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1.
Shock ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34618729

RESUMO

ABSTRACT: Blocking ferroptosis reduces ischemia-reperfusion injury in some pathological contexts. However, there is no evidence that ferroptosis contributes to post-resuscitation myocardial dysfunction (PRMD). Here, we evaluated the therapeutic performance of ferroptosis inhibitors (UAMC-3203 or/and Deferoxamine) on the PRMD in a rat model of cardiac arrest and surveyed the changes of essential ferroptosis markers in the myocardium. Remarkably, all treatments reduce the severity of cardiac dysfunction and microcirculation hypoperfusion after resuscitation compared with control. Consistently, we observe that the ferroptosis marker Glutathione peroxidase 4, 4-hydroxynonenal and non-heme iron altered (1 ±â€Š0.060 vs. 0.021 ±â€Š0.016, 1 ±â€Š0.145 vs. 3.338 ±â€Š0.221, 52.010 ±â€Š3.587 ug/g vs. 70.500 ±â€Š3.158 ug/g, all P < 0.05) in the myocardium after resuscitation. These changes were significantly suppressed by UAMC-3203 [(0.187 ±â€Š0.043, 2.848 ±â€Š0.169, all P < 0.05), (72.43 ±â€Š4.920 ug/g, P  > 0.05)], or Deferoxamine (0.203 ±â€Š0.025, 2.683 ±â€Š0.273, 55.95 ±â€Š2.497 ug/g, all P < 0.05). Briefly, UAMC-3203 or/and Deferoxamine improve post-resuscitation myocardial dysfunction and provide evidence of ferroptosis involvement, suggesting that ferroptosis inhibitors could potentially provide an innovative therapeutic approach for mitigating the myocardial damage caused by cardiopulmonary resuscitation.

2.
Chemosphere ; 287(Pt 4): 132397, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34597640

RESUMO

Reasonable design of three-dimensional (3D) catalytic particle electrodes (CPEs) is crucial for achieving efficient electrocatalytic oxidation of organic pollutants. Herein, the novel Fe3O4/SnO2/GO (FO/SO/GO) particle electrode has been developed and serviced to the 3D electrocatalytic berberine hydrochloride oxidation system with DSA (RuO2-IrO2-SnO2/Ti) electrode as anode and GDE (gas diffusion electrode) electrode as the cathode. Compared with 2D systems and other CPEs, FO/SO/GO electrode shows excellent electrocatalytic activity and remarkable stability for BH removal, that is, the removal rate of BH is 94.8% within 90 min, and the rate constant is 0.03095 min-1. More importantly, after five cycles, the ternary composite still maintains a strong ability to oxidize pollutants. The structural characterization and electrochemical measurement further uncover that the electron transfer ability and electrocatalytic oxidation efficiency are highly dependent on the surface structure regulation of CPEs. Furthermore, the quenching experiments show that hydroxyl radicals are the main active species in the 3D electro-Fenton (EF) system, which can oxidize BH molecules adsorbed on the surface of GO to CO2, H2O, or other products. The results could potentially provide new insights for designing and fabricating more stable and efficient 3D CPEs electrocatalytic removal of organic pollutants in the future.

3.
Crit Care Med ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34637412

RESUMO

OBJECTIVES: To investigate the therapeutic potential and underlying mechanisms of exogenous nicotinamide adenine dinucleotide+ on postresuscitation myocardial and neurologic dysfunction in a rat model of cardiac arrest. DESIGN: Thirty-eight rats were randomized into three groups: 1) Sham, 2) Control, and 3) NAD. Except for the sham group, untreated ventricular fibrillation for 6 minutes followed by cardiopulmonary resuscitation was performed in the control and NAD groups. Nicotinamide adenine dinucleotide+ (20 mg/kg) was IV administered at the onset of return of spontaneous circulation. SETTING: University-affiliated research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Nicotinamide adenine dinucleotide+. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and myocardial function were measured at baseline and within 4 hours following return of spontaneous circulation. Survival analysis and Neurologic Deficit Score were performed up to 72 hours after return of spontaneous circulation. Adenosine triphosphate (adenosine triphosphate) level was measured in both brain and heart tissue. Mitochondrial respiratory chain function, acetylation level, and expression of Sirtuin3 and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9 (NDUFA9) in isolated mitochondrial protein from both brain and heart tissue were evaluated at 4 hours following return of spontaneous circulation. The results demonstrated that nicotinamide adenine dinucleotide+ treatment improved mean arterial pressure (at 1 hr following return of spontaneous circulation, 94.69 ± 4.25 mm Hg vs 89.57 ± 7.71 mm Hg; p < 0.05), ejection fraction (at 1 hr following return of spontaneous circulation, 62.67% ± 6.71% vs 52.96% ± 9.37%; p < 0.05), Neurologic Deficit Score (at 24 hr following return of spontaneous circulation, 449.50 ± 82.58 vs 339.50 ± 90.66; p < 0.05), and survival rate compared with that of the control group. The adenosine triphosphate level and complex I respiratory were significantly restored in the NAD group compared with those of the control group. In addition, nicotinamide adenine dinucleotide+ treatment activated the Sirtuin3 pathway, down-regulating acetylated-NDUFA9 in the isolated mitochondria protein. CONCLUSIONS: Exogenous nicotinamide adenine dinucleotide+ treatment attenuated postresuscitation myocardial and neurologic dysfunction. The responsible mechanisms may involve the preservation of mitochondrial complex I respiratory capacity and adenosine triphosphate production, which involves the Sirtuin3-NDUFA9 deacetylation.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34599713

RESUMO

In this study, the biocarbon derived from aerobic granular sludge with different nutritive proportions was modified by Cu(NO3)2•3H2O (Cu-BC) to improve its adsorption capacity of doxycycline hydrochloride (DOX). The surface area, pores, functional groups, and element composition of biocarbon were characterized by scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET) surface area, X-ray photoelectron spectrometer, X-ray diffraction (XRD), the X-ray photoelectron spectrometer, and Fourier transform infrared spectrometry (FT-IR), respectively. Effects of DOX concentration, initial pH, and background electrolyte on adsorption effects of composite were analyzed. Furthermore, the adsorption kinetics, isotherm, thermodynamics, and diffusion model were investigated. Results demonstrated that biocarbons which were prepared with aerobic granular sludge under different nutritive proportions presented different performances. The BET specific surface area of Cu-NaAC/AGS-BC was 260.1592 m2/g, and the micropore volume was 0.054101 cm3/g. The BET specific surface area of Cu-GLC /AGS-BC was only 10.6821 m2/g, and the micropore volume was 0.008687 cm3/g. Both kinds of modified biochar contain a large number of oxygen-containing functional groups. The highest adsorption efficiency of Cu-BC could reach 99.54%. The adsorption of DOX on two modified biocarbons conforms to the pseudo-second-order dynamic model and Temkin isothermal model.

5.
J Phys Chem Lett ; 12(39): 9579-9583, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34582204

RESUMO

Oxygen vacancy is a common defect in metal oxides that causes appreciable damage to material properties and performance. Removing bulk defects of oxygen vacancy (VO) typically needs harsh conditions such as high-temperature annealing. Supported by first-principles simulations, we propose an effective strategy of removing VO bulk defects in metal oxides by evaporating hydrogen dopants. The hydrogen dopants not only lower the migration barrier of VO but also push VO away due to their repulsive interaction. The coevaporation mechanism was supported by a neural networks potential-based molecular dynamics simulation, which shows that the migration of hydrogen dopants from inside to surface at 400 K promotes the migration of VO as well. Our proof-of-concept study suggests an alternative and efficient way of modulating oxygen vacancies in metal oxides via reversible hydrogen doping.

6.
Bioorg Chem ; 116: 105278, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34474303

RESUMO

Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of cancers, neurodegenerative diseases and autoimmune disorders. Herein a novel series of pyrrolo[2,3-d]pyrimidine-based HDAC inhibitors were designed, synthesized and biologically evaluated, among which compounds 7a, 12a1, and 16a1 exhibited potent inhibitory activities and selectivities against HDAC6. Notably, compared with the well-known HDAC6 inhibitor Tubastatin A, our pyrrolo[2,3-d]pyrimidine-based HDAC6 inhibitors showed superior in vitro antiproliferative activity against human multiple myeloma cell lines RPMI 8226, U266 and MM.1S, while maintaining the low cytotoxicity against human breast cancer cell line MDA-MB-231 and two normal cell lines. The HDAC6 selective inhibition of one representative compound 12a1 in RPMI 8226 cells was confirmed by western blot analysis. Although pyrrolo[2,3-d]pyrimidine is a privileged structure in many kinase inhibitors, compound 12a1 showed negligible inhibition against several kinases including JAK family members and Akt1, indicating its acceptable off-target profile. Besides, compound 12a1 exhibited desirable metabolic stability in mouse liver microsome. The in vivo anti-multiple myeloma potency of 12a1, alone and in combination with bortezomib, was demonstrated in a RPMI 8226 xenograft model.

7.
Biomed Pharmacother ; 142: 111935, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34467895

RESUMO

The physiology and physiopathology process of mitochondrial function following cardiac arrest remains poorly understood. We aimed to assess mitochondrial respiratory function on the heart and brain homogenates from cardiac arrest rats. The expression level of SIRT1/PGC-1α pathway was measured by immunoblotting. 30 rats were assigned to the CA group and the sham group. Rats of CA were subjected to 6 min of untreated ventricular fibrillation (VF) followed by 8 min of cardiopulmonary resuscitation (CPR). Mitochondrial respiratory function was compromised following CA and I/R injury, as indicated by CIL (451.46 ± 71.48 vs. 909.91 ± 5.51 pmol/min*mg for the heart and 464.14 ± 8.22 vs. 570.53 ± 56.33 pmol/min*mg for the brain), CI (564.04 ± 64.34 vs. 2729.52 ± 347.39 pmol/min*mg for the heart and 726.07 ± 85.78 vs. 1762.82 ± 262.04 pmol/min*mg for the brain), RCR (1.88 ± 0.46 vs. 3.57 ± 0.38 for the heart and 2.05 ± 0.19 vs. 3.49 ± 0.19, for the brain) and OXPHOS coupling efficiency (0.45 ± 0.11 vs. 0.72 ± 0.03 for the heart and 0.52 ± 0.05 vs. 0.71 ± 0.01 for the brain). However, routine respiration was lower in the heart and comparable in the brain after CA. CIV did not change in the heart but was enhanced in the brain. Furthermore, both SIRT1 and PGC-1α were downregulated concurrently in the heart and brain. The mitochondrial respiratory function was compromised following CA and I/R injury, and the major affected respiratory state is complex I-linked respiration. Furthermore, the heart and the brain respond differently to the global I/R injury after CA in mitochondrial respiratory function. Inhibition of the SIRT1/PGC-1α pathway may be a major contributor to the impaired mitochondrial respiratory function.

8.
FASEB J ; 35(8): e21776, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34324740

RESUMO

Nonresponse, or acquired resistance to immune checkpoint inhibitors in colorectal cancer (CRC) highlight the importance of finding potential tolerance mechanisms. Low expression of major histocompatibility complex, class I (MHC-I) on the cell surface of the tumor is one of the main mechanisms of tumor escape from T-cell recognition and destruction. In this study, we demonstrated that a high level of calnexin (CANX) in the tumors is positively correlated with the overall survival in colorectal cancer patients. CANX is a chaperone protein involved in the folding and assembly of MHC-I molecules. Using miRNA target prediction databases and luciferase assays, we identified miR-148a-3p as a potential regulator of CANX. Inhibition of miR-148a-3p restores surface levels of MHC-I and significantly enhanced the effects of CD8+ T-cell-mediated immune attack in vitro and in vivo by promoting CANX expression. These results reveal that miR-148a-3p can function as a tumor promotor in CRC by targeting the CANX/MHC-I axis, which provides a rationale for immunotherapy through targeting the miR-148a-3p/CANX/MHC-I pathway in patients with CRC.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Calnexina/metabolismo , Neoplasias Colorretais/terapia , Antígenos de Histocompatibilidade Classe II/metabolismo , MicroRNAs/metabolismo , Animais , Calnexina/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Camundongos , MicroRNAs/genética , Neoplasias Experimentais/terapia
9.
J Am Chem Soc ; 143(29): 10860-10864, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34279083

RESUMO

Chiral chromophores and their ordered assemblies are intriguing for yielding circularly polarized luminescence (CPL) and exploring intrinsic structure-light emission relationships. With the extensively studied chiral organic molecules and inorganic nanoparticle assemblies for the amplified CPL, the assemblies of copper halide hybrid clusters have attracted intensive attention due to their potential efficient CPL. Here, we report robust chiral phosphine-copper iodide hybrid clusters and their layered assemblies in crystalline states for amplified CPL. We reveal that the intermolecular interactions endow the clusters with the capability of assembling into chiral crystalline CPL materials, including hexagonal platelet-shaped microcrystals (glum ≈ 9.5 × 10-3) and highly oriented crystalline films (glum ≈ 5 × 10-3). Owing to the high crystalline feature of the thin film, we demonstrate an electroluminescent device with bright electroluminescence (1200 cd m-2).

10.
Cancer Sci ; 112(9): 3585-3597, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252986

RESUMO

Diffuse large B cell lymphoma (DLBCL) heterogeneity promotes recurrence and anti-CD20-based therapeutic resistance. Previous studies have shown that downregulation of MS4A1/CD20 expression after chemoimmunotherapy with rituximab leads to rituximab resistance. However, the mechanisms of CD20 loss remain unknown. We identified that pyruvate dehydrogenase kinase 4 (PDK4) is markedly elevated in DLBCL cells derived from both patients and cell lines with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) resistance. We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression. Collectively, this is the first study showing that targeting PDK4 has the potential to overcome rituximab resistance in DLBCL.


Assuntos
Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/administração & dosagem , Reprogramação Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glicoproteínas/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Rituximab/administração & dosagem , Transdução de Sinais/genética , Adolescente , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Transfecção , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
11.
Plant Dis ; 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34132598

RESUMO

Orychophragmus violaceus, belonging to the Brassicaceae family, is widely grown in many provinces of China as an ornamental plant and also as a green manure crop. In December 2019, field investigations showed that a leaf spot disease occurred on O.violaceus with 50% to 80% incidence in Huize City, Yunnan Province of China. Infected leaves showed symptoms of small black point spots in the early stage of onset. The lesions are distributed throughout the leaves and finaly expand to 10-15 mm in diameter after 10-15 days of onset. At this time, the lesions are gray to black, and some have round patterns, and gray-white mildew layers can be seen on the front and back of the lesions in a humid environment. The leaves with typical lesion symptoms were sampled and photographed, and then subjected to isolate and characterize the pathogen. Six pure cultures (HEYA2; HEYA4; HEYC6; HEYD7; HEYD8; HEYD10) were obtained by single-hyphae isolation. On PCA medium, colony can reach 27 mm after 7d, at 25°C in darkness. Aerial hypha is cottony with white to pale gray color, while the colony reverse is fawn to dark. on V8 medium, conidiophore solitary or clustered, erect or knee-curved, occasionally branched, pare brown, separated, 82-130 × 5-9 µm. Conidia are solitary, straight or slightly curved, inverted rod-shaped, pare brown to brown, with 6-10 transverse septa, 0-5 oblique and longitudinal septa, columnar beak, conidial bodies (47.7-)69.3-103.8(-119.6)(11.2-)16.6-23.6(-27.8) µm. Beak septum, pare brown, (29.2-)34.4-72.4(-101.3)(4.2-)6.6-9.5(-11.3) µm. Morphologically these isolates resembled species belonging to genus Alternaria (Simmons, 2007). Genomic DNA of each culture was quickly extracted from mycelia using QS method (Chi et al. 2009). The ITS region, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), RNA polymerase II second largest subunit (RPB2) and translation elongation factor -1α (TEF -1α) genes were amplified according described procedures (White et al. 1990; Berbee et al. 1999; Liu et al. 1999;Sung et al. 2007; Carbone & Kohn 1999). The sequences obtained in this study were deposited in GenBank with accession numbers: MW867245, MW867246, MW867247, MW867248, MW867249, MW867250, MW882913, MW882914, MW882915, MW882916, MW882917, MW882918, MW882919, MW882920, MW882921, MW882922, MW882923, MW882924, MW882925, MW882926, MW882927, MW882928, MW882929, MW882930. Phylogenetic analysis was conducted with combined sequences of the four loci, using the maximum likelihood method and the maximum parsimony method. In the phylogenetic tree, the six isolates and Alternaria brassicae (CBS 116528) clustered together with high bootstrap support values (MLBS=100; MPBS= 100). Based on both morphological characters and phylogenetic results, the isolates were identified as Alternaria brassicae. Pathogenicity test of isolate HEYA2 was carried out on the detached leaves in a dark thermostat incubator at 25°C. Five pots per leaf were inoculated with mycelia plugs (5 mm in diameter), another five pots were inoculated with pure agar plugs and used as the negative control. In addition, conidia suspension (105 conidia/ml) of isolate HEYD8 were sprayed on 3-month-old healthy plants grown in a greenhouse at 22 °C-28 °C. The plants sprayed with sterilized water were used as negative controls. The test was conducted three times. After 5-7 days, the leaves inoculated with other the conidia suspension or the mycelium plugs showed brown necrotic lesions that are similar to the symptoms observed in the field, but the controls remained healthy. The pathogen was reisolated and confirmed to be A. brassicae, completing Koch's postulates. To our knowledge, this is the first report of leaf spot disease caused by A. brassicae on Orychophragmus violaceus in China.

12.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34185681

RESUMO

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), invades a human cell via human angiotensin-converting enzyme 2 (hACE2) as the entry, causing the severe coronavirus disease (COVID-19). The interactions between hACE2 and the spike glycoprotein (S protein) of SARS-CoV-2 hold the key to understanding the molecular mechanism to develop treatment and vaccines, yet the dynamic nature of these interactions in fluctuating surroundings is very challenging to probe by those structure determination techniques requiring the structures of samples to be fixed. Here we demonstrate, by a proof-of-concept simulation of infrared (IR) spectra of S protein and hACE2, that time-resolved spectroscopy may monitor the real-time structural information of the protein-protein complexes of interest, with the help of machine learning. Our machine learning protocol is able to identify fine changes in IR spectra associated with variation of the secondary structures of S protein of the coronavirus. Further, it is three to four orders of magnitude faster than conventional quantum chemistry calculations. We expect our machine learning protocol would accelerate the development of real-time spectroscopy study of protein dynamics.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Aprendizado de Máquina , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/química , Humanos , Cinética , Ligação Proteica , Estrutura Secundária de Proteína , Espectrofotometria Infravermelho , Glicoproteína da Espícula de Coronavírus/química
13.
Chem Commun (Camb) ; 57(53): 6562-6565, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34113947

RESUMO

A new type of non-intertwined ring-on-ring assembly was formed by the portal binding between a perfunctionalized polycationic pillar[5]arene and a cucurbit[10]uril, demonstrating a facile approach to solubilize a large macrocycle in water. Different binding behaviors towards guests were observed for the high-order complex, enriching the functional supramolecular systems.

14.
J Phys Chem B ; 125(23): 6171-6178, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34086461

RESUMO

Ultraviolet (UV) absorption spectra are commonly used for characterizing the global structure of proteins. However, the theoretical interpretation of UV spectra is hindered by the large number of required expensive ab initio calculations of excited states spanning a huge conformation space. We present a machine-learning (ML) protocol for far-UV (FUV) spectra of proteins, which can predict FUV spectra of proteins with comparable accuracy to density functional theory (DFT) calculations but with 3-4 orders of magnitude reduced computational cost. It further shows excellent predictive power and transferability that can be used to probe structural mutations and protein folding pathways.


Assuntos
Proteínas , Teoria Quântica , Aprendizado de Máquina , Conformação Molecular , Espectrofotometria Ultravioleta
15.
J Phys Chem Lett ; 12(22): 5233-5240, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34047561

RESUMO

Cooperative effects of adjacent active centers are critical for single-atom catalysts (SACs) as active site density matters. Yet, how it affects scaling relationships in many important reactions such as the nitrogen reduction reaction (NRR) is underexplored. Herein we elucidate how the cooperation of two active centers can attenuate the linear scaling effect in the NRR through a first-principle study on 39 SACs comprised of two adjacent (∼4 Å apart) four N-coordinated metal centers (MN4 duo) embedded in graphene. Bridge-on adsorption of dinitrogen-containing species appreciably tilts the balance of adsorption of N2H and NH2 toward N2H and thus substantially loosens the restraint of scaling relationships in the NRR, achieving low onset potential (V) and direct N≡N cleavage (Mo, Re) at room temperature, respectively. The potential of the MN4 duo in the NRR provides new insight into circumventing the limitations of scaling relationships in heterogeneous catalysis.

16.
J Am Heart Assoc ; 10(9): e019177, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33884887

RESUMO

Background To investigate the therapeutic potential of combined therapy with polyethylene glycol-20k (PEG-20k) and MCC950 on post-resuscitation myocardial function in a rat model of cardiac arrest. Methods and Results Thirty rats were randomized into 5 groups: Sham, Control, PEG-20k, MCC950, PEG-20k+ MCC950. Except for sham, animals were subjected to 6 minutes of ventricular fibrillation followed by 8 minutes cardiopulmonary resuscitation. Two milliliters PEG-20k was administered by intravenous injection coincident with the start of cardiopulmonary resuscitation; MCC950 (10 mg/kg), a highly selective NLRP3 inflammasome inhibitor, was delivered immediately after restoration of spontaneous circulation. Myocardial function, sublingual microcirculation, mitochondrial function, plasma cardiac troponin I, and interleukin-1ß, expression of proteins in SIRT1 (sirtuin 1)/PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and NLRP3 (the NOD-like receptor family protein 3) inflammasome pathways were evaluated. Following cardiopulmonary resuscitation, myocardial function was compromised with a significantly decreased cardiac output, ejection fraction, and increased myocardial performance index, cardiac troponin I. Sublingual microcirculation was disturbed with impaired perfused vessel density and microvascular flow index. Cardiac arrest reduced mitochondrial routine respiration, Complex I-linked respiration, respiratory control rates and oxidative phosphorylation coupling efficiency. PEG-20k or MCC950 alone restored mitochondrial respiratory function, restituted sublingual microcirculation, and preserved myocardial function, whereas a combination of PEG-20k and MCC950 further improved these aspects. PEG-20k restored the expression of SIRT1 and PGC-1α, and blunted activation of NLRP3 inflammasomes. MCC950 suppressed expression of cleaved-caspase-1/pro-caspase-1, ASC (apoptosis-associated speck-like protein), GSDMD [gasdermin d], and interleukin-1ß. Conclusions Combined therapy with PEG-20k and MCC950 is superior to either therapy alone for preserving post-resuscitated myocardial function, restituting sublingual microcirculation at restoration of spontaneous circulation at 6 hours. The responsible mechanisms involve upregulated expression of SIRT1/PGC1-α in tandem with inhibition of NLRP3 inflammasomes.

17.
J Phys Chem Lett ; 12(16): 3868-3874, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33856794

RESUMO

Through-space charge transfer (TSCT) has become a thriving strategy of modulating photogenerated charges in organic photoresponsive molecular systems for potential applications in luminescence, optoelectronics, and photochemical conversion. Yet fixed configuration between electron donor (D) and acceptor (A) is disadvantageous to mitigate charge recombination undermining their performances. By carrying out first-principle simulations, we proposed a protocol enabling dynamic control of TSCT within a D-A system by use of a bridged azobenzene (BAB), whose configuration is self-adaptive upon photoexcitation. While the Z-isomer of BAB facilitates π-π stacking of D-A pair with designated frontier orbital alignment to ensure TSCT, the E-isomer of BAB breaks that stacking and restrains charge recombination. Further, as a CO2 molecule is weakly bound to the anionic acceptor, the former goes bent as a result of charge transfer from the latter, suggesting a path for photodriven CO2 reduction aided by such a donor-switch-acceptor system. Our proof-of-concept study shows the potential of using specific photoswitch to adaptively steer spatial electron transfer within stacked π systems toward photochemical conversion.

18.
Nano Lett ; 21(9): 4115-4121, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33885323

RESUMO

As one fundamental property of light, polarization has a huge impact in quantum optics and optoelectronics through light-matter interactions. However, the bright and near-unity polarized light emissions in the visible range by solid crystalline materials are scantly realized. Here, we report well-defined quasi two-dimensional (2D) hybrid crystals based on the linear alignment of Cu2I2-dimer/bidentate ligand hybrid clusters for achieving bright and near-unity linearly polarized light emissions. Using first-principle calculations, we demonstrate that the superaligned transition dipole moments are the key for the observed excellent polarized light emissions. To further enhance the photoluminescence (PL) polarization degree, we fabricate Cu2I2-dimer-based hybrid nanobelts, which display high PL quantum yield (up to 64%) and ultrahigh PL polarization degree (∼0.99). Our reported copper iodine cluster-based luminescent hybrid materials for bright and highly polarized light emissions will have great potential for future quantum optics applications.

19.
J Phys Chem A ; 125(15): 3088-3094, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33830768

RESUMO

Charge separation and intersystem crossing play critical roles in various applications of organic long persistent luminescence materials, including light-emitting diodes, chemical sensors, theranostics, and many biomedical and information applications. Using first-principles calculations, we demonstrate that an azobenzene acting as a photoswitch can be used for altering the configuration of a donor-switch-acceptor (D-S-A) molecular system to ensure charge separation and promote intersystem crossing upon photoexcitation. The trans to cis photoisomerization of an azobenzene switch creates an electron trap that stabilizes the charge-separated state. The cis conformation further facilitates the singlet to triplet intersystem crossing in the excited state. Our theoretical study of the D-S-A system may help the design of long persistent luminescent organic devices.


Assuntos
Compostos Azo/química , Teoria da Densidade Funcional , Elétrons , Estrutura Molecular
20.
Biomed Pharmacother ; 133: 110970, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33166763

RESUMO

Accumulating evidence demonstrated that administration of ω-3 polyunsaturated fatty acid (ω-3 PUFA) or ascorbic acid (AA) following cardiac arrest (CA) improves survival. Therefore, we investigate the effects of ω-3 PUFA combined with AA on myocardial function after CA and cardiopulmonary resuscitation (CPR) in a rat model. Thirty male rats were randomized into 5 groups: (1) sham; (2) control; (3) ω-3 PUFA; (4) AA; (5) ω-3 PUFA + AA. Ventricular fibrillation (VF) was induced and untreated for 6 min followed by defibrillation after 8 min of CPR. Infusion of drug or vehicle occurred at the start of CPR. Myocardial function and sublingual microcirculation were measured at baseline and after return of spontaneous circulation (ROSC). Heart tissues and blood were collected 6 h after ROSC. Myocardial function and sublingual microcirculation improvements were seen with ω-3 PUFA or AA compared to control after ROSC (p < 0.05). ω-3 PUFA + AA shows a better myocardial function than ω-3 PUFA or AA (p < 0.05). ω-3 PUFA or AA decreases pro-inflammatory cytokines, cTnI, myocardium malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) modified proteins compared to control (p < 0.05). ω-3 PUFA and AA combined have lower MDA and 4-HNE modified proteins than alone (p < 0.05). ω-3 PUFA or AA treatment reduces the severity of post-resuscitation myocardial dysfunction, improves sublingual microcirculation, decreases lipid peroxidation and systemic inflammation in the early phase of recovery following CA and resuscitation. A combination of ω-3 PUFA and AA treatment confers an additive effect in suppressing lipid peroxidation and improving myocardial function.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Circulação Sanguínea/efeitos dos fármacos , Reanimação Cardiopulmonar , Ácidos Graxos Ômega-3/farmacologia , Parada Cardíaca/terapia , Miocárdio/metabolismo , Fibrilação Ventricular/terapia , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Parada Cardíaca/sangue , Parada Cardíaca/fisiopatologia , Mediadores da Inflamação/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fibrilação Ventricular/sangue , Fibrilação Ventricular/fisiopatologia
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