Secondary metabolites from acridocarpus orientalis inhibits 4T1 cells and promotes mesenchymal stem cells (MSCs) proliferation

Molecular Biology Reports - Among medicinal plants, Acridocarpus orientalis (AO) possesses a remarkable anti-cancer potential, possibly because of its anti-oxidant property. In this study, the leaf...     

De novo synthesis and cellular uptake of organic nanocapsules with tunable surface chemistry

Water-soluble organic nanocapsules were prepared from bottlebrush copolymers with triblock terpolymer side chains composed of a degradable inner block (polylactide), a cross-linkable middle block (poly(4-butenylstyrene)), and a functional outer block (poly(styrene-co-maleic anhydride)). Bottlebrush copolymers are macromolecules with a long linear backbone and shorter polymeric side chains densely grafted onto the backbone. Hollow cylindrical nanoparticles were prepared by peripheral cross-linking of the bottlebrush copolymers and subsequent selective removal of the core. Reactive anhydride groups of the outer functional layer allowed for the preparation of nanocapsules with tunable surface characteristics. Cellular uptake of negatively charged organic nanocapsules showed strong surface chemistry dependence. The presence of hydrophobic groups on the nanocapsule surface was necessary for their nonspecific association with the cell membrane and subsequent internalization by endocytosis. The length of surface grafted oligoethylene glycol chains also had a dramatic influence on the intracellular accumulation of nanocapsules. Macropinocytosis was shown to be the predominant pathway for the cellular uptake of organic nanocapsules.     

Noncanonical Matrix Metalloprotease-1-Protease-activated Receptor-1 Signaling Triggers Vascular Smooth Muscle Cell Dedifferentiation and Arterial Stenosis

Vascular injury that results in proliferation and dedifferentiation of vascular smooth muscle cells (SMCs) is an important contributor to restenosis following percutaneous coronary interventions or plaque rupture. Protease-activated receptor-1 (PAR1) has been shown to play a role in vascular repair processes; however, little is known regarding its function or the relative roles of the upstream proteases thrombin and matrix metalloprotease-1 (MMP-1) in triggering PAR1-mediated arterial restenosis. The goal of this study was to determine whether noncanonical MMP-1 signaling through PAR1 would contribute to aberrant vascular repair processes in models of arterial injury. A mouse carotid arterial wire injury model was used for studies of neointima hyperplasia and arterial stenosis. The mice were treated post-injury for 21 days with a small molecule inhibitor of MMP-1 or a direct thrombin inhibitor and compared with vehicle control. Intimal and medial hyperplasia was significantly inhibited by 2.8-fold after daily treatment with the small molecule MMP-1 inhibitor, an effect that was lost in PAR1-deficient mice. Conversely, chronic inhibition of thrombin showed no benefit in suppressing the development of arterial stenosis. Thrombin-PAR1 signaling resulted in a supercontractile, differentiated phenotype in SMCs. Noncanonical MMP-1-PAR1 signaling resulted in the opposite effect and led to a dedifferentiated phenotype via a different G protein pathway. MMP-1-PAR1 significantly stimulated hyperplasia and migration of SMCs, and resulted in down-regulation of SMC contractile genes. These studies provide a new mechanism for the development of vascular intimal hyperplasia and suggest a novel therapeutic strategy to suppress restenosis by targeting noncanonical MMP-1-PAR1 signaling in vascular SMCs.     

Immunopotentiation of outer membrane protein through anti-idiotype Pasteurella multocida vaccine in rabbits

Pasteurella multocida was isolated from cattle affected with haemorrhagic septicaemia and characterized on the basis of morphological, cultural and biochemical tests. Bacterial outer membrane proteins (OMPs) were extracted with 1% Sarkosyl method. P. multocida anti-idiotype vaccine prepared from OMPs (21.3 mg per 100 ml), was evaluated and compared with bacterin supplemented with 10% OMPs and plain alum-adsorbed bacterin in rabbit models. It was observed that OMPs-anti-idiotype vaccine induced high levels of antibody titres (geomean titres -GMT) detected using indirect haemagglutination (IHA) test. The OMPs anti-idiotype antibody titres of 168.9 GMT were obtained to 42.2 GMT in OMPs supplemented bacterin on 21 days post vaccination, while the plain bacterin had the least titre of 27.9 GMT. The OMPs-anti-idiotype vaccine provoked better immunogenic response in terms of highest GMT titres and long lasting effect in rabbits and 100% protection against the challenge with homologous strain of P. multocida,while 88% protection was obtained in rabbits, given OMPs supplemented bacterin.     

Bisindolylmethane thiosemicarbazides as potential inhibitors of urease: Synthesis and molecular modeling studies

Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by ¹H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC₅₀ values ranging between 0.14?±?0.01 to 18.50?±?0.90?μM when compared with the standard inhibitor thiourea having IC₅₀ value 21.25?±?0.90?μM. Among the series, analog 9 (0.14?±?0.01?μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.     

Corrigendum to “Synthesis,structure-activity relationship and molecular docking studies of 3-O-flavonol glycosides as cholinesterase inhibitors” [Bioorg. Med. Chem. 26 (12) (2018) 3696–3706]

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Biological control of Fusarium oxysporum f. sp. radicis-cucumerinum by some Trichoderma harzianum isolates

The purpose of this study was to investigate the effects of isolates T₂₂, T₉ and T₆ of Trichoderma harzianum on isolate F₄₂ of Fusarium oxysporum f. sp. radicis-cucumerinum. The effect of T. harzianum isolates on controlling disease was examined under greenhouse conditions. Results showed that these three isolates, respectively, had the high effect on inhibition of pathogen growth. In examining the severity of disease in the greenhouse, it was found that isolate T₂₂ had the greatest effect on controlling the pathogen. The results of volatile compounds showed that these isolates, respectively, were effective in reducing mycelial growth of isolate F₄₂. The highest peroxidase activity was observed on the fourth day in isolate T₆ and the highest phenylalanine ammonia lyase enzyme activity was observed on the fifth day in isolate T₂₂. Based on the results, isolate of T₂₂ showed the greatest effect on the induction of resistance against F₄₂ and may be a successful agent for biological control of root and stem rot of cucumber.     

Endothelin-1 reduces mesenteric microvascular hydraulic permeability via cyclic AMP and protein kinase A signal transduction

We have previously shown that endothelin-1 (ET-1) decreases microvascular hydraulic permeability. In this study, we tested the hypothesis that ET-1 exerts its permeability-decreasing effect through cAMP, cGMP, and protein kinase A (PKA) by determining the effect of ET-1 on venular fluid leak during inhibition of cAMP synthesis, inhibition of cGMP degredation, and inhibition of PKA. Rat mesenteric venules were cannulated to measure hydraulic permeability, L(p) (units x 10(-7)cm/(s cmH(2)O)). L(p) was measured during continuous perfusion of 80 pM ET-1 and either (1) an inhibitor of cAMP synthesis (10 microM 2',5'ddA), (2) an inhibitor of cGMP degradation (100 microM Zaprinast), or (3) an inhibitor of PKA (10 microM H-89). Inhibition of cAMP synthesis blocked the permeability decreasing effects of ET-1. The peak L(p) of the cAMP inhibitor alone and with ET-1 was 4.11+/-0.53 and 3.86+/-0.19, respectively (p=0.36, n=6). Inhibition of cGMP degradation did not block the permeability decreasing effects of ET-1. The peak L(p) during inhibition of cGMP degradation alone and with ET-1 was 2.26+/-0.15 and 1.44+/-0.09, respectively (p<0.001, n=6). Inhibition of PKA activation blocked the permeability decreasing effects of ET-1. The peak L(p) of the PKA inhibitor alone and with ET-1 was 2.70+/-0.15 and 2.59+/-0.15, respectively (p=0.38, n=6). The data support the notion that the signal transduction mechanism of ET-1 with regard to decreasing microvascular fluid leak involves cAMP production and PKA activation, but not cGMP degradation. Further understanding of intracellular mechanisms that control microvascular fluid leak could lead to the development of a pharmacologic therapy to control third space fluid loss in severely injured or septic patients.