/MSN-PGA proportionately increased with increasing the amount of CHX during the fabrication of nanoparticles. For both time-periods (24 h or 30 days), the relative microbial viability significantly decreased by increasing the CHX content (P < 0.001). Generally, the cell viability percentage of DPSCs exposed to MSN-PGA/Blank, CHX-loaded/MSN, and CHX-loaded/MSN-PGA, respectively was > 80% indicating low cytotoxicity profiles of experimental nanoparticles. After 9 months in artificial saliva (pH 7.4), the significantly highest micro-tensile bond strength value was recorded for 25:50 CHX/MSN and 25:50:50 CHX/MSN-PGA. A homogenous and widely distributed 50:50:50 CHX-loaded/MSN-PGA nanoparticles exhibited excellent bonding with the application of commercially available dentin adhesive. CONCLUSIONS: A pH-sensitive CHX release response was noted when loaded in MSN grafted PGA nanoparticles. The formulated drug-loaded nanocarrier demonstrated excellent physicochemical, spectral, and biological characteristics. Showing considerable capacity to penetrate effectively inside dentinal tubules and having high antibacterial efficacy, this system could be potentially used in adhesive and restorative dentistry.

Small molecules restore the function of mutant CLC5 associated with Dent disease.

Dent disease type 1 is caused by mutations in the CLCN5 gene that encodes CLC5, a 2Cl- /H+ exchanger. The CLC5 mutants that have been functionally analysed constitute three major classes based on protein expression, cellular localization and channel function. We tested two small molecules, 4-phenylbutyrate (4PBA) and its analogue 2-naphthoxyacetic acid (2-NOAA), for their effect on mutant CLC5 function and expression by whole-cell patch-clamp and Western blot, respectively. The expression and function of non-Class I CLC5 mutants that have reduced function could be restored by either treatment. Cell viability was reduced in cells treated with 2-NOAA. 4PBA is a FDA-approved drug for the treatment of urea cycle disorders and offers a potential therapy for Dent disease.

Increased intracellular Cl- concentration improves airway epithelial migration by activating the RhoA/ROCK Pathway.

In the airway, Cl- is the most abundant anion and is critically involved in transepithelial transport. The correlation of the abnormal expression and activation of chloride channels (CLCs), such as cystic fibrosis transmembrane conductance regulators (CFTRs), anoctamin-1, and CLC-2, with cell migration capability suggests a relationship between defective Cl- transport and epithelial wound repair. However, whether a correlation exists between intracellular Cl- and airway wound repair capability has not been explored thus far, and the underlying mechanisms involved in this relationship are not fully defined. Methods: In this work, the alteration of intracellular chloride concentration ([Cl-]i) was measured by using a chloride-sensitive fluorescent probe (N-[ethoxycarbonylmethyl]-6-methoxyquinolium bromide). Results: We found that clamping with high [Cl-]i and 1 h of treatment with the CLC inhibitor CFTR blocker CFTRinh-172 and chloride intracellular channel inhibitor IAA94 increased intracellular Cl- concentration ([Cl-]i) in airway epithelial cells. This effect improved epithelial cell migration. In addition, increased [Cl-]i in cells promoted F-actin reorganization, decreased cell stiffness, and improved RhoA activation and LIMK1/2 phosphorylation. Treatment with the ROCK inhibitor of Y-27632 and ROCK1 siRNA significantly attenuated the effects of increased [Cl-]i on LIMK1/2 activation and cell migration. In addition, intracellular Ca2+ concentration was unaffected by [Cl-]i clamping buffers and CFTRinh-172 and IAA94. Conclusion: Taken together, these results suggested that Cl- accumulation in airway epithelial cells could activate the RhoA/ROCK/LIMK cascade to induce F-actin reorganization, down-regulate cell stiffness, and improve epithelial migration.

Design, Synthesis, and Activity Study of Water-Soluble, Rapid-Release Propofol Prodrugs.

In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma while preserving its safety. In animal experiments, prodrugs (3e, 3g, and 3j) were significantly better than fospropofol (the only water-soluble propofol prodrug that has been used clinically) in terms of safety, onset, and duration time of anesthesia. Their molar dose, onset time, and anesthesia duration time were comparable to those of propofol, helping to maintain the clinical benefits of propofol. The experimental results showed the potential of such compounds as water-soluble prodrugs of propofol.

A novel insight into the mode of action of glufosinate: how reactive oxygen species are formed.

Glufosinate targets glutamine synthetase (GS), but its fast herbicidal action is triggered by reactive oxygen species (ROS). The relationship between GS inhibition and ROS accumulation was investigated in Amaranthus palmeri. Glufosinate's fast action is light-dependent with no visual symptoms or ROS formation in the dark. Inhibition of GS leads to accumulation of ammonia and metabolites of the photorespiration pathway, such as glycolate and glyoxylate, as well as depletion of other intermediates such as glycine, serine, hydroxypyruvate, and glycerate. Exogenous supply of glycolate to glufosinate-treated plants enhanced herbicidal activity and dramatically increased hydrogen peroxide accumulation (possibly from peroxisomal glycolate oxidase activity). Glufosinate affected the balance between ROS generation and scavenging. The activity of superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase increased after glufosinate treatment in an attempt to quench the nascent ROS burst. Low doses of atrazine and dinoseb were used to investigate the sources of ROS by manipulating photosynthetic electron transport and oxygen (O2) evolution. ROS formation depended on electron flow and O2 evolution in photosystem II (PSII). Inhibition of GS disrupted photorespiration, carbon assimilation, and linear electron flow in the light reactions. Consequently, the antioxidant machinery and the water-water cycle are overwhelmed in the presence of light and glufosinate. The O2 generated by the splitting of water in PSII becomes the acceptor of electrons, generating ROS. The cascade of events leads to lipid peroxidation and forms the basis for the fast action of glufosinate.

pH-Dependent Antibacterial Activity of Glycolic Acid: Implications for Anti-Acne Formulations.

Glycolic acid is the smallest alpha hydroxy acid and widely used for skincare applications, including to treat acne vulgaris. Oftentimes, high concentrations of glycolic acid (~20-50 vol%) are incorporated into chemical peels to reduce acne-related inflammation while there is an outstanding need to determine to what extent glycolic acid can potently inhibit Cutibacterium acnes (formerly known as Propionibacterium acnes), which is a Gram-positive bacterium implicated in acne pathogenesis. Herein, we report that glycolic acid exhibits pH-dependent antibacterial activity against C. acnes and mechanistic studies identified that the nonionic form of glycolic acid is more active than the anionic form. The degree of antibacterial activity, including minimum bactericidal concentration (MBC), of glycolic acid was evaluated in the pH range of 3 to 4.5, and the greatest potency was observed at pH 3. In light of skincare formulation needs, we selected the pH 3.5 condition for further testing and determined that glycolic acid kills C. acnes cells by disrupting bacterial cell membranes. While most conventional treatments involve high concentrations of glycolic acid (>20%), our findings support the potential of developing anti-acne formulations with glycolic acid concentrations as low as 0.2% and with pH conditions that are suitable for over-the-counter applications.

Small Molecules Restore Bestrophin 1 Expression and Function of Both Dominant and Recessive Bestrophinopathies in Patient-Derived Retinal Pigment Epithelium.

Purpose: Bestrophinopathies are a group of untreatable inherited retinal dystrophies caused by mutations in the retinal pigment epithelium (RPE) Cl- channel bestrophin 1. We tested whether sodium phenylbutyrate (4PBA) could rescue the function of mutant bestrophin 1 associated with autosomal dominant and recessive disease. We then sought analogues of 4PBA with increased potency and determined the mode of action for 4PBA and a lead compound 2-naphthoxyacetic acid (2-NOAA). Lastly, we tested if 4PBA and 2-NOAA could functionally rescue bestrophin 1 function in RPE generated from induced pluripotent stem cells (iPSC-RPEs) derived from patients with a dominant or recessive bestrophinopathy. Methods: Global and plasma membrane expression was determined by Western blot and immunofluorescent microscopy, respectively. The effect of 4PBA and 2-NOAA on transcription was measured by quantitative RT-PCR and the rate of protein turnover by cycloheximide chase and Western blot. Channel function was measured by whole-cell patch clamp. Results: 4PBA and 2-NOAA can rescue the global and membrane expression of mutant bestrophin 1 associated with autosomal dominant disease (Best vitelliform macular dystrophy [BVMD]) and autosome recessive bestrophinopathy (ARB), and these small molecules have different modes of action. Both 4PBA and 2-NOAA significantly increased the channel function of mutant BVMD and ARB bestrophin 1 in HEK293T and iPSC-RPE cells derived from patients with BVMD and ARB. For 4PBA, the increased mutant channel function in BVMD and ARB iPSC-RPE was equal to that of wild-type iPSC-RPE bestrophin 1. Conclusions: The restoration of bestrophin 1 function in patient-derived RPE confirms the US Food and Drug Administration-approved drug 4PBA as a promising therapeutic treatment for bestrophinopathies.

Antimicrobial activity of glycolic acid as a final irrigant solution for root canal preparation.

The objective of this study was to evaluate the antimicrobial capacity of glycolic acid (GA) at different concentrations as a final irrigant during the preparation of root canals. The sample consisted of 77 extracted single-rooted human teeth with complete root formation, no previous endodontic treatment, and a root length of at least 14 mm. The root canals were prepared in a standardized manner with a rotary file system. During this process, irrigation was performed with 2.5% sodium hypochlorite (NaOCl), and the final irrigant was 17% ethylenediaminetetraacetic acid (EDTA). After the root canal sterilization procedure, Enterococcus faecalis was cultured in a Petri dish, and 70 sterilized root canals were inoculated with a suspension containing 3.0 × 108 colony-forming units (CFUs) per milliliter. The roots were divided into 7 groups (n = 10) according to the following solutions: 0.9% sodium chloride (NaCl); 6% NaOCl; 17% EDTA; 10%, 17%, or 25% GA; or 17% citric acid (CA). The capacity of the different substances to reduce E faecalis was evaluated by counting the CFUs before and after treatment with the final irrigant solutions. Data were subjected to an analysis of variance and the Tukey test at a 5% significance level. The greatest bacterial reduction was observed in the group irrigated with NaOCl (P < 0.05). There were no statistically significant differences among the groups irrigated with GA in different concentrations (P > 0.05), but they all demonstrated greater disinfection capacity than CA and EDTA (P < 0.05). CA showed significantly greater antimicrobial capacity than EDTA (P < 0.05). EDTA showed significantly greater antimicrobial capacity only in relation to NaCl (P < 0.05). At different concentrations, GA demonstrated greater capacity to eliminate E faecalis from root canals than did EDTA.

Glycolic acid: Characterization of a new final irrigant and effects on flexural strength and structural integrity of dentin.

The aim of this study was to characterize glycolic acid (GA) and examine its effects on powder and flexural strength of dentin. Particle size and energy-dispersive EDS in GA powder was performed for chemical analysis. Surface tension and pH levels of ethylenediaminetetraacetic acid (EDTA), citric acid (CA), and GA solutions were evaluated at different times and temperatures. Dentin powder and mineralized dentin beams were immersed for 1 min in EDTA, CA, or GA solutions and subjected to Fourier transform infrared spectroscopy for apatite/collagen ratio analysis and 3-point flexure test, respectively. GA showed the largest particle size (µm), and its surface tension was similar to that of EDTA and CA. Surface tension decreased in solutions of higher concentrations. GA showed pH stability at all times and temperatures evaluated. The apatite/collagen ratio reduced with increased GA concentrations, while flexural strength was not significantly affected by GA concentration. GA seems a good choice as a final irrigation solution after root canal preparation.

Self-healable and dual-functional guar gum-grafted-polyacrylamidoglycolic acid-based hydrogels with nano-silver for wound dressings.

Dual-functional carbohydrate polymer-based silver nanocomposite (AgNC) hydrogels with self-healing, injectable, and bacterial inactivation properties have attracted particular attention in the wound dressing field. In this study, a rapid formation of AgNC hydrogels were prepared via in situ addition of guar gum-grafted-polyacrylamidoglycolic acid (GG-g-PAGA) polymer and silver nitrate (AgNO3) and sodium borohydride (NaBH4). The GG-g-PAGA polymer and its AgNC hydrogels were analyzed by FTIR, 1H and 13C NMR, UV-vis spectra, FE-SEM, EDX, and FE-TEM. The GG-g-PAGA@AgNC hydrogels exhibited self-healing ability, injectability, stretchability, flowability, high swelling, porosity, upright mechanical behavior, and biodegradability. Moreover, their bacterial inactivation and cytotoxicity were tested against wound pathogens and skin fibroblast cells, respectively. Therefore, incorporating GG-g-PAGA@AgNC hydrogels could be a versatile strategy to speed up wound healing processes, but a clinical trial is still required for its medical applications.

Glycolic acid attenuates UVB-induced aquaporin-3, matrix metalloproteinase-9 expression, and collagen degradation in keratinocytes and mouse skin.

Ultraviolet-B exposure causes an inflammatory response, photoaged skin, and degradation of extracellular matrix proteins including collagen and elastin. The regulation of these genes was suggested as an important mechanism to attenuate skin aging. Glycolic acid (GA) is commonly present in fruits and recently used to treat dermatological diseases. We reported that GA slows down cell inflammation and aging caused by UVB. Little is known about GA retarding the skin premature senescence or how to impede these events. To investigate the potential of GA to regulate the expression of MMPs and collagen, GA was topically applied onto human keratinocytes and the C57BL/6J mice dorsal skin. In the present study, we demonstrated that GA reduced UVB-induced type-I procollagen expression and secretory collagen levels. GA reverted and dose-dependently increased the level of aquaporin-3 (AQP3), the expression of which was down-regulated by UVB. The UV-induced MMP-9 level and activity were reduced by GA pre-treatment. Concomitantly, GA reverted mitogen-activated protein kinase (MMP-9) activation and inhibited the extracellular signal-regulated kinase activation (p38, pERK) triggered by UVB. The animal model also presented that GA attenuated the wrinkles caused by UVB on the mouse dorsal skin. Finally, GA triggers the transient receptor potential vanilloid-1 (TRPV-1) channel to initiate the anti-photoaging mechanism in keratinocytes. These findings clearly indicated that the mechanisms of GA promote skin protection against UVB-induced photoaging and wrinkle formation. GA might be an important reagent and more widely used to prevent UVB-induced skin aging.