Synthesis, antibacterial, and antifungal activities of biolabile (E)-1-(4-morpholinophenyl)-3-aryl-prop-2-en-1-ones

Abstract  A collection of biolabile (E)-1-(4-morpholinophenyl)-3-aryl-prop-2-en-1-ones 8–13 are synthesized, characterized by melting point, elemental analysis, mass spectroscopy (MS), Fourier-transform infrared (FT-IR), and ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopic data and evaluated for their in vitro antibacterial and antifungal activities. Compounds 8–13 exerted a wide range of antibacterial activities against all tested Gram-positive and Gram-negative bacterial strains. All the compounds 8–13 were more active against Pseudomonas. Of the synthesized compounds, compounds 9 and 11 exhibited a wide range of antibacterial activities against Staphylococcus aureus, β-Heamolytic streptococcus, Escherichia coli, Klebsiella pneumonia, and Pseudomonas. Compounds 10, 12, and 13 exerted strong antifungal activities against all tested fungal strains, namely Aspergillus flavus, Mucor, Rhizopus, and Microsporum gypsuem. Graphical Abstract        

Symptomatic West Syndrome Secondary to Glucose Transporter-1(GLUT1) Deficiency with Complete Response to 4:1 Ketogenic Diet

Glucose transporter type 1 (GLUT-1) deficiency is a rare cause of preventable intellectual disability. Intellectual disability is due to refractory seizures in infancy and reduced supply of glucose to the brain. The authors report a third born male child of consanguineous parentage who presented with infantile spasms. Initially, he had refractory convulsions of focal, generalised, and myoclonic jerks, not responding to multiple anticonvulsants. He also had choreoathetoid movements. On examination he had microcephaly. MRI of brain was normal and EEG showing diffuse slowing. CSF glucose was low compared to blood glucose, with normal lactate and without any cells, hence diagnosed as Glucose transporter-1 deficiency and started on ketogenic diet. With ketogenic diet, child was seizure free, anticonvulsants decreased to 2 from 5, and improvements in development were noted.     

Co-solvent polarity tuned thermochromic nanotubes of cyclic dipeptide–polydiacetylene supramolecular system

The cooperative non-covalent interactions arising from structurally integrated multiple molecules have emerged as a powerful tool for the creation of functional supramolecular structures. Herein, we constructed cyclic dipeptide (CDP)–polydiacetylene (PDA) conjugate (CDP–DA) by introducing cyclo(l-Phe-l-Lys) to the linear 10,12-pentacosadiynoic acid. Owing to extensive hydrogen bonding characteristics, together with structural chirality of cyclo(l-Phe-l-Lys) and strong π–π stacking diacetylenic template, CDP–DA generated supramolecular nanotubes. The structural visualization using scanning and transmission electron microscopy revealed chloroform/methanol co-solvent polarity tuned morphological transformation of intrinsic lamellar assemblies into nanotubes comprising single-wall and multi-wall structure. The mechanistic understanding by X-ray diffraction patterns confirms bilayer organization in lamellar structure, which forms nanotubes via a gradual lamellar curling-to-scrolling process. The supramolecular CDP–DA nanotubes are transformed into the rigid covalently cross-linked blue-phase polydiacetylene (CDP–PDA) by UV irradiation. Very interestingly, the blue-phase nanotubes display reversible thermochromic changing temperature up to 150 °C with excellent repeatability over a dozen thermal cycles. This work provides an efficient strategy for precise morphological control and aiding the perspective for development in nanostructures for functional devices.

Co-solvent controlled fabrication of thermo-responsive chromogenic nanotubes of a cyclic dipeptide–polydiacetylene supramolecular system.     

Organ specific complement proteins inhibition can reduce the risk of antiphospholipid antibodies mediated fetal loss

Antiphospholipid syndrome is a pregnancy related, systemic autoimmune disorder in which antibodies directed against cell membrane phospholipids with multiple venous/arterial thromboses. Though the etiology of antiphospholipid syndrome has not been identified exactly, experimental evidences suggest the possible mechanisms involved in the pathogenicity of this syndrome. Antiphospholipid antibodies mediate deposition of complement proteins in placenta and over expression of tissue factor on the surface of neutrophils which are reported to be the prominent cause of prothrombotic phenotype. The activation complement components C3 and C5 by antiphospholipid antibodies would eventually activates blood coagulation pathway that leads to thrombosis. Inhibition of activated complement components C3a and C5a by anticomplement agents protects from antiphospholipid antibody mediated fetal loss. Since the interference of complement pathway may lead to deleterious effects, we hypothesis that local inhibition of complement proteins C3a and C5a at placenta would reduce the risk of antiphospholipid antibody mediated placental thrombosis and pregnancy complications.     

Magnetic resonance imaging of temporal changes of neurotoxic lesion in the rat

Destruction of striatal neurons in the rat brain, induced by intracerebral injection of N-methyl D-aspartic acid (NMDA), has been visualized noninvasively by magnetic resonance imaging (MRI). The changes in images were monitored from 12 h to one month after the stereotaxic microinfusion of NMDA (10 μg in 0.4 μl) into the striatum, using a T₂-weighted rapid acquisition by relaxation enhancement (RARE) sequence. A localised hyperintense (bright) area was visible after 12 h at the site of the injection, and it persisted for the next three days. The size of the hyperintense area decreased thereafter and, after one week, the increased brightness was restricted to the lateral ventricle. Post-mortem histological examination, done after one month, showed a dilated lateral ventricle. The size and location of the lesioned area, identified in histological sections, corresponded to the hyperintense area observed during these initial days after NMDA lesion. The present study demonstrates that noninvasive MRI techniques, using a typical RARE sequence, offer a powerful tool for the early detection of neurotoxic lesion of the brain area, although some caution is required in its use for estimating the size of the lesioned area three days after its formation. The present findings indicate that, in long-term studies, alterations of the neighbouring structures, such as enlargement of the ventricular system, may confound the MRI evaluation of neurotoxic lesions in vivo.     

In vitro biological activities of new heterocyclic chalcone derivatives

This work reports the synthesis and characterization of new heterocyclic chalcone derivatives 3(a–j) and in vitro biological evaluation for antiproliferative, antioxidant, antibacterial, antifungal, and antiviral properties. The antiproliferative efficacy and LC₅₀ of the compounds against HepG2 cell lines were determined. The LC₅₀ for 3d was found to be 8 μg/mL. All the compounds exhibited moderate DPPH scavenging activity and moderate to good antimicrobial activity against tested bacterial and fungal strains. Further, the compounds at their respective maximum non-toxic concentrations did not inhibit DNA viruses like buffalopox, camelpox, and goatpox.     

Role of the cystic fibrosis transmembrane conductance channel in human airway smooth muscle

Patients with cystic fibrosis (CF) suffer from asthma-like symptoms and gastrointestinal cramps, attributed to a mutation in the CF transmembrane conductance regulator (CFTR) gene present in a variety of cells. Pulmonary manifestations of the disease include the production of thickened mucus and symptoms of asthma, such as cough and wheezing. A possible alteration in airway smooth muscle (ASM) cell function of patients with CF has not been investigated. The aim of this study was to determine whether the (CFTR) channel is present and affects function of human ASM cells. Cell cultures were obtained from the main or lobar bronchi of patients with and without CF, and the presence of the CFTR channel detected by immunofluorescence. Cytosolic Ca(2+) was measured using Fura-2 and dual-wavelength microfluorimetry. The results show that CFTR is expressed in airway bronchial tissue and in cultured ASM cells. Peak Ca(2+) release in response to histamine was significantly decreased in CF cells compared with non-CF ASM cells (357 +/- 53 nM versus 558 +/- 20 nM; P < 0.001). The CFTR pharmacological blockers, glibenclamide and N-phenyl anthranilic acid, significantly reduced histamine-induced Ca(2+) release in non-CF cells, and similar results were obtained when CFTR expression was varied using antisense oligonucleotides. In conclusion, these data show that the CFTR channel is present in ASM cells, and that it modulates the release of Ca(2+) in response to contractile agents. In patients with CF, a dysfunctional CFTR channel could contribute to the asthma diathesis and gastrointestinal problems experienced by these patients.     

Sarcolemmal damage in dystrophin deficiency is modulated by synergistic interactions between mechanical and oxidative/nitrosative stresses

Dystrophin deficiency is the cause of Duchenne muscular dystrophy, but the precise physiological basis for muscle necrosis remains unclear. To determine whether dystrophin-deficient muscles are abnormally susceptible to oxidative and nitric oxide (NO)-driven tissue stress, a hindlimb ischemia/reperfusion (I/R) model was used. Dystrophic mdx mice exhibited abnormally high levels of lipid peroxidation and protein nitration, which were preceded by exaggerated NO production during ischemia. Visualization of NO with the fluorescent probe 4,5-diaminofluorescein diacetate suggested that excess NO production during ischemia occurred within a subset of mdx fibers. In mdx muscles only, prior exposure to I/R dramatically increased the level of sarcolemmal damage resulting from stretch-mediated mechanical stress, indicating greatly exacerbated hyperfragility of the dystrophic fiber membrane. Treatment with NO synthase inhibitors (l-N(G)-nitroarginine methyl ester hydrochloride or 7-nitroindazol) effectively blocked the synergistic interaction between I/R and mechanical stress-mediated sarcolemmal damage under these conditions. Taken together, our findings provide direct ex-perimental evidence that several prevailing hy-potheses regarding the cause of muscle fiber damage in dystrophin-deficient muscle can be integrated into a common pathophysiological framework involving interactions between oxidative stress, ab-normal NO regulation, and hyperfragility of the sarcolemma.     

Detection of estrus by male mice: Synergistic role of olfactory–vomeronasal system

In rodents, olfactory pathway comprises two distinct systems viz, the main olfactory and vomeronasal systems, both differing in anatomy, physiology and function. The precise role of the main olfactory/vomeronasal system in estrus detection is yet to be explored. Therefore, the present investigation was planned to elucidate the role of main olfactory and vomeronasal system in the estrus discriminating ability of male mice. Female urine samples of proestrus, estrus, metestrus, diestrus, ovarectomized, ovarectomized plus estrogen treated and prepubertal mice were used for the present study. In addition, the urine from intact, castrated and castrated with testosterone treated mice was also tested for odour preference by male mice. The male responders were categorized into three groups namely (a) normal, (b) ZnSO₄-irrigated and (c) vomeronasal organ (VNO)-ablated. The behavioural responses such as frequency and duration of visits to urine samples were carried out in a Y-maze apparatus to assess odour preference. The normal mice displayed more frequent visits to estrus urine samples than to non-estrus samples. In contrast, ZnSO₄-irrigated mice showed significant reduction in the frequency of visits towards estrus urine, whereas, the vomeronasal (VNO)-ablated mice did not show any noticeable preference. With regard to the duration of visits the VNO-ablated mice showed significant reduction in visiting time when compared to ZnSO₄-irrigated mice. This finding indicated that the main olfactory system (MOS) was involved primarily in the attraction from a distance, while the VNO played a major role in close proximity (pre-copulatory behaviour). The males spent less time with the urine of same-sex; however, the response was higher with castrated male urine which was reduced on testosterone treatment indicating that a specific odour in intact male causes aversive behaviour in male. This study provides support to the fact that volatile compounds could also be perceived by VNO, probably when the main olfactory system is in functional state. The study implies that the olfactory–vomeronasal system plays a synergistic role in the detection of estrus.