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1.
PLoS Pathog ; 20(6): e1012319, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38885290

RESUMO

Candida albicans is a leading cause of intravascular catheter-related infections. The capacity for biofilm formation has been proposed to contribute to the persistence of this fungal pathogen on catheter surfaces. While efforts have been devoted to identifying microbial factors that modulate C. albicans biofilm formation in vitro, our understanding of the host factors that may shape C. albicans persistence in intravascular catheters is lacking. Here, we used multiphoton microscopy to characterize biofilms in intravascular catheters removed from candidiasis patients. We demonstrated that, NETosis, a type of neutrophil cell death with antimicrobial activity, was implicated in the interaction of immune cells with C. albicans in the catheters. The catheter isolates exhibited reduced filamentation and candidalysin gene expression, specifically in the total parenteral nutrition culture environment. Furthermore, we showed that the ablation of candidalysin expression in C. albicans reduced NETosis and conferred resistance to neutrophil-mediated fungal biofilm elimination. Our findings illustrate the role of neutrophil NETosis in modulating C. albicans biofilm persistence in an intravascular catheter, highlighting that C. albicans can benefit from reduced virulence expression to promote its persistence in an intravascular catheter.


Assuntos
Biofilmes , Candida albicans , Candidíase , Infecções Relacionadas a Cateter , Armadilhas Extracelulares , Proteínas Fúngicas , Neutrófilos , Humanos , Biofilmes/crescimento & desenvolvimento , Proteínas Fúngicas/metabolismo , Candidíase/microbiologia , Candidíase/imunologia , Infecções Relacionadas a Cateter/microbiologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Armadilhas Extracelulares/imunologia , Catéteres/microbiologia , Regulação Fúngica da Expressão Gênica
2.
Nature ; 579(7797): 51-55, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132691

RESUMO

A wide range of metals exhibit anomalous electrical and thermodynamic properties when tuned to a quantum critical point (QCP), although the origins of such strange metals have posed a long-standing mystery. The frequent association of strange metals with unconventional superconductivity and antiferromagnetic QCPs1-4 has led to the belief that they are highly entangled quantum states5. By contrast, ferromagnets are regarded as an unlikely setting for strange metals, because they are weakly entangled and their QCPs are often interrupted by competing phases or first-order phase transitions6-8. Here we provide evidence that the pure ferromagnetic Kondo lattice9,10 CeRh6Ge4 becomes a strange metal at a pressure-induced QCP. Measurements of the specific heat and resistivity under pressure demonstrate that the ferromagnetic transition is continuously suppressed to zero temperature, revealing a strange-metal behaviour around the QCP. We argue that strong magnetic anisotropy has a key role in this process, injecting entanglement in the form of triplet resonating valence bonds into the ordered ferromagnet. We show that a singular transformation in the patterns of the entanglement between local moments and conduction electrons, from triplet resonating valence bonds to Kondo-entangled singlet pairs at the QCP, causes a jump in the Fermi surface volume-a key driver of strange-metallic behaviour. Our results open up a direction for research into ferromagnetic quantum criticality and establish an alternative setting for the strange-metal phenomenon. Most importantly, strange-metal behaviour at a ferromagnetic QCP suggests that quantum entanglement-not the destruction of antiferromagnetism-is the common driver of the varied behaviours of strange metals.

3.
Artigo em Inglês | MEDLINE | ID: mdl-38924496

RESUMO

RATIONALE: Outdoor fine particulate air pollution (PM2.5) contributes to millions of deaths around the world each year, but much less is known about the long-term health impacts of other particulate air pollutants including ultrafine particles (a.k.a. nanoparticles) which are in the nanometer size range (<100 nm), widespread in urban environments, and not currently regulated. OBJECTIVES: Estimate the associations between long-term exposure to outdoor ultrafine particles and mortality. METHODS: Outdoor air pollution levels were linked to the residential addresses of a large, population-based cohort from 2001 - 2016. Associations between long-term exposure to outdoor ultrafine particles and nonaccidental and cause-specific mortality were estimated using Cox proportional hazards models. MEASUREMENTS: An increase in long-term exposure to outdoor ultrafine particles was associated with an increased risk of nonaccidental mortality (Hazard Ratio = 1. 073, 95% Confidence Interval = 1. 061, 1. 085) and cause-specific mortality, the strongest of which was respiratory mortality (Hazard Ratio = 1.174, 95% Confidence Interval = 1.130, 1.220). MAIN RESULTS: Long-term exposure to outdoor ultrafine particles was associated with increased risk of mortality. We estimated the mortality burden for outdoor ultrafine particles in Montreal and Toronto, Canada to be approximately 1100 additional nonaccidental deaths every year. Furthermore, we observed possible confounding by particle size which suggests that previous studies may have underestimated or missed important health risks associated with ultrafine particles. CONCLUSIONS: As outdoor ultrafine particles are not currently regulated, there is great potential for future regulatory interventions to improve population health by targeting these common outdoor air pollutants.

4.
J Am Chem Soc ; 146(17): 11955-11967, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38640231

RESUMO

Hydroformylation reaction is one of the largest homogeneously catalyzed industrial processes yet suffers from difficulty and high cost in catalyst separation and recovery. Heterogeneous single-atom catalysts (SACs), on the other hand, have emerged as a promising alternative due to their high initial activity and reasonable regioselectivity. Nevertheless, the stability of SACs against metal aggregation and leaching during the reaction has rarely been addressed. Herein, we elucidate the mechanism of Rh aggregation and leaching by investigating the structural evolution of Rh1@silicalite-1 SAC in response to different adsorbates (CO, H2, alkene, and aldehydes) by using diffuse reflectance infrared Fourier transform spectroscopy, X-ray adsorption fine structure, and scanning transmission electron microscopy techniques and kinetic studies. It is discovered that the aggregation and leaching of Rh are induced by the strong adsorption of CO and aldehydes on Rh, as well as the reduction of Rh3+ by CO/H2 which weakens the binding of Rh with support. In contrast, alkene effectively counteracts this effect by the competitive adsorption on Rh atoms with CO/aldehyde, and the disintegration of Rh clusters. Based on these results, we propose a strategy to conduct the reaction under conditions of high alkene concentration, which proves to be able to stabilize Rh single atom against aggregation and/or leaching for more than 100 h time-on-stream.

5.
J Am Chem Soc ; 146(1): 695-706, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38150351

RESUMO

Ethylene methoxycarbonylation (EMC) to methyl propanoate (MP) is an industrially important reaction and commercially uses a homogeneous Pd-phosphine organometallic complex as the catalyst and corrosive strong acid as the promoter. In this work, we develop a Pt1/MoS2 heterogeneous single-atom catalyst (SAC) which exhibits high activity, selectivity, and good recyclability for EMC reaction without need of any liquid acid. The production rate of MP achieves 0.35 gMP gcat-1 h-1 with MP selectivity of 91.1% at 1 MPa CO, 1 MPa C2H4, and 160 °C, which can be doubled at 2 MPa CO and corresponds to 320.1 molMP molPt-1 h-1, at least 1 order of magnitude higher than the earlier reported heterogeneous catalyst and even comparable to some of homogeneous catalyst. Advanced characterizations and DFT calculations reveal that all the Pt single atoms are located at the Mo vacancies along the Mo edge of the MoS2 nanosheets, forming pocket-like Mo-S-Pt1-S-Mo ensembles with uniform and well-defined structure. Methanol is first adsorbed and dissociated on Mo sites, and the produced H spillovers to the adjacent Pt site forming Pt-H species which then activate ethylene, forming Pt-ethyl species. Meanwhile, CO adsorbed on the other Mo site reacts with the Pt-ethyl species, yielding propionyl species, and this carbonylation is the rate-determining step. The final methoxylation step proceeds via the nucleophilic attack of propionyl species by -OCH3 affording the final product MP. Such a metal-support concerted catalysis enabled by the Mo-S-Pt1-S-Mo multisite ensemble opens a new avenue for SACs to promote the multimolecular reactions that prevail in homogeneous catalysis.

6.
J Am Chem Soc ; 146(18): 12556-12564, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38660792

RESUMO

Transition metal nitride (TMN)-based nanostructures have emerged as promising materials for diverse applications in electronics, photonics, energy storage, and catalysis due to their highly desirable physicochemical properties. However, synthesizing TMN-based nanostructures with designed compositions and morphologies poses challenges, especially in the solution phase. The cation exchange reaction (CER) stands out as a versatile postsynthetic strategy for preparing nanostructures that are otherwise inaccessible through direct synthesis. Nevertheless, exploration of the CER in TMNs lags behind that in metal chalcogenides and metal phosphides. Here, we demonstrate cation exchange in colloidal metal nitride nanocrystals, employing Cu3N nanocrystals as starting materials to synthesize Ni4N and CoN nanocrystals. By controlling the reaction conditions, Cu3N@Ni4N and Cu3N@CoN core@shell heterostructures with tunable compositions can also be obtained. The Ni4N and CoN nanocrystals are evaluated as catalysts for the electrochemical oxygen evolution reaction (OER). Remarkably, CoN nanocrystals demonstrate superior OER performance with a low overpotential of 286 mV at 10 mA·cm-2, a small Tafel slope of 89 mV·dec-1, and long-term stability. Our CER approach in colloidal TMNs offers a new strategy for preparing other metal nitride nanocrystals and their heterostructures, paving the way for prospective applications.

7.
J Am Chem Soc ; 146(30): 20594-20603, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-38767649

RESUMO

Heterophase nanomaterials have sparked significant research interest in catalysis due to their distinctive properties arising from synergistic effects of different components and the formed phase boundary. However, challenges persist in the controlled synthesis of heterophase intermetallic compounds (IMCs), primarily due to the lattice mismatch of distinct crystal phases and the difficulty in achieving precise control of the phase transitions. Herein, orthorhombic/cubic Ru2Ge3/RuGe IMCs with engineered boundary architecture are synthesized and anchored on the reduced graphene oxide. The Ru2Ge3/RuGe IMCs exhibit excellent hydrogen evolution reaction (HER) performance with a high current density of 1000 mA cm-2 at a low overpotential of 135 mV. The presence of phase boundaries enhances charge transfer and improves the kinetics of water dissociation while optimizing the processes of hydrogen adsorption/desorption, thus boosting the HER performance. Moreover, an anion exchange membrane electrolyzer is constructed using Ru2Ge3/RuGe as the cathode electrocatalyst, which achieves a current density of 1000 mA cm-2 at a low voltage of 1.73 V, and the activity remains virtually undiminished over 500 h.

8.
J Am Chem Soc ; 146(29): 20069-20079, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-38984787

RESUMO

Electrocatalytic nitrate (NO3-) reduction reaction (NO3RR) holds great potential for the conversion of NO3- contaminants into valuable NH3 in a sustainable method. Unfortunately, the nonequilibrium adsorption of intermediates and sluggish multielectron transfer have detrimental impacts on the electrocatalytic performance of the NO3RR, posing obstacles to its practical application. Herein, we initially screen the adsorption energies of three key intermediates, i.e., *NO3, *NO, and *H2O, along with the d-band centers on 21 types of transition metal (IIIV and IB)-Sb/Bi-based intermetallic compounds (IMCs) as electrocatalysts. The results reveal that hexagonal CoSb IMCs possess the optimal adsorption equilibrium for key intermediates and exhibit outstanding electrocatalytic NO3RR performance with a Faradaic efficiency of 96.3%, a NH3 selectivity of 89.1%, and excellent stability, surpassing the majority of recently reported NO3RR electrocatalysts. Moreover, the integration of CoSb IMCs/C into a novel Zn-NO3- battery results in a high power density of 11.88 mW cm-2.

9.
Small ; 20(31): e2401327, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38429245

RESUMO

Crystal phase engineering has emerged as a powerful tool for tailoring the electrocatalytic performance, yet its impact on nitrate reduction to ammonia (NRA) remains largely uncharted territory. Herein, density functional theory (DFT) calculations are performed to unravel the influence of the crystal phase of FeOOH on the adsorption behavior of *NO3. Inspiringly, FeOOH samples with four distinct crystal phases (δ, γ, α, and ß) are successfully synthesized and deployed as electrocatalysts for NRA. Remarkably, among all FeOOH samples, δ-FeOOH demonstrates the superior NRA performance, achieving a NH3 Faradic efficiency ( FE NH 3 $\rm{FE} _ {\rm{NH_3}}$ ) of 90.2% at -1.0 V versus reversible hydrogen electrode (RHE) and a NH3 yield rate ( Yield NH 3 $\rm{Yield} _ {\rm{NH_3}}$ ) of 5.73 mg h-1 cm-2 at -1.2 V. In-depth experiments and theoretical calculations unveil the existence of hydrogen bonding interaction between δ-FeOOH and *NOx, which not only enhances the adsorption of *NOx but also disrupts the linear relationships between the free energy of *NO3 adsorption and various parameters, including limiting potential, d-band center (εd) and transferred charge from FeOOH to *NO3, ultimately contributing to the exceptional NRA performance.

10.
Opt Express ; 32(7): 11794-11800, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38571018

RESUMO

Weak measurement, which can amplify a weak signal, has shown great significance in precision measurements. The amplification is usually realized through the weak value and the propagation factor. We show that the orbital angular momentum (OAM) can provide another dimension for amplification that is linearly proportional to the OAM number. We employ OAM to measure the spin Hall effect of light and demonstrate that the OAM-enabled amplification is compatible with the weak value amplification and the propagation amplification. This work is probable to promote the application of OAM in precision measurements.

11.
Exp Eye Res ; 244: 109948, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38815790

RESUMO

Severe corneal injury can lead to blindness even after prompt treatment. 14-3-3zeta, a member of an adaptor protein family, contributes to tissue repair by enhancing cellular viability and inhibiting fibrosis and inflammation in renal disease or arthritis. However, its role in corneal regeneration is less studied. In this study, filter disc of 2-mm diameter soaked in sodium hydroxide with a concentration of 0.5 N was placed at the center of the cornea for 30 s to establish a mouse model of corneal alkali injury. We found that 14-3-3zeta, which is mainly expressed in the epithelial layer, was upregulated following injury. Overexpression of 14-3-3zeta in ocular tissues via adeno-associated virus-mediated subconjunctival delivery promoted corneal wound healing, showing improved corneal structure and transparency. In vitro studies on human corneal epithelial cells showed that 14-3-3zeta was critical for cell proliferation and migration. mRNA-sequencing in conjunction with KEGG analysis and validation experiments revealed that 14-3-3zeta regulated the mRNA levels of ITGB1, PIK3R1, FGF5, PRKAA1 and the phosphorylation level of Akt, suggesting the involvement of the PI3K-Akt pathway in 14-3-3zeta-mediated tissue repair. 14-3-3zeta is a potential novel therapeutic candidate for treating severe corneal injury.


Assuntos
Proteínas 14-3-3 , Queimaduras Químicas , Lesões da Córnea , Cicatrização , Animais , Humanos , Masculino , Camundongos , Proteínas 14-3-3/metabolismo , Proteínas 14-3-3/genética , Proteínas 14-3-3/biossíntese , Western Blotting , Queimaduras Químicas/metabolismo , Queimaduras Químicas/patologia , Queimaduras Químicas/tratamento farmacológico , Movimento Celular , Proliferação de Células , Células Cultivadas , Lesões da Córnea/metabolismo , Lesões da Córnea/patologia , Lesões da Córnea/genética , Modelos Animais de Doenças , Epitélio Corneano/metabolismo , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/lesões , Queimaduras Oculares/induzido quimicamente , Regulação da Expressão Gênica , Homeostase , Camundongos Endogâmicos C57BL , Hidróxido de Sódio , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia
12.
Wound Repair Regen ; 32(4): 500-510, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38551210

RESUMO

Flaps are mainly used to repair wounds in the clinical setting but can sometimes experience ischaemic necrosis postoperatively. This study investigated whether donepezil, an acetylcholinesterase inhibitor, can enhance the survival rate of flaps. We randomly allocated 36 rats into control, low-dose (3 mg/kg/day), and high-dose (5 mg/kg/day) groups. On Postoperative day 7, we assessed flap viability and calculated the mean area of viable flap. After euthanizing the rats, we employed immunological and molecular biology techniques to examine the changes in flap tissue vascularization, apoptosis, autophagy, and inflammation. Donepezil enhanced the expression of hypoxia-inducible factor and vascular endothelial growth factor to facilitate angiogenesis. In addition, it elevated the expression of LC3B, p62, and beclin to stimulate autophagy. Furthermore, it increased the expression of Bcl-2 while reducing the expression of Bax, thus inhibiting apoptosis. Finally, it had anti-inflammatory effects by reducing the levels of IL-1ß, IL-6, and TNF-α. The results suggest that donepezil can enhance the viability of randomly generated skin flaps by upregulating HIF-1α/VEGF signalling pathway, facilitating vascularization, inducing autophagy, suppressing cell apoptosis, and mitigating inflammation within the flap tissue.


Assuntos
Apoptose , Donepezila , Sobrevivência de Enxerto , Subunidade alfa do Fator 1 Induzível por Hipóxia , Indanos , Piperidinas , Ratos Sprague-Dawley , Transdução de Sinais , Retalhos Cirúrgicos , Fator A de Crescimento do Endotélio Vascular , Animais , Donepezila/farmacologia , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Piperidinas/farmacologia , Indanos/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Masculino , Apoptose/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Autofagia/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Modelos Animais de Doenças
13.
Brain ; 146(4): 1328-1341, 2023 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-36350566

RESUMO

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.


Assuntos
Atrofia Óptica Hereditária de Leber , Humanos , DNA Mitocondrial/genética , Terapia Genética , Inflamação/etiologia , Mutação/genética , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/terapia
14.
Neuroradiology ; 66(8): 1373-1382, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38866958

RESUMO

BACKGROUND AND PURPOSE: Neuronal intranuclear inclusion disease (NIID) is a rare complex neurodegenerative disorder presents with various radiological features. The study aimed to investigate the structural abnormalities in NIID using multi-shell diffusion MR. MATERIALS AND METHODS: Twenty-eight patients with adult-onset NIID and 32 healthy controls were included. Volumetric and diffusion MRI measures, including volume, fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) of six brain structures, including cortex, subcortical GM, cerebral WM, cerebellar GM and WM, and brainstem, were obtained and compared between NIID and healthy controls. Associations between MRI measures and clinical variables were investigated. RESULTS: Brain lesions of NIID included corticomedullary junction lesions on DWI, confluent leukoencephalopathy, lesions on callosum, cerebellar middle peduncle, cerebellar paravermal area and brainstem, and brain atrophy. Compared to healthy controls, NIID showed extensive volume loss of all the six brain regions (all p < 0.001); lower FA in cerebral WM (p < 0.001); higher MD in all WM regions; lower ODI in cortex (p < 0.001); higher ODI in subcortical GM (p < 0.001) and brainstem (p = 0.016); lower ICVF in brainstem (p = 0.001), and cerebral WM (p < 0.001); higher ISOVF in all the brain regions (p < 0.001). Higher MD of cerebellar WM was associated with worse cognitive level as evaluated by MoCA scores (p = 0.011). CONCLUSIONS: NIID patients demonstrated widespread brain atrophy but heterogeneous diffusion alterations. Cerebellar WM integrity impairment was correlated with the cognitive decline. The findings of the current study offer a sophisticated picture of brain structural alterations in NIID.


Assuntos
Imagem de Difusão por Ressonância Magnética , Corpos de Inclusão Intranuclear , Doenças Neurodegenerativas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/patologia , Corpos de Inclusão Intranuclear/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Estudos de Casos e Controles , Idoso , Adulto , Anisotropia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia
15.
Bioorg Chem ; 151: 107701, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39154520

RESUMO

Four new diterpenoid tropolones, salvirrddones A-D (1-4), and four new icetexanes, salvirrddices A-D (9-12), along with thirteen new 11,12-seco-norabietane diterpenoids, salvirrddnor A-M (14-24, 31, 32) and sixteen known compounds (5-8, 13, 25-30, 33-37), were isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Their structures were elucidated by comprehensive spectroscopic analyses, quantum chemical calculations, and X-ray crystallography. Structurally, compounds 1-8 represent a class of rare natural products featuring a unique cyclohepta-2,4,6-trienone moiety with diterpenoid skeletons. Bioassays showed that only diterpenoid tropolones 3, 5, 6, and 7 exhibited significant activity against several human cancer cell lines with IC50 values ranging from 3.01 to 11.63 µM. Additionally, 3 was shown to inhibit Hep3B cell proliferation, block the G0/G1 phase of the cell cycle, induce mitochondrial dysfunction and oxidative stress, promote apoptosis, as well as inhibit migration and invasion in vitro. Meanwhile, 3 demonstrated anti-proliferative, pro-apoptotic, and migration-inhibitory effects in the Hep3B xenograft zebrafish model in vivo. Network pharmacological analysis and molecular docking results suggested that 3 may treat hepatocellular carcinoma (HCC) through the PI3K-Akt signaling pathway, as well as by binding PARP1 and CDK2 targets. Overall, the present results extremely expand the repertoire of diterpenoids from natural products and may provide a novel chemical scaffold for the discovery of new antitumor drugs.


Assuntos
Antineoplásicos Fitogênicos , Apoptose , Proliferação de Células , Diterpenos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Salvia , Peixe-Zebra , Humanos , Salvia/química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Relação Estrutura-Atividade , Animais , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral
16.
Support Care Cancer ; 32(3): 155, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38347229

RESUMO

PURPOSE: Sleep problems are a significant issue in patients with lung cancer, and resilience is a closely related factor. However, few studies have identified subgroups of resilience and their relationship with sleep quality. This study aimed to investigate whether there are different profiles of resilience in patients with lung cancer, to determine the sociodemographic characteristics of each subgroup, and to determine the relationship between resilience and sleep quality in different subgroups. METHODS: A total of 303 patients with lung cancer from four tertiary hospitals in China completed the General Sociodemographic sheet, the Connor-Davidson Resilience Scale, and the Pittsburgh Sleep Quality Index. Latent profile analysis was applied to explore the latent profiles of resilience. Multivariate logistic regression was used to analyze the sociodemographic variables in each profile, and ANOVA was used to explore the relationships between resilience profiles and sleep quality. RESULTS: The following three latent profiles were identified: the "high-resilience group" (30.2%), the "moderate-resilience group" (46.0%), and the "low-resilience group" (23.8%). Gender, place of residence, and average monthly household income significantly influenced the distribution of resilience in patients with lung cancer. CONCLUSION: The resilience patterns of patients with lung cancer varied. It is suggested that health care providers screen out various types of patients with multiple levels of resilience and pay more attention to female, rural, and poor patients. Additionally, individual differences in resilience may provide an actionable means for addressing sleep problems.


Assuntos
Neoplasias Pulmonares , Testes Psicológicos , Resiliência Psicológica , Transtornos do Sono-Vigília , Humanos , Feminino , Qualidade do Sono , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia
17.
Cereb Cortex ; 33(3): 844-864, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-35296883

RESUMO

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.


Assuntos
Emoções , Esfingomielina Fosfodiesterase , Masculino , Camundongos , Animais , Feminino , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo , Consumo de Bebidas Alcoólicas , Ansiedade/metabolismo , Encéfalo/metabolismo , Etanol
18.
BMC Psychiatry ; 24(1): 583, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39192231

RESUMO

BACKGROUND: This study was intended to investigate the correlation between depression and suicidal ideation among Chinese college students during the COVID-19 pandemic and the potential mediating roles of chronotype and sleep quality in this relationship . METHODS: A sample of 4,768 college students was selected from four institutions in Anhui Province, China, and the study was conducted during the COVID-19 pandemic (November to December 2020) using a stratified, cluster, multi-stage sampling method. This study used the two-item Patient Health Questionnaire (PHQ-2) to assess depressive symptoms, the Morningness-Eveningness Questionnaire 19 (MEQ-19) to determine individual sleep chronotypes (i.e., morning or evening preference), and the Pittsburgh Sleep Quality Index (PSQI) to evaluate sleep quality. Participants were asked about suicidal ideation. MPLUS 8.3 software was used to analyze the mediating effect of chronotype and sleep quality on the relationship between depression and suicidal ideation. RESULTS: During the COVID-19 pandemic, the prevalence of suicidal ideation among Chinese college students was 5.4%. Depression was inversely correlated with chronotype (beta = - 0.346, P < 0.01) and positively correlated with sleep quality (beta = 0.846, P < 0.001), indicating that students experiencing depressive symptoms were more likely to have a later chronotype and poor sleep quality. A later chronotype (beta = - 0.019, P < 0.05) and poor sleep quality (beta = 0.066, P < 0.01) predicted suicidal ideation. Depression emerged as a direct and significant risk factor for suicidal ideation (effect value = 0.535, 95% confidence interval: 0.449 ~ 0.622). Chronotype and sleep quality were found to have potential mediating effects on the relationship between depression and suicidal ideation; however, the chain-mediating effect of chronotype and sleep quality was not statistically significant. CONCLUSIONS: Our findings suggest that during the COVID-19 pandemic, depression can precipitate suicidal ideation through its influence on sleep chronotype and quality. These compelling findings highlight the urgency of early intervention strategies intended to mitigate suicidal thoughts, particularly among students exhibiting depressive symptoms, who experience disrupted sleep patterns and poor sleep quality.


Assuntos
COVID-19 , Depressão , Qualidade do Sono , Estudantes , Ideação Suicida , Humanos , COVID-19/psicologia , COVID-19/epidemiologia , Estudantes/psicologia , Feminino , Masculino , China/epidemiologia , Depressão/psicologia , Depressão/epidemiologia , Adulto Jovem , Universidades , Adulto , Adolescente , Ritmo Circadiano/fisiologia , Inquéritos e Questionários , Prevalência , Cronotipo
19.
Cell Mol Life Sci ; 80(8): 239, 2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37540379

RESUMO

Retinal ganglion cells (RGCs) are essential for vision perception. In glaucoma and other optic neuropathies, RGCs and their optic axons undergo degenerative change and cell death; this can result in irreversible vision loss. Here we developed a rapid protocol for directly inducing RGC differentiation from human induced pluripotent stem cells (hiPSCs) by the overexpression of ATOH7, BRN3B, and SOX4. The hiPSC-derived RGC-like cells (iRGCs) show robust expression of various RGC-specific markers by whole transcriptome profiling. A functional assessment was also carried out and this demonstrated that these iRGCs display stimulus-induced neuronal activity, as well as spontaneous neuronal activity. Ethambutol (EMB), an effective first-line anti-tuberculosis agent, is known to cause serious visual impairment and irreversible vision loss due to the RGC degeneration in a significant number of treated patients. Using our iRGCs, EMB was found to induce significant dose-dependent and time-dependent increases in cell death and neurite degeneration. Western blot analysis revealed that the expression levels of p62 and LC3-II were upregulated, and further investigations revealed that EMB caused a blockade of lysosome-autophagosome fusion; this indicates that impairment of autophagic flux is one of the adverse effects of that EMB has on iRGCs. In addition, EMB was found to elevate intracellular reactive oxygen species (ROS) levels increasing apoptotic cell death. This could be partially rescued by the co-treatment with the ROS scavenger NAC. Taken together, our findings suggest that this iRGC model, which achieves both high yield and high purity, is suitable for investigating optic neuropathies, as well as being useful when searching for potential drugs for therapeutic treatment and/or disease prevention.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doenças do Nervo Óptico , Humanos , Células Ganglionares da Retina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças do Nervo Óptico/metabolismo , Apoptose , Etambutol/farmacologia , Etambutol/metabolismo , Fatores de Transcrição SOXC/metabolismo
20.
Oral Dis ; 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39315471

RESUMO

OBJECTIVES: Intricate associations between programmed cell death (PCD) and cancer development and treatment outcomes have been increasingly appreciated. Here, we integrated 12 PCD patterns to construct a novel biomarker, cell death index (CDI), for oral squamous cell carcinoma (OSCC) prognostication and therapeutic prediction. MATERIALS AND METHODS: Univariate Cox regression, Kaplan-Meier survival, and LASSO analyses were performed to construct the CDI. A nomogram combining CDI and selected clinicopathological parameters was established by multivariate Cox regression. The associations between CDI and immune landscape and therapeutic sensitivity were estimated. Single-cell RNA-seq data of OSCC was used to infer CDI genes in selected cell types and determine their expression along cell differentiation trajectory. RESULTS: Ten selected PCD genes derived a novel prognostic signature for OSCC. The predictive prognostic performance of CDI and nomogram was robust and superior across multiple independent patient cohorts. CDI was negatively associated with tumor-infiltrating immune cell abundance and immunotherapeutic outcomes. Moreover, scRNA-seq data reanalysis revealed that GSDMB, IL-1A, PRKAA2, and SFRP1 from this signature were primarily expressed in cancer cells and involved in cell differentiation. CONCLUSIONS: Our findings established CDI as a novel powerful predictor for prognosis and therapeutic response for OSCC and suggested its potential involvement in cancer cell differentiation.

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