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Identification of new oxospiro chromane quinoline-carboxylate antimalarials that arrest parasite growth at ring stage.

Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting Plasmodium proteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates 9(a-o) and carboxylic acids 10(a-b) for the inhibition of Plasmodium N-Myristoyltransferases (NMTs) using computational biology tools followed by chemical synthesis and functional analysis. Th

Design, Synthesis and Biological Evaluation of Syn and Anti-like Double Warhead Quinolinones Bearing Dihydroxy Naphthalene Moiety as Epidermal Growth Factor Receptor Inhibitors with Potential Apoptotic Antiproliferative Action.

Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a−e and 7a−e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a−e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal−Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn p

Direct binding of chloroquine to the multidrug resistance protein (MRP): possible role for MRP in chloroquine drug transport and resistance in tumor cells.

Multidrug resistance protein (MRP) transports a range of compounds that include glutathione S-conjugates, amphiphilic anionic drugs, and natural-product toxins. However, the mechanism of MRP drug binding and transport is presently unclear. We recently demonstrated the direct binding of a quinoline-based photoactive drug, N-[4-[1-hydroxy-2-(dibutylamino)ethyl]quinolin-8-yl]-4-az idosalicylamide (IAAQ), to MRP at a biologically relevant site [Vezmar et al., Biochem Biophys Res Commun 241: 104-111, 1997]. In the present report, we demonstrated that the lysosomotropic or antimalarial drug chloroqu

Multi-Strain Probiotic Improves Tryptophan Metabolism and Symptoms in Chronic Fatigue Syndrome Patients with Co-Occurring Irritable Bowel Syndrome: An Open-Label Pilot Study.

Background/Objectives: Gut dysbiosis in Chronic Fatigue Syndrome (CFS) drives low-grade inflammation and shifts tryptophan metabolism toward … proteolytic markers (3-IS), substrate depletion (low tryptophan), and a neurotoxic signature (high quinolinic acid [QA], low kynurenic acid [KYNA]). Following the intervention, fatigue scores declined by 40.3%, with 97.5% of patients reaching the remission threshold (FSS < 36). Biochemically, 3-IS levels decreased to the range observed in healthy controls and at …

Solvent-Triggered Long-Range Proton Transport in 7-Hydroxyquinoline Using a Sulfonamide Transporter Group.

The ability of long-range proton transport by substitution of 7-hydroxyquinoline at the eighth position with sulfonamide and sulfonylhydrazone rotor units to act as a crane-arm has been studied. Different proton transport pathways triggered by different stimuli have been established depending on the structure of the crane-arms. Solvent-driven proton switching from OH to the quinoline nitrogen (Nquin) site, facilitated by a sulfonamide transporter group in polar protic and aprotic solvents, has been confirmed by optical (absorption and fluorescence) and NMR spectroscopies as well as by single-c

Consensus Molecules Associated with Parkinson's Disease.

Parkinson's disease (PD) has been associated with some types of food and drugs. Here, we query PubMed for the association of PD with foods a … -Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 78%), tetrahydropyridine (77%), probenecid (4%), quinolinic acid (4%), 1,2,3,4-tetrahydroisoquinoline (TIQ, 16%), salsolinol (32%), rotenone (25%), and β-Methylamino-L-alanine (BMAA, 29%). Notably, our study highlights conditional essential endogenous cofactors associated with PD and emphasizes rational direction …

Tryptophan metabolism and ischemic stroke: An intricate balance.

Ischemic stroke, which is characterized by hypoxia and ischemia, triggers a cascade of injury responses, including neurotoxicity, inflammati … ne receptors, and scavenging of reactive oxygen species. In contrast, neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins, induce neurotoxicity mediated by reactive oxygen species, and disrupt mitochondrial function. Additionally, the enzymes involved in tryptophan metabolism play major roles in these …

Kynurenin Pathway Modulation by Working in Multical Sclerosis: Последствия для защиты от нейро и воспаления.

Множественный склероз (MS) — хроническое, воспалительное и нейродегенеративное заболевание центральной нервной системы (CNS), характеризующееся иммунной диагностикой и нейронным воспалением. Благодаря образованию нейроактивных метаболитов, кинуреньский путь (КП), один из ключевых путей метаболизма триптофана, влияет на патогенез MS, регулируя иммунную реакцию и нейронный гомеостаз. Регулирование КП приводит к перепроизводству таких нейротоксичных метаболитов, как квинолинская кислота (QUIN), для которых характерна потеря гомеостаза между нейрозащитой (например, кинуриновой кислотой, KYNA) и не

Совпадение в аннотации оригинала
Multiple Sclerosis (MS) is a chronic, inflammatory, and neurodegenerative disease of the Central Nervous System (CNS) that is characterized … ronal homeostasis. KP dysregulation results in the overproduction of neurotoxic metabolites such as quinolinic acid (QUIN), characterized by the loss of homeostasis between the neuroprotective (e.g., kynurenic acid, KYNA) and neurotoxic (e.g., QUIN) metabolites, contributing to neuroinflammation, excitotoxicity, and neurodegeneration. Recent evidence suggests tha …

Altered Tryptophan Metabolism on the Kynurenine Pathway in Depressive Patients with Small Intestinal Bacterial Overgrowth.

The causes of depression are diverse and are still not fully understood. Recently, an increasing role is attributed to nutritional and infla … Scale (HAM-D). The concentration of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QA) in urine was determined using an LC-MS/MS method, before and after cyclic treatment with an antibiotic drug, rifaximin, for three months. The number of intraepithelial lymphocytes (IELs) in the duodenum and small intestinal mucosa, fecal calpro …

Acute administration of ibuprofen increases serum concentration of the neuroprotective kynurenine pathway metabolite, kynurenic acid: a pilot randomized, placebo-controlled, crossover study.

RATIONALE: At least six different types of antidepressant treatments have been shown to either increase the neuroprotective kynurenine pathway (KP) metabolite, kynurenic acid (KynA), or decrease the neurotoxic KP metabolite, quinolinic acid (QA). Nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen have shown some efficacy in the treatment of depression but their effects on the KP have not been studied in humans. OBJECTIVES: To evaluate the effect of ibuprofen on circulating KP metabolites. METHODS: In a randomized, placebo-controlled, crossover study, 20 healthy adults (10 wome…

Associations between estrogen and progesterone, the kynurenine pathway, and inflammation in the post-partum.

BACKGROUND: Depression during and after pregnancy is common, affecting at least 15% of women. Features of depression in pregnancy range from … e was negatively correlated with IL-1β and several metabolites in the kynurenine pathway, including quinolinic acid. LIMITATIONS: Associative study design, did not attempt to assess causality. Did not adjust hormone levels for medication effects. CONCLUSIONS: Our study suggests that higher sex hormones in the post-partum are linked to depression severity over p …

Selective lesions of the dorsomedial striatum impair serial spatial reversal learning in rats.

Impairments in reversal learning have been attributed to orbitofrontal cortex (OFC) dysfunction in many species. However, the role of subcortical areas interconnected with the OFC such as the striatum remains poorly understood. This study directly evaluated the contribution of core and shell sub-regions of the nucleus accumbens (NAc), dorsomedial (DMS) and dorsolateral (DLS) striatum to reversal learning of an instrumental two-lever spatial discrimination task in rats. Selective NAc core, DMS and DLS lesions were achieved with microinjections of quinolinic acid and NAc shell lesions with ibote…

A Highly Selective Hg2+ Fluorescent Chemosensor Based On Photochromic Diarylethene With Quinoline Unit.

A novel diarylethene-based fluorescent chemosensor containing a quinoline unit (1o) had been designed and synthesized. 1o showed good photochromic ability and fluorescence switching properties by alternating UV/vis light irradiation. The chemosensor showed high "Turn-off" fluorescent selectivity for Hg2+ by competitive tests of the fluorescence reaction in the presence other ions in acetonitrile solution. The stoichiometry between the compound 1o and Hg2+ was 1:1 by Job's plot curve and HRMS analysis. In addition, the LOD for Hg2+ was calculated as 60 nM. The fluorescence emission can be back

Kynureninase deficiency ameliorated monocytic recruitment and severity in a mouse model of multiple sclerosis.

Multiple sclerosis (MS) is a common autoimmune demyelinating disease of the central nervous system (CNS). Although activation of the kynuren … hin monocytes in the spinal cord of EAE mice. This was accompanied by a significant accumulation of quinolinic acid (QUIN) in the spinal cord. Importantly, similar increases in KYNU expression and QUIN levels were observed in the spinal cord of proteolipid protein overexpressing mice (PLP-tg mice), another model of demyelination. Notably, KYNU knockout (KO) reduc …

3D Imaging of Striatal Transplants in a Small Animal Model of Huntington's Disease.

High-resolution imaging in small animal models of neurologic disease is a technical challenge. In a pilot project, we have explored a non-destructive synchrotron imaging technique for the 3D visualization of intracerebral tissue transplants in a well-established small animal model of Huntington's disease. Four adult female Sprague Dawley rats each received injections of 0.12 M quinolinic acid (QA) into two target positions in the left striatum, thus creating unilateral left-sided striatal lesions similar to those frequently seen in patients suffering from Huntington's disease. One week after l…

Beneficial behavioral effects of chronic cerebral dopamine neurotrophic factor (CDNF) infusion in the N171-82Q transgenic model of Huntington's disease.

Huntington's disease (HD) is a progressive inherited neurological disease characterized by the degeneration of basal ganglia and the accumul … Our recent study showed that CDNF improves motor coordination and protects NeuN positive cells in a Quinolinic acid toxin rat model of HD. Here we have investigated the effect of chronic intrastriatal CDNF administration on behavior and mHtt aggregates in the N171-82Q mouse model of HD. Data showed that CDNF did not significantly decrease the number of mHtt aggre …

Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons.

Medium-sized spiny neurons (MSNs) are the only neostriatum projection neurons, and their degeneration underlies some of the clinical feature … ne neuromodulation and synaptic integration ability in vivo. When transplanted into the striatum of quinolinic acid-lesioned rats, hPS-derived neurons survive and differentiate into DARPP-32(+) neurons, leading to a restoration of apomorphine-induced rotation behavior. In summary, hPS cells can be efficiently driven to acquire a functional striatal fate using an …

[18F]desmethoxyfallypride as a novel PET radiotracer for quantitative in vivo dopamine D2/D3 receptor imaging in rat models of neurodegenerative diseases.

INTRODUCTION: [(18)F]desmethoxyfallypride ([(18)F]DMFP) is a promising tracer for longitudinal assessment of striatal dopamine D2/D3-receptor (D2R) availability by positron emission tomography (PET) in small animal models. We explored the feasibility of [(18)F]DMFP-PET to image D2R availability in rat models of Huntington's (HD) and Parkinson's disease (PD). METHODS: Animals received either unilateral intrastriatal quinolinic acid lesions or medial forebrain bundle injections of 6-OHDA to produce the loss of striatal projection neurones or deplete the striatal dopamine, corresponding to estab…

A complementary diffusion tensor imaging (DTI)-histological study in a model of Huntington's disease.

In vivo diffusion tensor imaging (DTI) was performed on the quinolinic acid (QUIN) rat model of Huntington's disease, together with behavioral assessment of motor deficits and histopathological characterization. DTI and histology revealed the presence of a cortical lesion in 53% of the QUIN animals (QUIN(+ctx)). Histologically, QUIN(+ctx) were distinguished from QUIN(-ctx) animals by increased astroglial reaction within a subregion of the caudate putamen and loss of white matter in the external capsula. Although both techniques are complementary, the quantitative character of DTI makes it poss…