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IUCrData Mar 2024The structure of the title compound, [RuCl(CHN)(CHOS)], has monoclinic (2/) symmetry. The Ru-N distances of the coordination compound are influenced by the chloride or...
The structure of the title compound, [RuCl(CHN)(CHOS)], has monoclinic (2/) symmetry. The Ru-N distances of the coordination compound are influenced by the chloride or di-methyl-sulfoxide-κ ligands. The mol-ecular structure exhibits disorder for two of the terminal methyl groups of a dimethyl sulfoxide ligand.
PubMed: 38586520
DOI: 10.1107/S2414314624001913 -
IUCrData Oct 2023The asymmetric unit in the title salt, (CHN)[SnCl(CHClF)], features a di-butyl-ammonium cation in a general position and a diorganotin tetra-chloride dianion, ....
The asymmetric unit in the title salt, (CHN)[SnCl(CHClF)], features a di-butyl-ammonium cation in a general position and a diorganotin tetra-chloride dianion, . tetra-chlorido-bis-(3-trifuoro-methyl-phen-yl)stannate(IV), located on a centre of inversion; the Sn atom is octa-hedrally coordinated. In the crystal, charge-assisted N-H⋯Cl hydrogen bonds along with C-H⋯F contacts occur within supra-molecular layers that inter-digitate along the -axis direction.
PubMed: 37936588
DOI: 10.1107/S2414314623009136 -
Experimental Biology and Medicine... Nov 2023Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy,... (Review)
Review
Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.
Topics: Humans; Rett Syndrome; Mutation; Spasms, Infantile; Disks Large Homolog 4 Protein; Symporters
PubMed: 38057990
DOI: 10.1177/15353702231209419 -
Genes Jul 2023Salt and osmotic stress seriously restrict the growth, development, and productivity of horticultural crops in the greenhouse. The papain-like cysteine proteases (PLCPs)...
Salt and osmotic stress seriously restrict the growth, development, and productivity of horticultural crops in the greenhouse. The papain-like cysteine proteases (PLCPs) participate in multi-stress responses in plants. We previously demonstrated that salt and osmotic stress affect cysteine protease 15 of pepper ( L.) (); however, the role of in salt and osmotic stress responses is unknown. Here, the function of in regulating pepper salt and osmotic stress resistance was explored. Pepper plants were subjected to abiotic (sodium chloride, mannitol, salicylic acid, ethrel, methyl jasmonate, etc.) and biotic stress ( inoculation). The was silenced through the virus-induced gene silencing (VIGS) and transiently overexpressed in pepper plants. The full-length fragment is 1568 bp, with an open reading frame of 1032 bp, encoding a 343 amino acid protein. CaCP15 is a senescence-associated gene 12 (SAG12) subfamily member containing two highly conserved domains, Inhibitor 129 and Peptidase_C1. expression was the highest in the stems of pepper plants. The expression was induced by salicylic acid, ethrel, methyl jasmonate, and was infected by inoculation. Furthermore, was upregulated under salt and osmotic stress, and silencing in pepper enhanced salt and mannitol stress resistance. Conversely, transient overexpression of increased the sensitivity to salt and osmotic stress by reducing the antioxidant enzyme activities and negatively regulating the stress-related genes. This study indicates that negatively regulates salt and osmotic stress resistance in pepper via the ROS-scavenging.
Topics: Osmoregulation; Sodium Chloride; Capsicum; Antioxidants; Salicylic Acid; Mannitol
PubMed: 37510313
DOI: 10.3390/genes14071409 -
Frontiers in Immunology 2023Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not...
BACKGROUND
Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitochondria-bound HK2 is a key regulator of RA FLS phenotype.
METHODS
HK2 localization was evaluated by confocal microscopy after FLS stimulation. RA FLSs were infected with Green fluorescent protein (GFP), full-length (FL)-HK2, or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (Ad). RA FLS was also incubated with methyl jasmonate (MJ; 2.5 mM), tofacitinib (1 µM), or methotrexate (1 µM). RA FLS was tested for migration and invasion and gene expression. Gene associations with HK2 expression were identified by examining single-cell RNA sequencing (scRNA-seq) data from murine models of arthritis. Mice were injected with K/BxN serum and given MJ. Ad-FLHK2 or Ad-HK2ΔN was injected into the knee of wild-type mice.
RESULTS
Cobalt chloride (CoCl) and platelet-derived growth factor (PDGF) stimulation induced HK2 mitochondrial translocation. Overexpression of the HK2 mutant and MJ incubation reversed the invasive and migrative phenotype induced by FL-HK2 after PDGF stimulation, and MJ also decreased the expression of C-X-C Motif Chemokine Ligand 1 (CXCL1) and Collagen Type I Alpha 1 Chain (COL1A1). Of interest, tofacitinib but not methotrexate had an effect on HK2 dissociation from the mitochondria. In murine models, MJ treatment significantly decreased arthritis severity, whereas HK2FL was able to induce synovial hypertrophy as opposed to HK2ΔN.
CONCLUSION
Our results suggest that mitochondrial HK2 regulates the aggressive phenotype of RA FLS. New therapeutic approaches to dissociate HK2 from mitochondria offer a safer approach than global glycolysis inhibition.
Topics: Mice; Animals; Synoviocytes; Hexokinase; Arthritis, Rheumatoid; Synovitis; Methotrexate; Fibroblasts
PubMed: 37529037
DOI: 10.3389/fimmu.2023.1103231 -
Journal of Translational Medicine Aug 2023The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent...
Inhibiting NLRP3 inflammasome signaling pathway promotes neurological recovery following hypoxic-ischemic brain damage by increasing p97-mediated surface GluA1-containing AMPA receptors.
BACKGROUND
The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent secondary brain injury induced by ischemic stroke. However, the role and underlying mechanism of the NLRP3 inflammasome in neonates with hypoxic-ischemic encephalopathy (HIE) are still unclear.
METHODS
The protein expressions of the NLRP3 inflammasome including NLRP3, cysteinyl aspartate specific proteinase-1 (caspase-1) and interleukin-1β (IL-1β), the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) subunit, and the ATPase valosin-containing protein (VCP/p97), were determined by Western blotting. The interaction between p97 and AMPA glutamate receptor 1 (GluA1) was determined by co-immunoprecipitation. The histopathological level of hypoxic-ischemic brain damage (HIBD) was determined by triphenyltetrazolium chloride (TTC) staining. Polymerase chain reaction (PCR) and Western blotting were used to confirm the genotype of the knockout mice. Motor functions, including myodynamia and coordination, were evaluated by using grasping and rotarod tests. Hippocampus-dependent spatial cognitive function was measured by using the Morris-water maze (MWM).
RESULTS
We reported that the NLRP3 inflammasome signaling pathway, such as NLRP3, caspase-1 and IL-1β, was activated in rats with HIBD and oxygen-glucose deprivation (OGD)-treated cultured primary neurons. Further studies showed that the protein level of the AMPAR GluA1 subunit on the hippocampal postsynaptic membrane was significantly decreased in rats with HIBD, and it could be restored to control levels after treatment with the specific caspase-1 inhibitor AC-YVAD-CMK. Similarly, in vitro studies showed that OGD reduced GluA1 protein levels on the plasma membrane in cultured primary neurons, whereas AC-YVAD-CMK treatment restored this reduction. Importantly, we showed that OGD treatment obviously enhanced the interaction between p97 and GluA1, while AC-YVAD-CMK treatment promoted the dissociation of p97 from the GluA1 complex and consequently facilitated the localization of GluA1 on the plasma membrane of cultured primary neurons. Finally, we reported that the deficits in motor function, learning and memory in animals with HIBD, were ameliorated by pharmacological intervention or genetic ablation of caspase-1.
CONCLUSION
Inhibiting the NLRP3 inflammasome signaling pathway promotes neurological recovery in animals with HIBD by increasing p97-mediated surface GluA1 expression, thereby providing new insight into HIE therapy.
Topics: Mice; Animals; Rats; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, AMPA; Hypoxia-Ischemia, Brain; Signal Transduction; Caspase 1; Brain
PubMed: 37620837
DOI: 10.1186/s12967-023-04452-5 -
Acta Crystallographica. Section E,... Dec 2023The reaction between the (,)-fixolide 4-methyl-thio-semicarbazone and Pd chloride yielded the title compound, [Pd(CHNS)]·CHO {common name: -bis-[(,)-fixolide...
Synthesis, crystal structure and Hirshfeld analysis of -bis-(2-{1-[(6,)-3,5,5,6,8,8-hexa-methyl-5,6,7,8-tetra-hydronaphthalen-2-yl]ethyl-idene}--methyl-hydrazinecarbo-thio-amidato-κ,)palladium(II) ethanol monosolvate.
The reaction between the (,)-fixolide 4-methyl-thio-semicarbazone and Pd chloride yielded the title compound, [Pd(CHNS)]·CHO {common name: -bis-[(,)-fixolide 4-methyl-thio-semicarbazonato-κ ]palladium(II) ethanol monosolvate}. The asymmetric unit of the title compound consists of one bis-thio-semicarbazonato Pd complex and one ethanol solvent mol-ecule. The thio-semicarbazononato ligands act as metal chelators with a configuration in a distorted square-planar geometry. A C-H⋯S intra-molecular inter-action, with graph-set motif (6), is observed and the coordination sphere resembles a hydrogen-bonded macrocyclic environment. Additionally, one C-H⋯Pd anagostic inter-action can be suggested. Each ligand is disordered over the aliphatic ring, which adopts a half-chair conformation, and two methyl groups [s.o.f. = 0.624 (2):0.376 (2)]. The disorder includes the chiral carbon atoms and, remarkably, one ligand has the ()-isomer with the highest s.o.f. value atoms, while the other one shows the opposite, the atoms with the highest s.o.f. value are associated with the ()-isomer. The N-N-C(=S)-N fragments of the ligands are approximately planar, with the maximum deviations from the mean plane through the selected atoms being 0.0567 (1) and -0.0307 (8) Å (r.m.s.d. = 0.0403 and 0.0269 Å) and the dihedral angle with the respective aromatic rings amount to 46.68 (5) and 50.66 (4)°. In the crystal, the complexes are linked pairs of N-H⋯S inter-actions, with graph-set motif (8), into centrosymmetric dimers. The dimers are further connected by centrosymmetric pairs of ethanol mol-ecules, building mono-periodic hydrogen-bonded ribbons along [011]. The Hirshfeld surface analysis indicates that the major contributions for the crystal cohesion are [atoms with highest/lowest s.o.f.s considered separately]: H⋯H (81.6/82.0%), H⋯C/C⋯H (6.5/6.4%), H⋯N/N⋯H (5.2/5.0%) and H⋯S/S⋯H (5.0/4.9%).
PubMed: 38313134
DOI: 10.1107/S2056989023009908 -
Biomedicine & Pharmacotherapy =... Dec 2023Long-chain acylcarnitines (LCACs) are intermediates of fatty acid oxidation and are known to exert detrimental effects on mitochondria. This study aimed to test whether...
Long-chain acylcarnitines (LCACs) are intermediates of fatty acid oxidation and are known to exert detrimental effects on mitochondria. This study aimed to test whether lowering LCAC levels with the anti-ischemia compound 4-[ethyl(dimethyl)ammonio]butanoate (methyl-GBB) protects brain mitochondrial function and improves neurological outcomes after transient middle cerebral artery occlusion (MCAO). The effects of 14 days of pretreatment with methyl-GBB (5 mg/kg, p.o.) on brain acylcarnitine (short-, long- and medium-chain) concentrations and brain mitochondrial function were evaluated in Wistar rats. Additionally, the mitochondrial respiration and reactive oxygen species (ROS) production rates were determined using ex vivo high-resolution fluorespirometry under normal conditions, in models of ischemia-reperfusion injury (reverse electron transfer and anoxia-reoxygenation) and 24 h after MCAO. MCAO model rats underwent vibrissae-evoked forelimb-placing and limb-placing tests to assess neurological function. The infarct volume was measured on day 7 after MCAO using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Treatment with methyl-GBB significantly reduced the LCAC content in brain tissue, which decreased the ROS production rate without affecting the respiration rate, indicating an increase in mitochondrial coupling. Furthermore, methyl-GBB treatment protected brain mitochondria against anoxia-reoxygenation injury. In addition, treatment with methyl-GBB significantly reduced the infarct size and improved neurological outcomes after MCAO. Increased mitochondrial coupling efficiency may be the basis for the neuroprotective effects of methyl-GBB. This study provides evidence that maintaining brain energy metabolism by lowering the levels of LCACs protects against ischemia-induced brain damage in experimental stroke models.
Topics: Rats; Animals; Rats, Wistar; Reactive Oxygen Species; Mitochondria; Brain; Brain Ischemia; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Hypoxia; Reperfusion Injury
PubMed: 37924790
DOI: 10.1016/j.biopha.2023.115803 -
ACS Omega Aug 2023Sixteen chemically varied metabolites were isolated from the bulbs of (L'Her.) Herb., including eight flavonoids [3'-methyl isoliquiritigenin , 7-hydroxyflavan ,...
Sixteen chemically varied metabolites were isolated from the bulbs of (L'Her.) Herb., including eight flavonoids [3'-methyl isoliquiritigenin , 7-hydroxyflavan , 7-hydroxyflavanone , 7-hydroxyflavan-3-ol , 7-methoxy-3',4'-methylenedioxyflavan-3-ol , 7-hydroxy-3',4'-methylenedioxy flavan , 2',4'-dihydroxy-3'-methyl-3,4-methylenedioxychalcone , and isoliquiritigenin ], four acetophenones [2,6-dimethoxy-4-hydroxyacetophenone , 2,4-dihydroxyacetophenone , 2,4-dihydroxy-6-methoxy-3-methylacetophenone , and 2,4,6-trimethoxyacetophenone ], two alkaloids [lycorine and narciprimine ], one phenol derivative [-nitrophenol ], and one steroid [β-sitosterol 3--β-glucopyranoside ]. Their structures were elucidated by combining one- and two-dimensional NMR and ESI-MS techniques and by comparison with the reported literature data and some authentic samples. Except for lycorine , the isolated metabolites were obtained herein for the first time from plants, among which compound was identified as a new chalcone derivative. Additionally, the total phenolic and flavonoid contents of the total ethanol extract and different fractions of the bulbs were determined by the Folin-Ciocalteu and aluminum chloride colorimetric methods, respectively, whereas their antioxidant potential was compared using the phosphomolybdenum and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assays. Finally, the binding affinities of compounds to some key target proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), namely, main protease (M), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp), were screened and compared using molecular docking analysis. The possible chemotaxonomic significance of the identified metabolites was also discussed.
PubMed: 37546665
DOI: 10.1021/acsomega.2c07886 -
Respiratory Research Oct 2023The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional...
INTRODUCTION
The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease.
METHODS
After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.
RESULTS
Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.
CONCLUSION
Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the T2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
Topics: Mice; Rats; Humans; Animals; Guinea Pigs; Bronchoconstriction; Methacholine Chloride; Amitriptyline; Histamine; Bronchodilator Agents; Serotonin; Acetylcholine; Sympathomimetics; 1-Methyl-3-isobutylxanthine; Dilatation; Lung; Asthma; Albuterol; Endothelins; Thromboxanes
PubMed: 37907918
DOI: 10.1186/s12931-023-02580-6