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BackgroundCohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits.MethodsClinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations.ResultsWe identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population.ConclusionWe suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.

Phytochemical investigation of dried flower buds of Syzygium aromaticum (L.) Merr. & L.M.Perry. (clove) led to the isolation and identification of fourteen known compounds, oleanolic acid (1), betulinic acid (2), para methyl benzoic acid (3), sabrinic acid (4) eucalyptolic acid (5), nigricin (6), 3-O-trans-para-coumaroylmaslinic acid (7), methyl maslinate (8), maslinic acid (9), 3, 4, 5-trimethoxy-3′,4′-O,O-methylideneflavellagic acid (10), lantanone (11) 3,4,3′-trimethoxyellagic acid (12), 11-oxo-oleanolic acid (13), and β-sitosterol-3-O-β-D-glucopyranoside (14). Their structures were identified by 1H NMR, 13C NMR, Mass spectroscopic techniques, and comparison with the literature data. Compounds 3, and 7–9 showed a strong mortality against root knot nematode, Meloidogyne incognita at 0.125% concentration after 72 hours (88–92% inhibition). Compound 4 showed a good anti-glycation activity with IC50 = 142.0 ± 1.8 µM when compared with standard, i.e. rutin (IC50 = 54.59 ± 2.20 µM). Compound 10 showed a comparable urease inhibitory activity (IC50 = 26.1 ± 0.19 µM) with the positive control thiourea (IC50 = 24.5 ± 0.34 µM). [ABSTRACT FROM AUTHOR]

Urease plays a significant role in the pathogenesis of urolithiasis pyelonephritis, urinary catheter encrustation, hepatic coma, hepatic encephalopathy, and peptic acid duodenal ulcers. Salvinia molesta was explored to identify new bioactive compounds with particular emphasis on urease inhibitors. The aqueous methanol extract was fractionated using solvents of increasing polarity. A series of column chromatography and later HPLC were performed on butanol extract. The structures of the resulting pure compounds were resolved using NMR (1D and 2D), infrared, and mass spectroscopy. The novel isolate was evaluated for antioxidant activity (using DPPH, superoxide anion radical scavenging, oxidative burst, and Fe+2 chelation assays), anti‐glycation behavior, anticancer activity, carbonic anhydrase inhibition, phosphodiesterase inhibition, and urease inhibition. One new glucopyranose derivative 6′‐O‐(3,4‐dihydroxybenzoyl)‐4′‐O‐(4‐hydroxybenzoyl)‐α/β‐D‐glucopyranoside (1) and four known glycosides were identified. Glycoside 1 demonstrated promising antioxidant potential with IC50 values of 48.2 ± 0.3, 60.3 ± 0.6, and 42.1 ± 1.8 μM against DPPH, superoxide radical, and oxidative burst, respectively. Its IC50 in the Jack bean urease inhibition assay was 99.1 ± 0.8 μM. The mechanism‐based kinetic studies presented that compound 1 is a mixed‐type inhibitor of urease with a Ki value of 91.8 ± 0.1 μM. Finally, molecular dynamic simulations exploring the binding mode of compound 1 with urease provided quantitative agreement between estimated binding free energies and the experimental results. The studies corroborate the use of compound 1 as a lead for QSAR studies as an antioxidant and urease inhibitor. Moreover, it needs to be further evaluated through the animal model, that is, in vivo or tissue culture‐based ex‐vivo studies, to establish their therapeutic potential against oxidative stress phosphodiesterase‐II and urease‐induced pathologies. [ABSTRACT FROM AUTHOR]

A new sesquiterpene lactone geigerianoloide (1) and four known flavonoids axillarin (2), quercetin (3), 3-methoxy-5,7,3',4'-tetrahydroxy-flavone (4) and hispidulin (5) were isolated from Geigeria alata (DC) Oliv. & Hiern. (Asteraceae). Structures were deduced using 1H- and 13C- NMR spectroscopy, mass spectrometry, while the structure of compound 1 was also deduced using X-ray crystallography technique. Geigeria alata is traditionally used for diabetes, therefore compounds were tested for anti-glycation activity, in which compounds 2 and 3 showed potent activities (IC50 values of 246.97 ± 0.83 and 262.37 ± 0.22 µM, respectively) compared to IC50 value 294.50 ± 1.5 µM of rutin. Moreover, compound 4 exhibited a comparable activity to rutin (IC50 = 293.28 ± 1.34 µM). Compound 5 showed a weak activity. Compounds 2, 3, and 4 exhibited potent DPPH radical scavenging activity (IC50 = 0.1 ± 0.00, 0.13 ± 0.00 and 0.15 ± 0.01 µM, respectively). Compounds 2, 3, and 4 demonstrated significant superoxide anion scavenging activity with IC50 values of 0.14 ± 0.001, 0.17 ± 0.00, and 0.11 ± 0.006 µM, respectively. [ABSTRACT FROM AUTHOR]

Fifteen benzophenone thiosemicarbazones were synthesized and their in vitro antiglycation activity was evaluated. The most active compound 2 (IC50 = 118.15±2.41µM) showed two folds potent activity than the standard, rutin (IC50 = 294.5±1.5µM). Compounds 1 and 3-7 showed good to moderate antiglycation activity in the range of 204.14 - 488.54µM. These compounds were also evaluated for antioxidant activity. Their structure-activity relationships have been developed. The results reveal the potential of these compounds as leads for further studies towards the development of antidiabetic drugs. [ABSTRACT FROM AUTHOR]

The present study was aimed to synthesize and characterize a series of Pd(II)- benzohydrazide complexes with subsequent high throughput screening to seek their effects as enzyme inhibitors and antiglycating agents. Based on complete characterization via elemental (CHN, Pd) analysis, physical (conductivity, magnetic moment) measurements and spectral (FT-IR, ¹HNMR, 13C-NMR) techniques, all Pd(II) complexes were identified as diamagnetic, neutral and orienting in trans square planar geometry with general formula [PdL2Cl2]. The benzohydrazide (L) in these complexes depicts monodentate behavior, providing terminal amino nitrogen as a donor atom. Compared to inactive precursors (free benzohydrazides and Pd2+), almost all Pd(II) complexes showed in vitro antiglycation activity, illustrating the potential role of resulting complexes in the suppression of diabetes and related disorders. The presence of free carbonyl group in complexes has been recognized as possible cause of antiglycation. This study also indicated Pd(II) compounds as far more superior inhibitors of urease and phosphodiesterase-I than parent ligands; many of them exhibited inhibitions equivalent or even greater than the standard inhibitors (thiourea, urease; EDTA, phosphodiesterase), which shows their potential use in future in the control of peptic ulcer and arthritis, respectively. The structure activity relationship (SAR) study demonstrated that complexation, steric hindrance, position of substituents, electron density around metal centre, hydrogen bonding and coordination mode of complexed ligands play prime role in modulating the biological activities of complexes. [ABSTRACT FROM AUTHOR]