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Proceedings of the National Academy of... Mar 2024The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates electrolyte and fluid balance in epithelial tissues. While activation...
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates electrolyte and fluid balance in epithelial tissues. While activation of CFTR is vital to treating cystic fibrosis, selective inhibition of CFTR is a potential therapeutic strategy for secretory diarrhea and autosomal dominant polycystic kidney disease. Although several CFTR inhibitors have been developed by high-throughput screening, their modes of action remain elusive. In this study, we determined the structure of CFTR in complex with the inhibitor CFTR-172 to an overall resolution of 2.7 Å by cryogenic electron microscopy. We observe that CFTR-172 binds inside the pore near transmembrane helix 8, a critical structural element that links adenosine triphosphate hydrolysis with channel gating. Binding of CFTR-172 stabilizes a conformation in which the chloride selectivity filter is collapsed, and the pore is blocked from the extracellular side of the membrane. Single-molecule fluorescence resonance energy transfer experiments indicate that CFTR-172 inhibits channel gating without compromising nucleotide-binding domain dimerization. Together, these data reconcile previous biophysical observations and provide a molecular basis for the activity of this widely used CFTR inhibitor.
Topics: Cystic Fibrosis Transmembrane Conductance Regulator; Dimerization; Adenosine Triphosphate; Benzoates; Thiazolidines
PubMed: 38422021
DOI: 10.1073/pnas.2316675121 -
Polymers May 2023This study investigated the nitration of nanostructured bacterial cellulose (NBC). The NBC, obtained using symbiotic Sa-12 as the microbial producer and then...
This study investigated the nitration of nanostructured bacterial cellulose (NBC). The NBC, obtained using symbiotic Sa-12 as the microbial producer and then freeze-dried, was nitrated herein by two methods, the first using mixed sulphuric-nitric acids (MA) and the second using concentrated nitric acid in the presence of methylene chloride (NA+MC). The synthesized samples of NBC nitrates (NBCNs) exhibited 11.77-12.27% nitrogen content, a viscosity of 1086 mPa·s or higher, 0.7-14.5% solubility in an alcohol-ester mixture, and 0.002% ash. Scanning electron microscopy showed that the nitration compacted the NBC structure, with the original reticulate pattern of the structure being preserved in full. Infrared spectroscopy for the presence of functional nitro groups at 1658-1659, 1280, 838-840, 749-751 and 693-694 cm confirmed the synthesis of cellulose nitrates in particular. Thermogravimetric and differential thermal analyses showed the resultant NBCNs to have a high purity and high specific heats of decomposition of 6.94-7.08 kJ/g. The NBCN samples differ conceptually from plant-based cellulose nitrates by having a viscosity above 1086 mPa·s and a unique 3D reticulate structure that is retained during the nitration. The findings suggest that the NBCNs can be considered for use in novel high-tech materials and science-driven fields distinct from the application fields of plant-based cellulose nitrates. The NBCN sample obtained with NA+MC has the ability to generate an organogel when it is dissolved in acetone. Because of the said property, this NBCN sample can find use as a classical adhesive scaffold and an energetic gel matrix for creating promising energetic polymers.
PubMed: 37177359
DOI: 10.3390/polym15092213 -
Molecules (Basel, Switzerland) Oct 2023The recent rapid growth of the battery industry has led to a rapid increase in methylene chloride emissions. Methylene chloride causes health and social problems in...
The recent rapid growth of the battery industry has led to a rapid increase in methylene chloride emissions. Methylene chloride causes health and social problems in humans. In this study, cellulose-based activated carbon fibers (CACFs) with improved yield were prepared for the removal of methylene chloride. The concentration of ammonium phosphate in the pretreatment controlled the crosslink density of cellulose fibers and improved the yield. From the results, the specific surface area and total pore volume of cellulose-based activated carbon fibers pretreated with ammonium phosphate (AP-CACFs) were determined to be 1920-2060 m/g and 0.83-1.02 cm/g, respectively, and the total yield improved by 6.78-11.59% compared to that of CACFs (4.97%). In particular, a correlation between the textural properties of CACFs and methylene chloride adsorption/desorption behavior was obtained. This correlation can be used to develop efficient adsorbents for methylene chloride removal.
PubMed: 37836838
DOI: 10.3390/molecules28196997 -
ACS Omega May 2022or Maca is widely cultivated as a health care food supplement due to its nutritional and medicinal properties. Although there are a few in-depth studies evaluating Maca...
or Maca is widely cultivated as a health care food supplement due to its nutritional and medicinal properties. Although there are a few in-depth studies evaluating Maca antihypertensive effects, the correlations between the chemical constituents and bioactivity of the plant have not been studied before. Thus, the roots were extracted using different solvents (aqueous, methanol, 50% methanol, and methylene chloride) and investigated for their antihypertensive and antioxidant activities through several assays. The methanolic extract exhibited the best renin and angiotensin converting enzyme (ACE) inhibitory activities with IC values of 24.79 ± 1.3 ng/mL and 22.02 ± 1.1 ng/mL, respectively, along with the highest antioxidant activity. In total, 120 metabolites from different classes, e.g., alkylamides, alkaloids, glucosinolates, organic acids, and hydantoin derivatives, were identified in the methanolic extract using ultrahigh-performance liquid chromatography/high-resolution mass spectrometry (UPLC/HRMS). Molecular docking simulations were used to investigate the potential binding modes and the intermolecular interactions of the identified compounds with ACE and renin active sites. Glucotropaeolin, β-carboline alkaloids, succinic acid, and 2,4-dihydroxy-3,5-cyclopentyl dienoic acid showed the highest affinity to target the ACE with high docking scores ( ranging from -35.32 to -22.51 kcal mol) compared to lisinopril ( = -36.64 kcal mol). Interestingly, macamides displayed the greatest binding affinity to the active site of renin with docking scores ( ranging from -22.47 to -28.25 kcal mol). Further, β-carbolines achieved docking scores comparable to that of the native ligand ( ranging from -13.50 to -20.06 kcal mol). Molecular dynamics simulations and MMPBSA were also carried out and confirmed the docking results. Additionally, the computational ADMET study predicted that the compounds attaining promising docking results had proper pharmacokinetics, drug-likeness characteristics, and safe toxicological profiles. Ultimately, our findings revealed that Maca roots could be considered a promising candidate as an antihypertensive drug.
PubMed: 35647470
DOI: 10.1021/acsomega.2c01342 -
BMC Complementary Medicine and Therapies Oct 2021Microbial resistance, diabetes mellitus, and obesity are global health care problems that have posed a serious threat to both human and environmental ecosystems. The...
BACKGROUND
Microbial resistance, diabetes mellitus, and obesity are global health care problems that have posed a serious threat to both human and environmental ecosystems. The goals of the present investigations are to investigate the phytoconstituents, antilipase, anti-α-amylase, and antimicrobial activity of Orobanche aegyptiaca Pers. (OA) from Palestine.
METHODS
Identification of the phytoconstituents of OA plant petroleum ether, methylene chloride, chloroform, acetone, and methanol extracts were conducted using pharmacopeia's methods, while porcine pancreatic lipase and α-amylase inhibitory activities were examined using p-nitrophenyl butyrate and 3,5-dinitro salicylic acid methods, respectively. Moreover, the antimicrobial activity was evaluated utilizing broth microdilution assay against eight bacterial and fungal strains.
RESULTS
The phytochemical screening results showed that the methanol extract of the OA plant is rich in phytochemical components, also this extract has powerful antilipase potential with an IC value of 19.49 ± 0.16 μg/ml comparing with the positive control (Orlistat) which has antilipase activity with IC value of 12.3 ± 0.35 μg/ml. Moreover, the methanol and chloroform extracts have powerful α-amylase inhibitory activity with IC values of 28.18 ± 0.22 and 28.18 ± 1.22 μg/ml, respectively comparing with Acarbose which has α-amylase inhibitory activity with IC dose of 26.3.18 ± 0.28 μg/ml. The antibacterial results showed that the methylene chloride extract exhibited the highest antibacterial activity among the other OA plant extracts with a MIC value of 0.78 mg/ml against S. aureus, while, the methylene chloride, petroleum ether, and chloroform extracts of the OA plant showed potential antifungal activity against C. albicans strains with MIC value of 0.78 mg/ml.
CONCLUSION
The OA methanol and chloroform extracts could be excellent candidates as antilipase and anti-α-amylase bioactive materials. In addition, methylene chloride, petroleum ether, and chloroform extracts could be potential natural antimicrobial products.
Topics: Animals; Anti-Infective Agents; Anti-Obesity Agents; Humans; Hypoglycemic Agents; Lipase; Microbial Sensitivity Tests; Middle East; Orobanche; Phytochemicals; Swine; alpha-Amylases
PubMed: 34625075
DOI: 10.1186/s12906-021-03431-x -
ACS Omega Dec 2022Amphiphilic aryl radicals generated upon visible light irradiation of arylazo sulfones have been exploited in the development of a solventylation strategy via hydrogen...
Amphiphilic aryl radicals generated upon visible light irradiation of arylazo sulfones have been exploited in the development of a solventylation strategy via hydrogen atom transfer (HAT). The present protocol succeeded in the versatile functionalization of various olefins with carbon-centered radicals deriving from acetone, acetonitrile, chloroform, methylene chloride, nitromethane, methyl acetate, and methyl formate under metal- and photocatalyst-free conditions. The direct addition of the aryl radicals onto the olefin substrates was suppressed under high dilution conditions.
PubMed: 36591128
DOI: 10.1021/acsomega.2c07172 -
Animals : An Open Access Journal From... Oct 2023Besides living as a free-ranging primate in the horn of Africa and the Arabian Peninsula, the hamadryas baboon has an important place in zoos and can be found in...
Besides living as a free-ranging primate in the horn of Africa and the Arabian Peninsula, the hamadryas baboon has an important place in zoos and can be found in biomedical research centers worldwide. To be valuable as a non-human primate laboratory model for man, its anatomy should be portrayed in detail, allowing for the correct interpretation and translation of obtained research results. Reviewing the literature on the use of the baboon in biomedical research revealed that very limited anatomical works on this species are available. Anatomical atlases are incomplete, use archaic nomenclature and fail to provide high-definition color photographs. Therefore, the skeletons of two male hamadryas baboons were prepared by manually removing as much soft tissues as possible followed by maceration in warm water to which enzyme-containing washing powder was added. The bones were bleached with hydrogen peroxide and degreased by means of methylene chloride. Photographs of the various bones were taken, and the anatomical structures were identified using the latest version of the Nomina Anatomica Veterinaria. As such, the present article shows 31 annotated multipanel figures. The skeleton of the hamadryas baboon generally parallels the human skeleton, but some remarkable differences have been noticed. If these are taken into consideration when evaluating the results of experiments using the hamadryas baboon, justified conclusions can be drawn.
PubMed: 37835730
DOI: 10.3390/ani13193124 -
Indian Journal of Plastic Surgery :... Jan 2021Chemical burns account for a small percentage of burns but contribute to significant number of burn-related mortalities. The major challenge posed by chemical burns is...
Chemical burns account for a small percentage of burns but contribute to significant number of burn-related mortalities. The major challenge posed by chemical burns is difficulty in correct depth estimation, as the damage continues to progress until they are effectively neutralized. Besides the most common etiology of chemical burns by alkalis and acids, there are many other unique causes of chemical burns. The author describes a case of chemical burns by heavy duty paint remover, the main composition of which is methylene chloride. Although several studies about methylene chloride poisoning are available in literature, only one case report of burns due to methylene chloride exists in literature. These burns are unique in their presentation. The author describes the presentation and challenges in management of this burn. Not applicable.
PubMed: 33814750
DOI: 10.1055/s-0041-1725224 -
Molecules (Basel, Switzerland) Mar 2022Pentacoordinate silicon derivatives with a chloromethyl ligand are versatile compounds that are usually obtained from the corresponding tetravalent trialkoxy- or...
Pentacoordinate silicon derivatives with a chloromethyl ligand are versatile compounds that are usually obtained from the corresponding tetravalent trialkoxy- or trihalogeno(chloromethyl)silane. We describe herein the synthesis of a chloromethylsilicate bearing two Martin's ligands readily obtained by addition of in situ generated chloromethyllithium to a spirosilane. The reactivity of this new species was evaluated and it has been established that the chloride is displaced by strong nucleophiles such as alkyllithiums and (hetero)aryllithiums. In Lewis acidic conditions, the pentacoordinate silicon species rearranges through a formal insertion of a methylene into one Si-C bond, to form a new tetravalent spirosilane with a six-membered ring. The same kind of rearrangement can be triggered also by addition of a Lewis base. The mechanism of the rearrangement in both conditions has been studied by means of DFT calculations.
PubMed: 35335132
DOI: 10.3390/molecules27061767 -
Scientific Reports Mar 2022Volatile organic compounds (VOCs) profile for diagnosis and monitoring therapeutic response of hepatocellular carcinoma (HCC) has not been well studied. We determined...
Volatile organic compounds (VOCs) profile for diagnosis and monitoring therapeutic response of hepatocellular carcinoma (HCC) has not been well studied. We determined VOCs profile in exhaled breath of 97 HCC patients and 111 controls using gas chromatography-mass spectrometry and Support Vector Machine algorithm. The combination of acetone, 1,4-pentadiene, methylene chloride, benzene, phenol and allyl methyl sulfide provided the highest accuracy of 79.6%, with 76.5% sensitivity and 82.7% specificity in the training set; and 55.4% accuracy, 44.0% sensitivity, and 75.0% specificity in the test set. This combination was correlated with the HCC stages demonstrating by the increased distance from the classification boundary when the stage advanced. For early HCC detection, d-limonene provided a 62.8% sensitivity, 51.8% specificity and 54.9% accuracy. The levels of acetone, butane and dimethyl sulfide were significantly altered after treatment. Patients with complete response had a greater decreased acetone level than those with remaining tumor post-treatment (73.38 ± 56.76 vs. 17.11 ± 58.86 (× 10 AU, p = 0.006). Using a cutoff of 35.9 × 10 AU, the reduction in acetone level predicted treatment response with 77.3% sensitivity, 83.3% specificity, 79.4%, accuracy, and AUC of 0.784. This study demonstrates the feasibility of exhaled VOCs as a non-invasive tool for diagnosis, monitoring of HCC progression and treatment response.
Topics: Breath Tests; Carcinoma, Hepatocellular; Exhalation; Humans; Liver Neoplasms; Volatile Organic Compounds
PubMed: 35351916
DOI: 10.1038/s41598-022-08678-z