Peptidomic analysis of skin secretions demonstrates that the allopatric populations of Xenopus muelleri (Pipidae) are not conspecific

Mueller's clawed frog Xenopus muelleri (Peters 1844) occupies two non-contiguous ranges in east and west Africa. The phylogenetic relationship between the two populations is unclear and it has been proposed that the western population represents a separate species. Peptidomic analysis of norepinephrine-stimulated skin secretions from X. muelleri from the eastern range resulted in the identification of five antimicrobial peptides structurally related to the magainins (magainin-M1 and -M2), xenopsin-precursor fragments (XPF-M1) and caerulein-precursor fragments (CPF-M1 and -M2) previously found in skin secretions of other Xenopus species. A cyclic peptide (WCPPMIPLCSRF.NH₂) containing the RFamide motif was also isolated that shows limited structural similarity to the tigerinins, previously identified only in frogs of the Dicroglossidae family. The components identified in skin secretions from X. muelleri from the western range comprised one magainin (magainin-MW1), one XPF peptide (XPF-MW1), two peptides glycine-leucine amide (PGLa-MW1 and -MW2), and three CPF peptides (CPF-MW1, -MW2 and -MW3). Comparison of the primary structures of these peptides suggest that western population of X. muelleri is more closely related to X. borealis than to X. muelleri consistent with its proposed designation as a separate species. The CPF peptides showed potent, broad-spectrum activity against reference strains of bacteria (MIC 3-25 μM), but were hemolytic against human erythrocytes.     

Angiotensin-converting enzyme gene polymorphisms and T2DM in a case�Ccontrol association study of the Bahraini population

Bahrain has one of the highest incidence rates of type 2 diabetes mellitus (T2DM). Development of diabetic nephropathy (DN) as a complication was noticed in some patients while absent in others. This interesting observation raises the role of certain genetic risk factors for the development of DN. Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was found to be associated with T2DM. While some patients have predisposition to DN in the population, others have negative association. The present case-control association study was designed to investigate the association of ACE I/D polymorphism in T2DM patients in Bahrain especially in those who developed DN. A total of 360 T2DM patients (110 with DN and 250 without DN) and 360 healthy (non-diabetic) age-matched subjects were recruited for this study for comparison. The presence (insertion)/absence (deletion) (I/D) polymorphism of a 287-bp Alu1 element inside intron 16 of the ACE gene was investigated using PCR-gel electrophoresis. The results show that the distribution of the homozygote DD genotype of the ACE gene was high among Bahraini T2DM patients compared to the healthy non-diabetic subjects. In addition, the distribution of the deletion (D) allele was high among Bahraini T2DM patients with DN when compared to the healthy non-diabetic subjects. However, there was no significant difference in the distribution of ACE I/D allele and genotypes between DN patients when compared to those T2DM patients without DN. The results obtained in this study are in closely agreement with some previous reports which show a strong association of ACE polymorphism with T2DM patients, yet not a risk factor for development of DN.     

Optimizing anti-gene oligonucleotide ‘Zorro-LNA’ for improved strand invasion into duplex DNA

Zorro-LNA (Zorro) is a newly developed, oligonucleotide (ON)-based, Z-shaped construct with the potential of specific binding to each strand of duplex DNA. The first-generation Zorros are formed by two hybridized LNA/DNA mixmers (2-ON Zorros) and was hypothesized to strand invade. We have now established a method, which conclusively demonstrates that an LNA ON can strand invade into duplex DNA. To make Zorros smaller in size and easier to design, we synthesized 3′–5′–5′–3′ single-stranded Zorro-LNA (ssZorro) by using both 3′- and 5′-phosphoramidites. With ssZorro, a significantly greater extent and rate of double-strand invasion (DSI) was obtained than with conventional 2-ON Zorros. Introducing hydrophilic PEG-linkers connecting the two strands did not significantly change the rate or extent of DSI as compared to ssZorro with a nucleotide-based linker, while the longest alkyl-chain linker tested (36 carbons) resulted in a very slow DSI. The shortest alkyl-chain linker (3 carbons) did not reduce the extent of DSI of ssZorro, but significantly decreased the DSI rate. Collectively, ssZorro is smaller in size, easier to design and more efficient than conventional 2-ON Zorro in inducing DSI. Analysis of the chemical composition of the linker suggests that it could be of importance for future therapeutic considerations.     

Strategies to lower the Pgp efflux liability in a series of potent indole azetidine MCHR1 antagonists

A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify 1-dihydroindolyl azetidine derivatives with CNS penetration and excellent rMCHR1 binding affinity.     

TRPC5 channel sensitivities to antioxidants and hydroxylated stilbenes

Transient receptor potential canonical 5 (TRPC5) forms cationic channels that are polymodal sensors of factors including oxidized phospholipids, hydrogen peroxide, and reduced thioredoxin. The aim of this study was to expand knowledge of the chemical-sensing capabilities of TRPC5 by investigating dietary antioxidants. Human TRPC5 channels were expressed in HEK 293 cells and studied by patch clamp and intracellular Ca(2+) recording. GFP- and HA-tagged channels were used to quantify plasma membrane localization. Gallic acid and vitamin C suppressed TRPC5 activity if it was evoked by exogenous hydrogen peroxide or lanthanide ions but not by lysophosphatidylcholine or carbachol. Catalase mimicked the effects, suggesting that lanthanide-evoked activity depended on endogenous hydrogen peroxide. Trans-resveratrol, by contrast, inhibited all modes of TRPC5, and its effect was additive with that of vitamin C, suggesting antioxidant-independent action. The IC(50) was ～10 μM. Diethylstilbestrol, a related hydroxylated stilbene, inhibited TRPC5 with a similar IC(50), but its action contrasted sharply with that of resveratrol in outside-out membrane patches where diethylstilbestrol caused strong and reversible inhibition and resveratrol had no effect, suggesting indirect modulation by resveratrol. Resveratrol did not affect channel surface density, but its effect was calcium-sensitive, indicating an action via a calcium-dependent intermediate. The data suggest previously unrecognized chemical-sensing properties of TRPC5 through multiple mechanisms: (i) inhibition by scavengers of reactive oxygen species because a mode of TRPC5 activity depends on endogenous hydrogen peroxide; (ii) direct channel blockade by diethylstilbestrol; and (iii) indirect, antioxidant-independent inhibition by resveratrol.     

Cyanidin-3-Glucoside Modulates hsa_circ_0001345/miRNA106b/ATG16L1 Axis Expression as a Potential Protective Mechanism against Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common form of malignancy in the liver. Autophagy was found to have a significant effect in controlling HCC. Anthocyanins, which are naturally occurring pigments in a variety of fruits and vegetables, have been thoroughly documented to be involved in a variety of bioactive activities and are widely employed for their antioxidant capabilities. Cyanidin-3-glucoside (C3G) extracted from Morus alba L. has promising antioxidant and anti-tumour activities. The current study aims to examine the protective action of C3G against hepatocellular carcinoma through the investigation of the autophagy protein ATG16L1 expression along with its related RNA molecules (hsa_circ_0001345 and miRNA106b) in Wistar rats. In vivo precancerous lesions (PCL) were induced using diethylnitrosamine (DEN) and acetamidofluorene (2-AAF). Rats were treated with C3G (10, 15, and 20 mg/kg; 4 times weekly) for 112 days (16 weeks). Liver function tests, alfa fetoprotein, ATG16L1 expression, hsa_circ_0001345, and miRNA106b differential expression were examined. Liver sections were examined by histological and immunohistochemical approaches. The current study’s findings indicated that C3G administration protects against the negative effects of DEN-2-AAF on liver functions and liver histopathological sections, which nominated C3G as a potential prophylactic agent against HCC.     

A Comprehensive Study on the Mechanistic Way of Hexaflumuron and Hymexazol Induced Neurobehavioral Toxicity in Rats

Neurochemical Research - Pesticides are widely used in agriculture to kill pests, but their action is non-selective and results in several hazardous effects on humans and animals. Pesticide...     

Production of transgenic Allium cepa by nanoparticles to resist Aspergillus niger infection

Molecular Biology Reports - Transgenic plants are becoming a more powerful tool in modern biotechnology. Genetic engineering was used in biotech-derived products to create genetically modified (GM)...     

Novel Synthesis,Reactions, and Biological Study of New Morpholino-Thieno[2,3-c][2,7]Naphthyridines as Anti-Cancer and Anti-Microbial Agents

Russian Journal of Bioorganic Chemistry - The biological uses of 2,7-naphthyridines have sparked great attention in recent years. For this reason, we synthesized a series of novel...