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Nature Communications Dec 2023A thorough comprehension of the mechanism behind organic electrooxidation is crucial for the development of efficient energy conversion technology. Here, we find that...
A thorough comprehension of the mechanism behind organic electrooxidation is crucial for the development of efficient energy conversion technology. Here, we find that trivalent nickel is capable of oxidizing organics through a nucleophilic attack and electron transfer via a nonredox process. This nonredox trivalent nickel exhibits exceptional kinetic efficiency in oxidizing organics that possess the highest occupied molecular orbital energy levels ranging from -7.4 to -6 eV (vs. Vacuum level) and the dual local softness values of nucleophilic atoms in nucleophilic functional groups, such as hydroxyls (methanol, ethanol, benzyl alcohol), carbonyls (formamide, urea, formaldehyde, glucose, and N-acetyl glucosamine), and aminos (benzylamine), ranging from -0.65 to -0.15. The rapid electrooxidation kinetics can be attributed to the isoenergetic channels created by the nucleophilic attack and the nonredox electron transfer via the unoccupied e orbitals of trivalent nickel (te). Our findings are valuable in identifying kinetically fast organic electrooxidation on nonredox catalysts for efficient energy conversions.
PubMed: 38042856
DOI: 10.1038/s41467-023-43649-6 -
Journal of the American Heart... Apr 2024The phase 2 PIONEER-HCM (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract... (Clinical Trial)
Clinical Trial
BACKGROUND
The phase 2 PIONEER-HCM (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction) study showed that mavacamten improved left ventricular outflow tract gradients, exercise capacity, and symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), but the results of longer-term treatment are less well described. We report interim results from the PIONEER-OLE (PIONEER Open-Label Extension) study, the longest-term study of mavacamten in patients with symptomatic obstructive HCM.
METHODS AND RESULTS
Patients who previously completed PIONEER-HCM (n=20) were eligible to enroll in PIONEER-OLE. Patients received oral mavacamten, 5 mg once daily (starting dose), with individualized dose titration at week 6. Evaluations included serial monitoring of safety, echocardiography, Kansas City Cardiomyopathy Questionnaire-Overall Summary Score, and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Thirteen patients enrolled and received mavacamten (median study duration at data cutoff, 201 weeks). Most patients (92.3%) received β-blockers concomitantly. Treatment-emergent adverse events were predominantly mild/moderate. One patient had an isolated reduction in left ventricular ejection fraction to 47%, which recovered and remained normal with continued treatment at a reduced dose. At week 180, mavacamten was associated with New York Heart Association class improvements from baseline (class II to I, n=9; class III to II, n=1; and unchanged, n=2), sustained reductions in left ventricular outflow tract gradients (mean [SD] change from baseline: resting, -50 [55] mm Hg; Valsalva, -70 [41] mm Hg), and serum NT-proBNP levels (median [interquartile range] change from baseline: -498 [-2184 to -76] ng/L), and improved Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (mean [SD] change from baseline: +17 [16]).
CONCLUSIONS
This long-term analysis supports the continued safety and effectiveness of mavacamten for >3 years in obstructive HCM.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03496168.
Topics: Humans; Benzylamines; Cardiomyopathy, Hypertrophic; Pilot Projects; Stroke Volume; Uracil; Ventricular Function, Left
PubMed: 38591260
DOI: 10.1161/JAHA.123.030607 -
Journal of the American Chemical Society Feb 2024Protein-ligand interactions can be detected by observing changes in the transverse relaxation rates of the ligand upon binding. The ultrafast NMR technique, which...
Protein-ligand interactions can be detected by observing changes in the transverse relaxation rates of the ligand upon binding. The ultrafast NMR technique, which correlates the chemical shift with the transverse relaxation rate, allows for the simultaneous acquisition of for carbon spins at different positions. In combination with dissolution dynamic nuclear polarization (D-DNP), where the signal intensity is enhanced by thousands of times, the values of several carbon signals from unlabeled benzylamine are observable within a single scan. The hyperpolarized ultrafast chemical shift- correlated experiment separates chemical shift encoding from the readout phase in the NMR pulse sequence, which allows it to beat the fundamental limit on the spectral resolution otherwise imposed by the sampling theorem. Applications enabled by the ability to measure multiple relaxation rates in a single scan include the study of structural properties of protein-ligand interactions.
Topics: Nuclear Magnetic Resonance, Biomolecular; Ligands; Proteins; Magnetic Resonance Spectroscopy; Carbon
PubMed: 38373110
DOI: 10.1021/jacs.3c14359 -
Revista de Neurologia Oct 2023Parkinson's Disease (PD) is a progressive age-related neurodegenerative condition requiring new therapeutic alternatives. Safinamide, a novel levodopa add-on therapy,... (Observational Study)
Observational Study
SYNAPSES. A European observational study to evaluate the safety and the effectiveness of safinamide in routine clinical practice: post-hoc analysis of the Spanish study population.
INTRODUCTION
Parkinson's Disease (PD) is a progressive age-related neurodegenerative condition requiring new therapeutic alternatives. Safinamide, a novel levodopa add-on therapy, positively affects disease fluctuations by modulating both dopaminergic and glutamatergic systems. To further investigate the use of safinamide in European routine clinical practice, the present post-hoc analysis aimed to understand safinamide's safety profile within the Spanish study population.
PATIENTS AND METHODS
Five hundred eleven Spanish patients with PD were evaluated at baseline, four (±1), eight (±1), and 12 (±1) months after initiating safinamide treatment. Unified Parkinson's Disease Rating Scale (UPDRS) total score and UPDRS part III score during on time were used to measure the overall severity of PD and motor complications, respectively, while the severity of adverse events was evaluated following the investigators' criteria.
RESULTS
Safinamide showed a favourable safety profile within the Spanish study population, although prescription to patients with psychiatric conditions and off-label use were more frequent than in the European study population. In Spain, clinically meaningful improvements were observed in UPDRS scores when safinamide was used as the only add-on therapy to levodopa (57.4% and 53.7% of patients) and when switching from rasagiline (55.1% of patients). Motor complications were reduced from 83.2% to 63.3% after the study period. Increased safety concerns were undetected in any patient subgroup, although patients with cognitive impairment showed a slightly higher frequency of adverse events.
CONCLUSIONS
This subanalysis further supports safinamide use as a safe and efficacious option for the management of motor fluctuations in different subgroups of levodopa-treated patients. However, safinamide should be used with caution in patients with cognitive impairment.
Topics: Humans; Levodopa; Synapses; Parkinson Disease; Benzylamines
PubMed: 37752685
DOI: 10.33588/rn.77s02.2023217 -
Annals of Medicine Dec 2024The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with... (Meta-Analysis)
Meta-Analysis
AIM
The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma (HL). This systematic review and meta-analysis aimed to determine the ability of G-CSF + plerixafor to mobilize peripheral blood (PB) CD34+ cells and examine its safety profile.
METHODS
We performed a database search using the terms 'granulocyte colony stimulating factor', 'G-CSF', 'AMD3100', and 'plerixafor', published up to May 1, 2023. The methodology is described in further detail in the PROSPERO database (CRD42023425760).
RESULTS
Twenty-three studies were included in this systematic review and meta-analysis. G-CSF + plerixafor resulted in more patients achieving the predetermined apheresis yield of CD34+ cells than G-CSF alone (OR, 5.33; 95%, 4.34-6.55). It was further discovered that G-CSF + plerixafor could mobilize more CD34+ cells into PB, which was beneficial for the next transplantation in both randomized controlled (MD, 18.30; 95%, 8.74-27.85) and single-arm (MD, 20.67; 95%, 14.34-27.00) trials. Furthermore, G-CSF + plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87-1.80).
CONCLUSIONS
This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB.
Topics: Humans; Hematopoietic Stem Cell Mobilization; Multiple Myeloma; Granulocyte Colony-Stimulating Factor; Heterocyclic Compounds; Lymphoma; Lymphoma, Non-Hodgkin; Hematopoietic Stem Cells; Transplantation, Autologous; Benzylamines; Hematopoietic Stem Cell Transplantation
PubMed: 38470973
DOI: 10.1080/07853890.2024.2329140 -
Haematologica May 2024High-dose melphalan plus autologous stem cell transplantation (ASCT) is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM),... (Observational Study)
Observational Study
A prospective, multicenter study on hematopoietic stemcell mobilization with cyclophosphamide plus granulocyte colony-stimulating factor and 'on-demand' plerixafor in multiple myeloma patients treated with novel agents.
High-dose melphalan plus autologous stem cell transplantation (ASCT) is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM), and adequate hematopoietic stem cell (HSC) collection is crucial to ensure hematologic recovery after ASCT. In this prospective, observational study we evaluated HSC mobilization with granulocyte colony-stimulating factor (G-CSF), cyclophosphamide, and 'on-demand' plerixafor (in patients with <20×106 CD34+ cells/L after at least 4 days of G-CSF or failing to collect ≥1×106 CD34+ cells/kg after the first apheresis) in NDMM patients treated with novel agent-based induction therapy. The primary endpoint was the rate of poor mobilizers (patients collecting <2×106 CD34+ cells/kg or requiring plerixafor rescue to reach an adequate HSC harvest). Secondary endpoints included the rate of patients collecting ≥2×106 CD34+ cells/kg after plerixafor administration and the identification of factors predicting mobilization failure or plerixafor need. Overall, 301 patients (median age 60 years) were enrolled. Two hundred and eighty-seven of 301 (95%) and 274 of 301 (93%) patients collected ≥2×106 and ≥4×106 CD34+ cells/kg, respectively, with a median of 9.9×106 CD34+ cells/kg collected. Poor mobilizers were 48 of 301 (16%): 34 of 301 (11%) required plerixafor rescue, and 14 of 301 (5%) failed HSC collection regardless of plerixafor. Thirty-four of 38 (90%) patients receiving plerixafor collected ≥2×106 CD34+ cells/kg. Bone marrow plasmacytosis at diagnosis >60% (odds ratio [OR]=4.14), lenalidomide use (OR=4.45), and grade 3-4 hematologic toxicities during induction (OR=3.53) were independently associated with a higher risk of mobilization failure or plerixafor need. Cyclophosphamide plus G-CSF and 'on-demand' plerixafor is an effective strategy in NDMM patients treated with novel agents, resulting in a high rate of HSC collection and high HSC yield (clinicaltrials gov. identifier: NCT03406091).
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Mobilization; Cyclams; Benzylamines; Middle Aged; Male; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Aged; Prospective Studies; Heterocyclic Compounds; Adult; Hematopoietic Stem Cell Transplantation; Antineoplastic Combined Chemotherapy Protocols; Transplantation, Autologous; Treatment Outcome
PubMed: 37981892
DOI: 10.3324/haematol.2023.284023 -
International Journal of Molecular... Jan 2024Adipose-derived stem cells (ASCs) possess therapeutic potential for ischemic brain injury, and the chemokine CXCL12 has been shown to enhance their functional...
Adipose-derived stem cells (ASCs) possess therapeutic potential for ischemic brain injury, and the chemokine CXCL12 has been shown to enhance their functional properties. However, the cumulative effects of ASCs when combined with various structures of CXCL12 on ischemic stroke and its underlying molecular mechanisms remain unclear. In this study, we genetically engineered mouse adipose-derived ASCs with CXCL12 variants and transplanted them to the infarct region in a mice transient middle cerebral artery occlusion (tMCAO) model of stroke. We subsequently compared the post-ischemic stroke efficacy of ASC-mCXCL12 with ASC-dCXCL12, ASC-wtCXCL12, and unmodified ASCs. Neurobehavior recovery was assessed using modified neurological severity scores, the hanging wire test, and the elevated body swing test. Changes at the tissue level were evaluated through cresyl violet and immunofluorescent staining, while molecular level alterations were examined via Western blot and real-time PCR. The results of the modified neurological severity score and cresyl violet staining indicated that both ASC-mCXCL12 and ASC-dCXCL12 treatment enhanced neurobehavioral recovery and mitigated brain atrophy at the third and fifth weeks post-tMCAO. Additionally, we observed that ASC-mCXCL12 and ASC-dCXCL12 promoted angiogenesis and neurogenesis, accompanied by an increased expression of bFGF and VEGF in the peri-infarct area of the brain. Notably, in the third week after tMCAO, the ASC-mCXCL12 exhibited superior outcomes compared to ASC-dCXCL12. However, when treated with the CXCR4 antagonist AMD3100, the beneficial effects of ASC-mCXCL12 were reversed. The AMD3100-treated group demonstrated worsened neurological function, aggravated edema volume, and brain atrophy. This outcome is likely attributed to the interaction of monomeric CXCL12 with CXCR4, which regulates the recruitment of bFGF and VEGF. This study introduces an innovative approach to enhance the therapeutic potential of ASCs in treating ischemic stroke by genetically engineering them with the monomeric structure of CXCL12.
Topics: Animals; Mice; Benzylamines; Chemokine CXCL12; Cyclams; Genetic Engineering; Ischemic Stroke; Mesenchymal Stem Cells; Stem Cell Transplantation; Vascular Endothelial Growth Factor A
PubMed: 38255866
DOI: 10.3390/ijms25020792 -
Scientific Reports Feb 2024We investigated the participation of the nucleus of the tractus solitarius (NTS) in tonic‒clonic seizures and postictal antinociception control mediated by NMDA...
GABAergic and glutamatergic inputs to the medulla oblongata and locus coeruleus noradrenergic pathways are critical for seizures and postictal antinociception neuromodulation.
We investigated the participation of the nucleus of the tractus solitarius (NTS) in tonic‒clonic seizures and postictal antinociception control mediated by NMDA receptors, the role of NTS GABAergic interneurons and noradrenergic pathways from the locus coeruleus (LC) in these phenomena. The NTS-lateral nucleus reticularis paragigantocellularis (lPGi)-LC pathway was studied by evaluating neural tract tracer deposits in the lPGi. NMDA and GABAergic receptors agonists and antagonists were microinjected into the NTS, followed by pharmacologically induced seizures. The effects of LC neurotoxic lesions caused by DSP-4, followed by NTS-NMDA receptor activation, on both tonic‒clonic seizures and postictal antinociception were also investigated. The NTS is connected to lPGi neurons that send outputs to the LC. Glutamatergic vesicles were found on dendrites and perikarya of GABAergic interneurons in the NTS. Both tonic‒clonic seizures and postictal antinociception are partially dependent on glutamatergic-mediated neurotransmission in the NTS of seizing rats in addition to the integrity of the noradrenergic system since NMDA receptor blockade in the NTS and intrathecal administration of DSP-4 decrease the postictal antinociception. The GABA receptor activation in the NTS decreases both seizure severity and postictal antinociception. These findings suggest that glutamatergic inputs to NTS-GABAergic interneurons, in addition to ascending and descending noradrenergic pathways from the LC, are critical for the control of both seizures and postictal antinociception.
Topics: Rats; Animals; Locus Coeruleus; Receptors, N-Methyl-D-Aspartate; Medulla Oblongata; Solitary Nucleus; Norepinephrine; Seizures; Benzylamines
PubMed: 38374419
DOI: 10.1038/s41598-024-53744-3 -
Experimental Lung Research 2024The aim of this study is to assess the impact of Liver X receptors (LXRs) on airway inflammation, airway remodeling, and lipid deposition induced by cigarette smoke and...
OBJECTIVE
The aim of this study is to assess the impact of Liver X receptors (LXRs) on airway inflammation, airway remodeling, and lipid deposition induced by cigarette smoke and lipopolysaccharide (LPS) exposure in the lung.
METHODS
Wild mice and LXR-deficient mice were exposed to cigarette smoke and LPS to induce airway inflammation and remodeling. In addition, some wild mice received intraperitoneal treatment with the LXR agonist GW3965 before exposure to cigarette smoke and LPS. Lung tissue and bronchoalveolar lavage fluid were collected to evaluate airway inflammation, airway remodeling and lipid deposition.
RESULTS
Exposure to cigarette smoke and LPS resulted in airway inflammation, emphysema and lipid accumulation in wild mice. These mice also exhibited downregulated LXRα and ABCA1 in the lung. Treatment with GW3965 mitigated inflammation, remodeling and lipid deposition, while the deletion of LXRs exacerbated these effects. Furthermore, GW3965 treatment following exposure to cigarette smoke and LPS increased LXRα and ABCA1 expression and attenuated MyD88 expression in wild mice.
CONCLUSION
LXRs demonstrate the potential to mitigate cigarette smoke and LPS- induced airway inflammation, emphysema and lipid disposition in mice.
Topics: Animals; Mice; Airway Remodeling; Benzoates; Benzylamines; Bronchoalveolar Lavage Fluid; Cigarette Smoking; Emphysema; Inflammation; Lipopolysaccharides; Liver X Receptors; Lung; Mice, Inbred C57BL; Pulmonary Emphysema
PubMed: 38509754
DOI: 10.1080/01902148.2024.2329436 -
ACS Omega Jun 2023In this study, benzylpiperidine, the active group of donepezil (DNP), was connected with the neurotransmitter phenylethylamine by square amide, in which the fat chain of...
In this study, benzylpiperidine, the active group of donepezil (DNP), was connected with the neurotransmitter phenylethylamine by square amide, in which the fat chain of phenylethylamine was reduced and the benzene rings were substituted. A series of multifunctional hybrid compounds, including DNP-aniline hybrids (), DNP-benzylamine hybrids (), and DNP-phenylethylamine hybrids () were obtained and their cholinesterase inhibitory activity and neuroprotection of the SH-SY5Y cell line were determined. Results showed that compound exhibited excellent acetylcholinesterase inhibitory activity with an IC value of 4.4 μM, higher than that of positive control DNP and significant neuroprotective effects against HO-induced oxidative damage in SH-SY5Y cells with 80.11% viability rate at 12.5 μM, much higher than that of the model group (viability rate = 53.1%). The mechanism of action of compound was elucidated by molecular docking, reactive oxygen species (ROS), and immunofluorescence analysis. The results suggest that compound could be further explored as a lead compound for the treatment of Alzheimer's disease. In addition, molecular docking research indicated that the square amide group formed strong interactions with the target protein. Based on the above analysis, we believe that square amide could be an interesting construction unit in anti-AD agents.
PubMed: 37360465
DOI: 10.1021/acsomega.3c01427