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Inorganic Chemistry Jul 2024Separation of CH/CH mixtures is of significant importance in the chemical industry but remains a challenge due to the physicochemical similarities of CH and CH. Herein,...
Separation of CH/CH mixtures is of significant importance in the chemical industry but remains a challenge due to the physicochemical similarities of CH and CH. Herein, a metal-organic framework (MOF), [Zn(μ-O)(PCTF)] (Zn-PCTF) (PCTF= 5-trifluoromethyl-1H-pyrazole-4-carboxylic), is provided for the removal of CH from CH/CH mixtures. Zn-PCTF displays a three-dimensional framework featuring one-dimensional pore channels with periodic bottleneck segments. The well-balanced CH adsorption capacity (79.0 cm g at 298 K) and CH/CH selectivity (1.8) for Zn-PCTF under ambient conditions boost Zn-PCTF with highly promising potentials for efficient purification of CH from CH/CH mixtures, which is verified by the dynamic column breakthrough experiments. The well-matched caged pores and suitable pore chemistry (particularly the presence of abundant Lewis base sites (N, O, and F) on the pore surfaces) for CH account for the high-performance CH/CH separation of Zn-PCTF unveiled by computational simulations.
PubMed: 38889441
DOI: 10.1021/acs.inorgchem.4c01733 -
Journal of Medicinal Chemistry Jun 2024Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great...
Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great significance for exploring antidepressants and their mechanisms of action. Herein, a series of novel phenylpyrazole analogues were rationally designed and synthesized. Among them, compound exhibited potent inhibitory activity (IC = 0.87 μM) and good drug-like properties. studies demonstrated that compound was involved in multiple antidepressant mechanisms of action, which were associated with a decline of ceramide, including increasing the Bcl-2/Bax ratio and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating oxidative stress, reducing the levels of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, and elevating 5-HT levels in the brains of mice, respectively. These meaningful results reveal for the first time that direct inhibitors exhibit remarkable antidepressant effects in the CUMS-induced mouse model through multiple mechanisms of antidepressant action.
Topics: Animals; Antidepressive Agents; Pyrazoles; Mice; Sphingomyelin Phosphodiesterase; Structure-Activity Relationship; Male; Depression; Drug Discovery; Enzyme Inhibitors; Humans; Brain-Derived Neurotrophic Factor; Oxidative Stress
PubMed: 38888140
DOI: 10.1021/acs.jmedchem.4c00831 -
Chemphyschem : a European Journal of... Jun 2024Coordination complexes of rare-earth ions (REI) show optical transitions with narrow linewidths enabling the creation of coherent light-matter interfaces for quantum...
Coordination complexes of rare-earth ions (REI) show optical transitions with narrow linewidths enabling the creation of coherent light-matter interfaces for quantum information processing (QIP) applications. Among the REI-based complexes, Eu(III) complexes showing the 5D0 → 7F0 transition are of interest for QIP applications due to the narrow linewidths associated with the transition. Herein, we report on the synthesis, structure, and optical properties of a novel Eu(III) complex and its Gd(III) analogue composed of 2,9-bis(pyrazol-1-yl)-1,10-phenanthroline (dpphen) and three nitrate (NO3) ligands. The Eu(III) complex-[Eu(dpphen)(NO3)3]-showed sensitized metal-centred emission (5D0 → 7FJ; J = 0,1,2,3, 4, 5, or 6) in the visible region, upon irradiation of the ligand-centered band at 369 nm, with the 5D0 → 7F0 transition centred at 580.9 nm. Spectral hole-burning (SHB) studies of the complex with stoichiometric Eu(III) concentration revealed a narrow homogeneous linewidth (Γh) of 1.55 MHz corresponding to a 0.205 µs long optical coherence lifetime (T2opt). Remarkably, long nuclear spin lifetimes (T1spin) of up to 41 s have been observed for the complex. The narrow optical linewidths and long T1spin lifetimes obtained for the Eu(III) complex showcase the utility of Eu(III) complexes as tunable, following molecular engineering principles, coherent light-matter interfaces for QIP applications.
PubMed: 38887965
DOI: 10.1002/cphc.202400280 -
Obesity (Silver Spring, Md.) Jul 2024Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006... (Review)
Review
Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006 in Europe but subsequently rejected by the US Food and Drug Administration (FDA) in 2007. The FDA cited the increased risk of suicidality in its opposition to rimonabant's approval, leading to the drug's eventual worldwide withdrawal and the abandonment of this class of therapeutics. Seventeen years later, a new class of CB1-targeting drugs is emerging, but the impact of the 2007 FDA decision remains a formidable obstacle to its clinical development. We revisit the suicidality data presented by the FDA in light of the evolution of suicidality assessment and cross-reference this with the data in the subsequently published clinical trials. We conclude that the publicly available data do not support the FDA's conclusion that the use of rimonabant was associated with an increase in the risk of suicidality.
Topics: Rimonabant; Humans; United States Food and Drug Administration; United States; Anti-Obesity Agents; Suicide; Obesity; Receptor, Cannabinoid, CB1; Cannabinoid Receptor Antagonists; Drug Approval; Pyrazoles; Piperidines
PubMed: 38887179
DOI: 10.1002/oby.24019 -
Dalton Transactions (Cambridge, England... Jul 2024The current work aims to generate multifunctional MOFs by incorporating a well-known inorganic motif, a trinuclear Cu-pyrazolate [Cu(μ-OH)(μ-Pyz)] (T-CuP) unit, as a...
The current work aims to generate multifunctional MOFs by incorporating a well-known inorganic motif, a trinuclear Cu-pyrazolate [Cu(μ-OH)(μ-Pyz)] (T-CuP) unit, as a node of the network. Accordingly, we report herein the synthesis and properties of five new compounds using five V-shaped dicarboxylic acids as auxiliary ligands. The structural features are consistent with the theme of grafting T-CuP units as nodal points of architectures whose chassis are primarily made of bent acids. V-shaped acids also induce a helical nature inside resulting frameworks. Beside their structural and physical features, T-CuP unit-based MOFs also vindicate our thematic approach of the trinuclear Cu-pyrazolate unit imparting specific physicochemical properties, such as magnetic, electrical, and catalytic properties, to resultant MOFs. The MOFs show excellent catalytic properties in reducing 4-nitrophenol, which could be attributed to the porous nature of the network along with the presence of metal centres with unsaturated coordination within the T-CuP unit. Furthermore, efficient photocatalytic degradation of harmful organic dyes confirms their importance for environmental remediation. The presence of a T-CuP unit and various functional groups also make some of the MOFs suitable candidates for electrical applications, which is indeed manifested in encouraging proton conductivity. Finally, the potential of current MOFs, fitted with a magnetically important trinuclear Cu-pyrazolate motif, as magnetic materials has also been thoroughly investigated.
PubMed: 38881376
DOI: 10.1039/d4dt00986j -
Expert Opinion on Drug Delivery May 2024Regadenoson, an agonist of adenosine A2 receptors, enables transient blood-brain barrier (BBB) disruption. The relevance of regadenoson as a pharmacological strategy for...
BACKGROUND
Regadenoson, an agonist of adenosine A2 receptors, enables transient blood-brain barrier (BBB) disruption. The relevance of regadenoson as a pharmacological strategy for brain delivery was investigated using in vivo PET imaging in rats.
RESEARCH DESIGN AND METHODS
Kinetic modeling of brain PET data was performed to estimate the impact of regadenoson (0.05 mg.kg, i.v.) on BBB permeation compared with control rats ( = 4-6 per group). Three radiolabeled compounds of different sizes, which do not cross the intact BBB, were tested.
RESULTS
Regadenoson significantly increased the BBB penetration (+116 ± 13%, < 0.001) of [F]2-deoxy-2-fluoro-D-sorbitol ([F]FDS, MW = 183 Da), a small-molecule marker of BBB permeability. The magnitude of the effect was different across brain regions, with a maximum increase in the striatum. Recovery of BBB integrity was observed 30 min after regadenoson injection. Regadenoson also increased the brain penetration (+72 ± 45%, < 0.05) of a radiolabeled nanoparticle [Zr]AGuIX (MW = 9 kDa). However, the brain kinetics of a monoclonal antibody ([Zr]mAb, MW = 150 kDa) remained unchanged ( > 0.05).
CONCLUSIONS
PET imaging showed the features and limitations of BBB disruption induced by regadenoson in terms of extent, regional distribution, and reversibility. Nevertheless, regadenoson enables the brain delivery of small molecules or nanoparticles in rats.
Topics: Animals; Blood-Brain Barrier; Purines; Pyrazoles; Rats; Positron-Emission Tomography; Brain; Male; Adenosine A2 Receptor Agonists; Drug Delivery Systems; Nanoparticles; Rats, Sprague-Dawley; Permeability; Fluorine Radioisotopes; Rats, Wistar
PubMed: 38881261
DOI: 10.1080/17425247.2024.2369765 -
Expert Review of Clinical Immunology Jul 2024Vitiligo is a chronic, autoimmune condition characterized by skin depigmentation caused by inflammatory-mediated melanocyte degradation. Treatment of vitiligo is... (Review)
Review
INTRODUCTION
Vitiligo is a chronic, autoimmune condition characterized by skin depigmentation caused by inflammatory-mediated melanocyte degradation. Treatment of vitiligo is challenging due to the chronic nature of the condition. Ruxolitinib cream 1.5% was recently approved by the Food and Drug Administration (FDA) as a Janus kinase 1 and 2 inhibitor for use in nonsegmental vitiligo for those 12 years and older.
AREAS COVERED
The purpose of this review is to describe the role of ruxolitinib in treating nonsegmental vitiligo.We searched PubMed using search terms nonsegmental vitiligo, jak inhibitor, and ruxolitinib. Clinicaltrials.gov was used to identify clinical trial data including efficacy, pharmacodynamics, pharmacokinetics, safety, and tolerability.
EXPERT OPINION
In both phase II and phase III (TRuE-V1 and TRuE-V2) trials, ruxolitinib cream 1.5% improved repigmentation with minimal adverse effects. Topical ruxolitinib is a much needed new vitiligo treatment option. Real life efficacy may not match that seen in clinical trials if the hurdle of poor adherence to topical treatment is not surmounted.
Topics: Nitriles; Humans; Vitiligo; Pyrimidines; Pyrazoles; Skin Pigmentation; Janus Kinase 1; Skin Cream; Janus Kinase 2; Janus Kinase Inhibitors
PubMed: 38879876
DOI: 10.1080/1744666X.2024.2326858 -
Arthritis Research & Therapy Jun 2024Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at...
Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons.
BACKGROUND
Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis.
METHODS
We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells.
RESULTS
Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1β and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells.
CONCLUSIONS
Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.
Topics: Animals; Azetidines; Sulfonamides; Pyrazoles; STAT3 Transcription Factor; Purines; Arthritis, Experimental; Ganglia, Spinal; Neuralgia; Janus Kinases; Signal Transduction; Mice; Interleukin-6; Male; Neurons; Mice, Inbred DBA; Inflammation; Janus Kinase Inhibitors
PubMed: 38879555
DOI: 10.1186/s13075-024-03354-1 -
Bioorganic & Medicinal Chemistry Letters Sep 2024Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET...
Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 inhibitor, a more potent and highly selective pyrazolopyridone derivative 13a, and confirmed its in vivo efficacy.
Topics: Humans; Administration, Oral; Structure-Activity Relationship; Animals; Pyridones; Pyrazoles; Drug Discovery; Transcription Factors; Molecular Structure; Cell Cycle Proteins; Mice; Protein Domains; Dose-Response Relationship, Drug; Antineoplastic Agents; Rats; Bromodomain Containing Proteins
PubMed: 38876177
DOI: 10.1016/j.bmcl.2024.129849