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1.
Front Pharmacol ; 15: 1390294, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720773

RESUMO

Introduction: Ganoderma lucidum (G. lucidum, Lingzhi) has long been listed as a premium tonic that can be used to improve restlessness, insomnia, and forgetfulness. We previously reported that a rat model of sporadic Alzheimer's disease (sAD) that was induced by an intracerebroventricular injection of streptozotocin (ICV-STZ) showed significant learning and cognitive deficits and sleep disturbances. Treatment with a G. lucidum spore extract with the sporoderm removed (RGLS) prevented learning and memory impairments in sAD model rats. Method: The present study was conducted to further elucidate the preventive action of RGLS on sleep disturbances in sAD rats by EEG analysis, immunofluorescence staining, HPLC-MS/MS and Western blot. Results: Treatment with 720 mg/kg RGLS for 14 days significantly improved the reduction of total sleep time, rapid eye movement (REM) sleep time, and non-REM sleep time in sAD rats. The novelty recognition experiment further confirmed that RGLS prevented cognitive impairments in sAD rats. We also found that RGLS inhibited the nuclear factor-κB (NF-κB)/Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammatory pathway in the medial prefrontal cortex (mPFC) in sAD rats and ameliorated the lower activity of γ-aminobutyric acid (GABA)-ergic neurons in the parabrachial nucleus (PBN). Discussion: These results suggest that inhibiting the neuroinflammatory response in the mPFC may be a mechanism by which RGLS improves cognitive impairment. Additionally, improvements in PBN-GABAergic activity and the suppression of neuroinflammation in the mPFC in sAD rats might be a critical pathway to explain the preventive effects of RGLS on sleep disturbances in sAD.

2.
Front Pharmacol ; 15: 1406127, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720779

RESUMO

Introduction: Ganoderma lucidum: (G. lucidum, Lingzhi) is a medicinal and edible homologous traditional Chinese medicine that is used to treat various diseases, including Alzheimer's disease and mood disorders. We previously reported that the sporoderm-removed G. lucidum spore extract (RGLS) prevented learning and memory impairments in a rat model of sporadic Alzheimer's disease (sAD), but the effect of RGLS on depression-like behaviors in this model and its underlying molecular mechanisms of action remain unclear. Method: The present study investigated protective effects of RGLS against intracerebroventricular streptozotocin (ICV-STZ)-induced depression in a rat model of sAD and its underlying mechanism. Effects of RGLS on depression- and anxiety-like behaviors in ICV-STZ rats were assessed in the forced swim test, sucrose preference test, novelty-suppressed feeding test, and open field test. Results: Behavioral tests demonstrated that RGLS (360 and 720 mg/kg) significantly ameliorated ICV-STZ-induced depression- and anxiety-like behaviors. Immunofluorescence, Western blot and enzyme-linked immunosorbent assay results further demonstrated that ICV-STZ rats exhibited microglia activation and neuroinflammatory response in the medial prefrontal cortex (mPFC), and RGLS treatment reversed these changes, reflected by the normalization of morphological changes in microglia and the expression of NF-κB, NLRP3, ASC, caspase-1 and proinflammatory cytokines. Golgi staining revealed that treatment with RGLS increased the density of mushroom spines in neurons. This increase was associated with elevated expression of brain-derived neurotrophic protein in the mPFC. Discussion: In a rat model of ICV-STZ-induced sAD, RGLS exhibits antidepressant-like effects, the mechanism of which may be related to suppression of the inflammatory response modulated by the NF-κB/NLRP3 pathway and enhancement of synaptic plasticity in the mPFC.

3.
Bioorg Chem ; 148: 107434, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38744168

RESUMO

Azaphilones represent a particular group of fascinating pigments from fungal source, with easier industrialization and lower cost than the traditional plant-derived pigments, and they also display a wide range of pharmacological activities. Herein, 28 azaphilone analogs, including 12 new ones, were obtained from the fermentation culture of a marine fungus Penicillium sclerotium UJNMF 0503. Their structures were elucidated by MS, NMR and ECD analyses, together with NMR and ECD calculations and biogenetic considerations. Among them, compounds 1 and 2 feature an unusual natural benzo[d][1,3]dioxepine ring embedded with an orthoformate unit, while 3 and 4 represent the first azaphilone examples incorporating a novel rearranged 5/6 bicyclic core and a tetrahydropyran ring on the side chain, respectively. Our bioassays revealed that half of the isolates exhibited neuroprotective potential against H2O2-induced injury on RSC96 cells, while compound 13 displayed the best rescuing capacity toward the cell viability by blocking cellular apoptosis, which was likely achieved by upregulating the PI3K/Akt signaling pathway.

4.
Artigo em Inglês | MEDLINE | ID: mdl-38748345

RESUMO

INTRODUCTION: Atopic dermatitis (AD) is a chronic immuno-inflammatory skin disease. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild to moderate AD. This post hoc analysis assesses the efficacy and safety of crisaborole in Chinese patients aged ≥ 2 years with mild to moderate AD. METHODS: We evaluated the efficacy and safety of crisaborole in Chinese patients from the vehicle-controlled, phase 3 CrisADe CLEAR study. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily, respectively, for 28 days. The primary endpoint was percent change from baseline in Eczema Area and Severity Index (EASI) total score at day 29. Key secondary endpoints were improvement in Investigator's Static Global Assessment (ISGA), ISGA success, and change from baseline in weekly average Peak Pruritus Numerical Rating Scale (PP-NRS) score. Adverse events were documented. RESULTS: Of 391 patients in the overall study, 237 were from China, 157 assigned to crisaborole and 80 assigned to vehicle. A greater reduction in percent change from baseline in EASI total score at day 29 was shown in the crisaborole vs. vehicle group (least squares mean [LSM]: -66.34 [95% (confidence interval) CI -71.55 to -61.12] vs. -50.18 [95% CI -58.02 to -42.34]). Response rates for achievement of ISGA improvement (43.2% [95% CI 35.4-51.1] vs. 33.4% [95% CI 22.5-44.2]) and ISGA success (31.7% [95% CI 24.3-39.0] vs. 21.5% [95% CI 12.1-30.9]) at day 29 were higher in the crisaborole vs. vehicle group. A greater reduction in change from baseline in weekly average PP-NRS score at week 4 was observed in the crisaborole vs. vehicle group (LSM: -1.98 [95% CI -2.34 to -1.62] vs. -1.08 [95% CI -1.63 to -0.53]). No new safety signals were observed. CONCLUSION: Crisaborole was effective and well tolerated in Chinese patients aged ≥ 2 years with mild to moderate AD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04360187.

5.
Molecules ; 29(9)2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38731506

RESUMO

The mechanism of ammonia formation during the pyrolysis of proteins in biomass is currently unclear. To further investigate this issue, this study employed the AMS 2023.104 software to select proteins (actual proteins) as the model compounds and the amino acids contained within them (assembled amino acids) as the comparative models. ReaxFF molecular dynamics simulations were conducted to explore the nitrogen transformation and NH3 generation mechanisms in three-phase products (char, tar, and gas) during protein pyrolysis. The research results revealed several key findings. Regardless of whether the model compounds are actual proteins or assembled amino acids, NH3 is the primary nitrogen-containing product during pyrolysis. However, as the temperature rises to higher levels, such as 2000 K and 2500 K, the amount of NH3 decreases significantly in the later stages of pyrolysis, indicating that it is being converted into other nitrogen-bearing species, such as HCN and N2. Simultaneously, we also observed significant differences between the pyrolysis processes of actual proteins and assembled amino acids. Notably, at 2000 K, the amount of NH3 generated from the pyrolysis of assembled amino acids was twice that of actual proteins. This discrepancy mainly stems from the inherent structural differences between proteins and amino acids. In proteins, nitrogen is predominantly present in a network-like structure (NH-N), which shields it from direct external exposure, thus requiring more energy for nitrogen to participate in pyrolysis reactions, making it more difficult for NH3 to form. Conversely, assembled amino acids can release NH3 through a simpler deamination process, leading to a significant increase in NH3 production during their pyrolysis.


Assuntos
Amônia , Simulação de Dinâmica Molecular , Proteínas , Pirólise , Amônia/química , Proteínas/química , Aminoácidos/química , Nitrogênio/química
6.
RSC Chem Biol ; 5(5): 447-453, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38725907

RESUMO

Pyk2 is a multi-domain non-receptor tyrosine kinase that serves dual roles as a signaling enzyme and scaffold. Pyk2 activation involves a multi-stage cascade of conformational rearrangements and protein interactions initiated by autophosphorylation of a linker site. Linker phosphorylation recruits Src kinase, and Src-mediated phosphorylation of the Pyk2 activation loop confers full activation. The regulation and accessibility of the initial Pyk2 autophosphorylation site remains unclear. We employed peptide-binding molecularly imprinted nanoparticles (MINPs) to probe the regulatory conformations controlling Pyk2 activation. MINPs differentiating local structure and phosphorylation state revealed that the Pyk2 autophosphorylation site is protected in the autoinhibited state. Activity profiling of Pyk2 variants implicated FERM and linker residues responsible for constraining the autophosphorylation site. MINPs targeting each Src docking site disrupt the higher-order kinase interactions critical for activation complex maturation. Ultimately, MINPs targeting key regulatory motifs establish a useful toolkit for probing successive activational stages in the higher-order Pyk2 signaling complex.

7.
Artigo em Inglês | MEDLINE | ID: mdl-38730220

RESUMO

Triclosan is a widely used antibacterial agent and disinfectant, and its overuse endangered ecological safety and human health. Therefore, reducing residual TCS concentrations in the environment is an urgent issue. Bacillus sp. DL4, an aerobic bacterium with TCS biodegradability, was isolated from pharmaceutical wastewater samples. Response surface methodology (RSM) and artificial neural network (ANN) were carried out to optimize and verify the different condition variables, and the optimal growth conditions of strain DL4 were obtained (35 °C, initial pH 7.31, and 5% v/v). After 48 h of cultivation under the optimal conditions, the removal efficiency of strain DL4 on TCS was 95.89 ± 0.68%, which was consistent with the predicted values from RSM and ANN models. In addition, higher R2 value and lower MSE and ADD values indicated that the ANN model had a stronger predictive capability than the RSM model. Whole genome sequencing results showed that many functional genes were annotated in metabolic pathways related to TCS degradation (e.g., amino acid metabolism, xenobiotics biodegradation and metabolism, carbohydrate metabolism). Main intermediate metabolites were identified during the biodegradation process by liquid chromatography-mass spectrometry (LC-MS), and a possible pathway was hypothesized based on the metabolites. Overall, this study provides a theoretical foundation for the characterization and mechanism of TCS biodegradation in the environment by Bacillus sp. DL4.

8.
Phys Chem Chem Phys ; 26(19): 14186-14193, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38713092

RESUMO

Cost-effective and readily accessible 3d transition metals (TMs) have been considered as promising candidates for alkane activation while 3d TMs especially the early TMs are usually not very reactive with light alkanes. In this study, the reactivity of Vn+ and VnO+ (n = 1-9) cluster cations towards ethane under thermal collision conditions has been investigated using mass spectrometry and density functional theory calculations. Among Vn+ (n = 1-9) clusters, only V3-5+ can react with C2H6 to generate dehydrogenation products and the reaction rate constants are below 10-13 cm3 molecule-1 s-1. In contrast, the reaction rate constants for all VnO+ (n = 1-9) with C2H6 significantly increase by about 2-4 orders of magnitude. Theoretical analysis evidences that the addition of ligand O affects the charge distribution of the metal centers, resulting in a significant increase in the cluster reactivity. The analysis of frontier orbitals indicates that the agostic interaction determines the size-dependent reactivity of VnO+ cluster cations. This study provides a novel approach for improving the reactivity of early 3d TMs.

9.
Sci Rep ; 14(1): 11322, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760393

RESUMO

Based on the theory of empty hole effect of cutting blasting, the Hopkinson effect and Saint-Venant principle are integrated to establish a two-dimensional calculation model of dynamic stress evolution of the holes wall, and then the dynamic fracture mechanism and damage distribution mode of the rock mass in the cutting area under the action of longitudinal waves are predicted. The results of the calculation and numerical simulation are verified by experiments, and the results show that: The time-varying stress function of the circular cavity wall conforms to the periodic dynamic evolution of the trigonometric function, and the theoretical calculation is consistent with the simulation results. Through the calculation of the round holes cut model and the square empty hole cut model, the change of the shape of the holes in the cut area changes the failure form of the surrounding rock mass. The circular empty hole wall is affected by the stress wave to produce "interval ring" destruction, and the effect of the reflected stretch wave is inhibited. The large range of rock mass in the square empty hole wall produces tensile and shear failure, and the rock mass collapses inward under the influence of the second stage stress. Among them, the empty space utilization rate of the square empty hole model is about 8.5 times that of the circular holes model. Vibration monitoring in the center of the cutting area shows that the vibration effect of the circular empty hole is larger than that of the square empty hole, and the proportion of rock breaking energy is lower.

10.
Int J Biol Macromol ; : 132497, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38763236

RESUMO

To alleviate the adverse effects of chemotherapy and bolster immune function, a novel polysaccharide derived from Sargassum fusiforme named as SFP-αII. The structural composition of SFP-αII predominantly consisted of guluronic and mannuronic acids in a molar ratio of 33.8:66.2, with an average molecular weight of 16.5 kDa. Its structure was primarily characterized by →4)-α-GulA-(1 → and →4)-ß-ManA-(1 → linkages confirmed by FT-IR, methylation, and NMR analyses. The absence of a triple-helix structure was in SFP-αII was confirmed using circular dichroism and Congo red dye assays. The dimensions varied with lengths ranging from 20 nm up to 3 µm revealed by atomic force microscopy (AFM). SFP-αII has been found to enhance immunomodulatory activity in cyclophosphamide (CTX)-induced immunosuppressed mice. This was evidenced by improvements in immune organ indices, cytokine levels, and the release of nitric oxide (NO). Specifically, SFP-αII mitigated immunosuppression by upregulating the secretion of IL-1ß (167.3 %) and TNF-α (227.1 %) at a dose of 400 mg/kg, compared with the CTX group in macrophages. Ultimately, SFP-αII may serve as a mechanism for immune enhancement through modulation of TLR4-mediated NF-κB and MAPK signaling pathways. This integration of traditional Chinese and Western medicine, leveraging SFP-αII as a potential functional food could be pivotal in alleviating immunosuppressive side effects in CTX treatment.

11.
ChemSusChem ; : e202400604, 2024 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-38763908

RESUMO

The strategic formulation of a compatible electrolyte plays a pivotal role in extending the longevity of lithium-metal batteries (LMBs). Here, we present findings on a partially fluorinated electrolyte distinguished by a subdued solvation affinity towards Li+ ions and a concentrated anion presence within the primary solvation layer. This distinctive solvation arrangement redirects the focal points of reactions from solvent molecules to anions, facilitating the predominant involvement of anions in the creation of a LiF-enriched solid-electrolyte interphase (SEI). Electrochemical assessments showcase effective Li+ transport kinetics, diminished overpotential polarization for Li nucleation, and prolonged cycling durability in Li||Li cells employing the partially fluorinated electrolyte. When tested in Li||NCM811 cells, the designed electrolyte delivers a capacity retention of 89.30% and exhibits a high average Coulombic efficiency of 99.80% over 100 cycles with a charge-potential cut-off of 4.6 V vs. Li/Li+ under the current density of 0.4 C. Furthermore, even at a current density of 1C, the cells maintain 81.90% capacity retention and a high average Coulombic efficiency of 99.40% after 180 cycles. This work underscores the significance of weak-solvation interaction in partially fluorinated electrolytes and highlights the crucial role of solvent structure in enabling the long-term stability and high-energy density of LMBs.

12.
Food Chem ; 452: 139579, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38735111

RESUMO

Novel metal-organic framework MIL-101(Cr)-NH2 functionalised hydrophilic polydopamine-modified Fe3O4 magnetic nanoparticles (Fe3O4@PDA@MIL-101(Cr)-NH2) were synthesised and used as magnetic solid-phase extraction (MSPE) adsorbents for extracting tetracyclines (TCs) from milk samples. The integrated Fe3O4@PDA@MIL-101(Cr)-NH2 exhibited convenient magnetic separation and exceptional multi-target binding capabilities. Furthermore, the PDA coating significantly enhanced the hydrophilicity and extraction efficiency of the material, thereby facilitating the extraction of trace TCs. Various factors affecting MSPE, such as adsorbent dosage, extraction time, pH value, and desorption conditions, were optimised. The developed MSPE method coupled with high-performance liquid chromatography demonstrated good linearity (R2 ≥ 0.9989), acceptable accuracy (82.2%-106.1%), good repeatability (intra-day precision of 0.8%-4.7% and inter-day precision of 1.1%-4.5%), low limits of detection (2.18-6.25 µg L-1), and low limits of quantification (6.54-18.75 µg L-1) in TCs detection. The approach was successfully used for the quantification of trace TCs in real milk samples.

13.
J Hazard Mater ; 472: 134527, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38735184

RESUMO

Toxic metal(loid)s released into the soil by non-ferrous metal mining and smelting activities pose a serious threat to residents and the surrounding ecosystem. Considering only total metal(loid) concentrations likely overestimates routine (eco)toxicological risk assessment of soil. We hypothesize that considering metal(loid) bioavailability/accessibility will improve the accuracy of risk assessment. To test this hypothesis, four mining areas in Southwest China, including mining and surrounding sites, were studied. Bioavailability was determined considering metal(loid)s leached by a simulated strong acid rain (SSAR) treatment. In the four areas, the mining site showed higher cumulative releases of metal(loid)s under SSAR treatment than the agricultural field located in the surrounding sites. Thus, the bioavailable metal(loid)s contents were continuously being released during SSAR treatment and likely increased the environmental risk. Ecological and health risk assessment of soil, calculated using total metal(loid)s content, was corrected considering bioavailable/accessible metal(loid)s, which was determined by the heavy metal(loid)s forms and in vitro simulated intestinal stages. Although the corrected indices indicated that the risk of metal(loid)s-contaminated soil was reduced, unfavorable ecological and health risks remained in the four areas. Our study provides new perspectives to better predict the risk of bioavailable/accessible metal(loid)s in non-ferrous metal contaminated and surrounding soils.

14.
Cancer Lett ; 592: 216934, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38710299

RESUMO

The Staphylococcal nuclease and Tudor domain containing 1 (SND1) has been identified as an oncoprotein. Our previous study demonstrated that SND1 impedes the major histocompatibility complex class I (MHC-I) assembly by hijacking the nascent heavy chain of MHC-I to endoplasmic reticulum-associated degradation. Herein, we aimed to identify inhibitors to block SND1-MHC-I binding, to facilitate the MHC-I presentation and tumor immunotherapy. Our findings validated the importance of the K490-containing sites in SND1-MHC-I complex. Through structure-based virtual screening and docking analysis, (-)-Epigallocatechin (EGC) exhibited the highest docking score to prevent the binding of MHC-I to SND1 by altering the spatial conformation of SND1. Additionally, EGC treatment resulted in increased expression levels of membrane-presented MHC-I in tumor cells. The C57BL/6J murine orthotopic melanoma model validated that EGC increases infiltration and activity of CD8+ T cells in both the tumor and spleen. Furthermore, the combination of EGC with programmed death-1 (PD-1) antibody demonstrated a superior antitumor effect. In summary, we identified EGC as a novel inhibitor of SND1-MHC-I interaction, prompting MHC-I presentation to improve CD8+ T cell response within the tumor microenvironment. This discovery presents a promising immunotherapeutic candidate for tumors.

15.
Mol Neurobiol ; 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769227

RESUMO

Accumulating evidence suggests that prenatal stress (PNS) increases offspring susceptibility to depression, but the underlying mechanisms remain unclear. We constructed a mouse model of prenatal stress by spatially restraining pregnant mice from 09:00-11:00 daily on Days 5-20 of gestation. In this study, western blot analysis, quantitative real-time PCR (qRT‒PCR), immunofluorescence, immunoprecipitation, chromatin immunoprecipitation (ChIP), and mifepristone rescue assays were used to investigate alterations in the GR/P300-MKP1 and downstream ERK/CREB/TRKB pathways in the brains of prenatally stressed offspring to determine the pathogenesis of the reduced neurogenesis and depression-like behaviors in offspring induced by PNS. We found that prenatal stress leads to reduced hippocampal neurogenesis and depression-like behavior in offspring. Prenatal stress causes high levels of glucocorticoids to enter the fetus and activate the hypothalamic‒pituitary‒adrenal (HPA) axis, resulting in decreased hippocampal glucocorticoid receptor (GR) levels in offspring. Furthermore, the nuclear translocation of GR and P300 (an acetylation modifying enzyme) complex in the hippocampus of PNS offspring increased significantly. This GR/P300 complex upregulates MKP1, which is a negative regulator of the ERK/CREB/TRKB signaling pathway associated with depression. Interestingly, treatment with a GR antagonist (mifepristone, RU486) increased hippocampal GR levels and decreased MKP1 expression, thereby ameliorating abnormal neurogenesis and depression-like behavior in PNS offspring. In conclusion, our study suggested that the regulation of the MKP1 signaling pathway by GR/P300 is involved in depression-like behavior in prenatal stress-exposed offspring and provides new insights and ideas for the fetal hypothesis of mental health.

16.
Ecol Evol ; 14(5): e11459, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38774145

RESUMO

Plant invasions severely threaten natural ecosystems, and invasive plants often outcompete native plants across various ecosystems. Arbuscular mycorrhizal (AM) fungi, serving as beneficial microorganisms for host plants, can greatly influence the competitive outcomes of invasive plants against native plants. However, it remains unclear how AM fungi alter the competitive balance between native and invasive species. A competitive experiment was conducted using an invasive Eupatorium adenophorum paired with a native congener Eupatorium lindleyanum. Specifically, both species were inoculated with (M+) or without (M-) the fungus Glomus etunicatum under intraspecific (Intra-) and interspecific (Inter-) competition. Plant traits were measured and analyzed regarding the growth and nutrition of both species. The results exhibited that the AM fungus significantly increased the height, diameter, biomass, C, N, and P acquisition of both the invasive E. adenophorum and the native E. lindleyanum. The root mycorrhizal colonization and the mycorrhizal dependency of native E. lindleyanum were greater than those of invasive E. adenophorum. Under M+, the Inter-competition inhibited the growth and nutrition of invasive E. adenophorum compared to the Intra- competition. Further, native E. lindleyanum exhibited higher competitiveness than invasive E. adenophorum in growth and nutrition. Meanwhile, the AM fungus significantly improved the competitiveness of native E. lindleyanum over invasive E. adenophorum. In conclusion, AM fungus improved the competitive advantage of native E. lindleyanum over invasive E. adenophorum in growth and nutrition, potentially contributing to native species competitively resisting the invasion of exotic species. These findings emphasize the importance of AM fungi in helping native plants resist the invasion of exotic plants and further contribute to understanding plant invasion prevention mechanisms.

17.
J Neuroimmune Pharmacol ; 19(1): 20, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758335

RESUMO

Neuroinflammation has emerged as a crucial factor in the development of depression. Despite the well-known anti-inflammatory properties of 6-gingerol, its potential impact on depression remains poorly understood. This study aimed to investigate the antidepressant effects of 6-gingerol by suppressing microglial activation. In vivo experiments were conducted to evaluate the effect of 6-gingerol on lipopolysaccharide (LPS)-induced behavioral changes and neuroinflammation in rat models. In vitro studies were performed to examine the neuroprotective properties of 6-gingerol against LPS-induced microglial activation. Furthermore, a co-culture system of microglia and neurons was established to assess the influence of 6-gingerol on the expression of synaptic-related proteins, namely synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), which are influenced by microglial activation. In the in vivo experiments, administration of 6-gingerol effectively alleviated LPS-induced depressive behavior in rats. Moreover, it markedly suppressed the activation of rat prefrontal cortex (PFC) microglia induced by LPS and the activation of the NF-κB/NLRP3 inflammatory pathway, while also reducing the levels of inflammatory cytokines IL-1ß and IL-18. In the in vitro experiments, 6-gingerol mitigated nuclear translocation of NF-κB p65, NLRP3 activation, and maturation of IL-1ß and IL-18, all of which were induced by LPS. Furthermore, in the co-culture system of microglia and neurons, 6-gingerol effectively restored the decreased expression of SYP and PSD95. The findings of this study demonstrate the neuroprotective effects of 6-gingerol in the context of LPS-induced depression-like behavior. These effects are attributed to the inhibition of microglial hyperactivation through the suppression of the NF-κB/NLRP3 inflammatory pathway.


Assuntos
Catecóis , Depressão , Álcoois Graxos , Lipopolissacarídeos , Microglia , Plasticidade Neuronal , Ratos Sprague-Dawley , Animais , Álcoois Graxos/farmacologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Ratos , Lipopolissacarídeos/toxicidade , Masculino , Catecóis/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Depressão/metabolismo , Técnicas de Cocultura , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Células Cultivadas , Antidepressivos/farmacologia
18.
J Org Chem ; 89(10): 6704-6713, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38709904

RESUMO

EMM (electromagnetic mill)-promoted Pd-catalyzed solid state intramolecular Heck-type cyclization/boronation and Suzuki couplings are reported. Compared to previous mechanochemistry that constructed one chemical bond through a cross-coupling reaction, this strategy realizes cascade transformation along with multiple chemical bond formation. This conversion does not require organic solvents or additional heating, and it shows a good substrate scope and high functional group tolerance.

19.
Nat Commun ; 15(1): 3890, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719850

RESUMO

Shigella flexneri is a Gram-negative bacterium causing severe bloody dysentery. Its pathogenesis is largely dictated by a plasmid-encoded type III secretion system (T3SS) and its associated effectors. Among these, the effector OspG has been shown to bind to the ubiquitin conjugation machinery (E2~Ub) to activate its kinase activity. However, the cellular targets of OspG remain elusive despite years of extensive efforts. Here we show by unbiased phosphoproteomics that a major target of OspG is CAND1, a regulatory protein controlling the assembly of cullin-RING ubiquitin ligases (CRLs). CAND1 phosphorylation weakens its interaction with cullins, which is expected to impact a large panel of CRL E3s. Indeed, global ubiquitome profiling reveals marked changes in the ubiquitination landscape when OspG is introduced. Notably, OspG promotes ubiquitination of a class of cytoskeletal proteins called septins, thereby inhibiting formation of cage-like structures encircling cytosolic bacteria. Overall, we demonstrate that pathogens have evolved an elaborate strategy to modulate host ubiquitin signaling to evade septin-cage entrapment.


Assuntos
Proteínas de Bactérias , Septinas , Shigella flexneri , Transdução de Sinais , Ubiquitina , Ubiquitinação , Shigella flexneri/metabolismo , Shigella flexneri/patogenicidade , Septinas/metabolismo , Septinas/genética , Humanos , Ubiquitina/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Fosforilação , Interações Hospedeiro-Patógeno , Células HeLa , Proteínas Culina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Células HEK293 , Disenteria Bacilar/microbiologia , Disenteria Bacilar/metabolismo
20.
Burns Trauma ; 12: tkae006, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716051

RESUMO

Septic shock is a severe form of sepsis characterized by high global mortality rates and significant heritability. Clinicians have long been perplexed by the differential expression of genes, which poses challenges for early diagnosis and prompt treatment of septic shock. Genetic polymorphisms play crucial roles in determining susceptibility to, mortality from, and the prognosis of septic shock. Research indicates that pathogenic genes are known to cause septic shock through specific alleles, and protective genes have been shown to confer beneficial effects on affected individuals. Despite the existence of many biomarkers linked to septic shock, their clinical use remains limited. Therefore, further investigation is needed to identify specific biomarkers that can facilitate early prevention, diagnosis and risk stratification. Septic shock is closely associated with multiple signaling pathways, including the toll-like receptor 2/toll-like receptor 4, tumor necrosis factor-α, phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase, nuclear factor κB, Janus kinase/signal transducer and activator of transcription, mammalian target of rapamycin, NOD-like receptor thermal protein domain-associated protein 3 and hypoxia-induced-factor-1 pathways. Understanding the regulation of these signaling pathways may lead to the identification of therapeutic targets for the development of novel drugs to treat sepsis or septic shock. In conclusion, identifying differential gene expression during the development of septic shock allows physicians to stratify patients according to risk at an early stage. Furthermore, auxiliary examinations can assist physicians in identifying therapeutic targets within relevant signaling pathways, facilitating early diagnosis and treatment, reducing mortality and improving the prognosis of septic shock patients. Although there has been significant progress in studying the genetic polymorphisms, specific biomarkers and signaling pathways involved in septic shock, the journey toward their clinical application and widespread implementation still lies ahead.

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