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1.
Chem Biodivers ; 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36691852

RESUMO

One new alkaloid, picrasine A, two new quassinoids, picralactone A-B, together with eleven known compounds were isolated from Picrasma chinensis P.Y. Chen. The structures of these compounds were determined using 1D and 2D NMR, HR-ESI-MS, and IR spectroscopic data, and by comparison with published data. Some compounds were tested for tyrosinase inhibiting activity, however, none of them exhibited strong inhibitory effects.

2.
Mater Horiz ; 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36692037

RESUMO

Solar-driven vapor generation has emerged as a promising wastewater remediation technology for clean water production. However, the complicated and diversified contaminants in wastewater still restrict its practical applications. Herein, inspired by the melanin in nature, a robust aerogel was facilely fabricated for multifunctional water remediation via a one-pot condensation copolymerization of 5,6-dihydroxyindole and formaldehyde. Benefiting from the superhydrophilicity, underwater superoleophobicity, and synergistic coordination effects, the resulting aerogel not only showed excellent performances in underwater oil resistance and oil-water separation ability, but also removed organic dyes and heavy metal ions contaminants in wastewater simultaneously. Moreover, owing to its admirable light harvesting capacity and porous microstructure for fast water transportation, the aerogel-based evaporator exhibited an excellent evaporation rate of 1.42 kg m-2 h-1 with a 91% evaporation efficiency under 1 sun illumination, which can be reused for long-term water evaporation. Note that such a stable evaporation rate could be maintained even in wastewater containing complex multicomponent contaminants. Outdoor evaporation experiments for lotus pond wastewater under natural sunlight also proved its great potential in practical applications. All those promising features of this all-in-one melanin-inspired aerogel may provide new strategies for the development of robust photothermal devices for multifunctional solar-driven water remediation.

3.
Molecules ; 28(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36677954

RESUMO

MnS has been explored as an anode material for lithium-ion batteries due to its high theoretical capacity, but low electronic conductivity and severe volume change induce low reversible capacity and poor cycling performance. In this work, the nanocapsule consisting of MnS nanopolyhedrons confined in independent, closed and conductive hollow polyhedral nanospheres is prepared by embedding MnCO3 nanopolyhedrons into ZIF-67, followed by coating of RF resin and gaseous sulfurization/carbonization. Benefiting from the unique nanocapsule structure, especially inner CoS/C shell and outer pure C shell, the MnS@CoS/C@C composite as anode material presents excellent cycling performance (674 mAh g-1 at 1 A g-1 after 300 cycles; 481 mAh g-1 at 5 A g-1 after 300 cycles) and superior rate capability (1133.3 and 650.6 mAh g-1 at 0.1 and 4 A g-1), compared to the control materials (MnS and MnS@CoS/C) and other MnS composites. Kinetics measurements further reveal a high proportion of the capacitive effect and low reaction impedance of MnS@CoS/C@C. SEM and TEM observation on the cycled electrode confirms superior structural stability of MnS@CoS/C@C during long-term cycles. Excellent lithium storage performance and the convenient synthesis strategy demonstrates that the MnS@CoS/C@C nanocapsule is a promising high-performance anode material.


Assuntos
Nanocápsulas , Nanosferas , Lítio , Carbono , Eletrodos
4.
Angew Chem Int Ed Engl ; : e202217275, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629025

RESUMO

Alkaline fuel cells can permit the adoption of platinum group metal-free (PGM-free) catalysts and cheap bipolar plates, thus further lowering the cost. With the exploration of PGM-free hydrogen oxidation reaction (HOR) catalysts, nickel-based compounds have been considered as the most promising HOR catalysts in alkali. Here we report an interfacial engineering through the formation of nickel-vanadium oxide (Ni/V2 O3 ) heterostructures to activate Ni for efficient HOR catalysis in alkali. The strong electron transfer from Ni to V2 O3 could modulate the electronic structure of Ni sites. The optimal Ni/V2 O3 catalyst exhibits a high intrinsic activity of 0.038 mA cm-2 and outstanding stability. Experimental and theoretical studies reveal that Ni/V2 O3 interface as the active sites can enable to optimize the hydrogen and hydroxyl bindings, as well as protect metallic Ni from extensive oxidation, thus achieving the notable activity and durability.

5.
Onco Targets Ther ; 16: 17-22, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36698436

RESUMO

For advanced non-small cell lung cancer (NSCLC) patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), tyrosine kinase inhibitors (TKIs) are the standard therapies. However, EGFR germline mutations are extremely rare in lung cancer, and the effective therapy is unclear. This study reports a patient with primary breast and lung cancer carried rare germline EGFR R776H and somatic L861Q mutation, who benefit from EGFR TKIs. Her family cancer history review demonstrated that her three out of four sisters with lung cancer were positive for EGFR R776H. Interestingly, only her healthy sister had type O blood, different from other sisters with type B blood. Our study provides a meaningful insight into the potential treatment option for patients with germline EGFR R776H and somatic L861Q mutation and highlights the importance of next-generation sequencing (NGS) in discovering rare genetic alterations to guide the prevention of genetic disease.

6.
Scand J Gastroenterol ; : 1-7, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604805

RESUMO

BACKGROUND: Gastric adenocarcinoma of the fundic gland type is a new subtype of gastric adenocarcinoma. In 2019, the World Health Organization (WHO) listed gastric adenocarcinoma of the fundic gland type (GA-FG) as a new and rare gastric tumour with a low incidence due to the small number of cumulative cases worldwide. Twenty cases of GA-FG found in our centre were retrospectively analysed to improve the diagnostic ability of endoscopy and pathology in this disease. OBJECTIVE: To investigate the clinicopathological features of fundus-derived gastric tumours and to improve the understanding of and diagnostic accuracy of endoscopy for this disease. METHODS: The clinicopathological characteristics of 20 GA-FG cases between 2018 and 2022 were analysed using clinical and follow-up data and endoscopic, immunohistochemical, and pathological morphology characteristics. RESULTS: In all cases, GA-FG was found in the fundus and the body of the stomach. In total, there were 19 patients with 20 lesions, with most of the patients having a single lesion. One patient had multiple lesions, and another patient had complications from signet ring cell carcinoma (SRCC). All lesions occurred in non-atrophic areas, and 10 patients had gastric fundic gland polyps simultaneously. There were 14 cases of gastric fundus adenocarcinoma and 6 cases of acid-secreting adenoma. Fourteen lesions were treated with endoscopic submucosal dissection (ESD), without recurrence or metastasis during the follow up; 6 patients were followed up for observation, 2 of whom showed no lesions after the first biopsy by gastric endoscopy, and 4 of whom showed no significant changes. CONCLUSIONS: The incidence rate for GA-FG lesions may be underestimated due to their benign course. ESD seems to be an adequate treatment for GA-FG. MAIN POINTS: Gastric adenocarcinoma of the fundic gland type (GA-FG) is located in the fundus and body of the stomach. All lesions occur in non-atrophic areas, and almost one-half involve gastric fundus polyps simultaneously. GA-FG lesions typically follow a benign disease course. ESD seems to be an adequate treatment for GA-FG.

7.
Small Methods ; : e2201156, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36610015

RESUMO

Printed electronics, which fabricate electrical components and circuits on various substrates by leveraging functional inks and advanced printing technologies, have recently attracted tremendous attention due to their capability of large-scale, high-speed, and cost-effective manufacturing and also their great potential in flexible and wearable devices. To further achieve multifunctional, practical, and commercial applications, various printing technologies toward smarter pattern-design, higher resolution, greater production flexibility, and novel ink formulations toward multi-functionalities and high quality have been insensitively investigated. 2D materials, possessing atomically thin thickness, unique properties and excellent solution-processable ability, hold great potential for high-quality inks. Besides, the great variety of 2D materials ranging from metals, semiconductors to insulators offers great freedom to formulate versatile inks to construct various printed electronics. Here, a detailed review of the progress on 2D material inks formulation and its printed applications has been provided, specifically with an emphasis on emerging printed memristors. Finally, the challenges facing the field and prospects of 2D material inks and printed electronics are discussed.

8.
Sci Bull (Beijing) ; 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36681591

RESUMO

The interfacial solar desalination has been considered a promising method to address the worldwide water crisis without sophisticated infrastructures and additional energy consumption. Although various advanced solar evaporators have been developed, their practical applications are still restricted by the unsustainable materials and the difficulty of precise customization for structure to escort high solar-thermal efficiency. To address these issues, we employed two kinds of naturally occurring molecules, tannic acid and iron (III), to construct a low-cost, highly efficient and durable interfacial solar evaporator by three-dimensional (3D) printing. Based on a rational structural design, a robust and 3D-printed evaporator with conical array surface structure was developed, which could promote the light harvesting capacity significantly via the multiple reflections and anti-reflection effects on the surface. By optimizing the height of the conical arrays, the 3D-printed evaporator with tall-cone structure could achieve a high evaporation rate of 1.96 kg m-2 h-1 under one sun illumination, with a photothermal conversion efficiency of 94.4%. Moreover, this evaporator was also proved to possess excellent desalination performance, recycle stability, anti-salt property, underwater oil resistance, as well as adsorption capacity of organic dye contaminants for multipurpose water purification applications. It was believed that this study could provide a new strategy to fabricate low-cost, structural regulated solar evaporators for alleviating the dilemma of global water scarcity using abundant naturally occurring building blocks.

9.
Chemosphere ; 316: 137797, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36634713

RESUMO

Transition metal doped WO3 mixed oxides (named as W-M-O, M = Nb, Fe, Cr, Cu, Ti or Sn, respectively) with high structure stability were synthesized by modified sol-gel method using citric acid as organic crosslinking agent, and were evaluated for catalytic elimination of low-concentration toluene, monochlorobenzene and 1,2-dichloroethance with high toxicity and relatively stable molecule structure, as the typical examples for the pollutants of various volatile organic compounds (VOCs). Results of the structure-property-performance relationship research showed that mesoporous structure and nanocrystalline/amorphous state were formed, and binary metal components were dispersed into each other, which contributed to promoting the metal/metal electron interaction and adjusting the physicochemical properties of mixed metal oxides. The sequence of apparent catalytic activity for toluene degradation was: W-Nb-O>W-Fe-O>W-Cr-O, W-Cu-O>W-Ti-O>W-Sn-O>WO3, and the sequence for monochlorobenzene degradation was: W-Nb-O>W-Fe-O>W-Cr-O, W-Ti-O>W-Cu-O>W-Sn-O>WO3. There existed cooperative catalytic effect: mesopore and surface acid sites of catalysts facilitated adsorption, activation and breakage of the C-X bond, and then redox sites of catalysts promoted deep oxidation of a series of reaction intermediates to transform into CO2 and H2O. Especially, the optimized W-Nb-O catalyst deserved more attention, since it represented remarkable catalytic activity, selectivity and durability for three typical VOCs degradation along with good resistance to water vapor and corrosion of HCl.

10.
Nat Commun ; 14(1): 121, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624102

RESUMO

Vegetation change can alter surface energy balance and subsequently affect the local climate. This biophysical impact has been well studied for forestation cases, but the sign and magnitude for persistent earth greening remain controversial. Based on long-term remote sensing observations, we quantify the unidirectional impact of vegetation greening on radiometric surface temperature over 2001-2018. Here, we show a global negative temperature response with large spatial and seasonal variability. Snow cover, vegetation greenness, and shortwave radiation are the major driving factors of the temperature sensitivity by regulating the relative dominance of radiative and non-radiative processes. Combined with the observed greening trend, we find a global cooling of -0.018 K/decade, which slows down 4.6 ± 3.2% of the global warming. Regionally, this cooling effect can offset 39.4 ± 13.9% and 19.0 ± 8.2% of the corresponding warming in India and China. These results highlight the necessity of considering this vegetation-related biophysical climate effect when informing local climate adaptation strategies.


Assuntos
Mudança Climática , Clima , Temperatura , China , Índia , Ecossistema
11.
Adv Sci (Weinh) ; : e2206176, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36638249

RESUMO

The currently available materials cannot meet the requirements of human thermal comfort against the hot and cold seasonal temperature fluctuations. In this study, a dual-mode Janus film with a bonded interface to gain dual-mode functions of both highly efficient radiative cooling and solar heating for year-round thermal management is designed and prepared. The cooling side is achieved by embedding NaH2 PO2 particles with high infrared radiation (IR) emittance into a porous polymethyl methacrylate (PMMA) film during pore formation process, which is reported for the first time to the knowledge. A synergistic enhancement of NaH2 PO2 and 3D porous structure leads to efficient radiant cooling with high solar reflectance (R̅solar ≈ 92.6%) and high IR emittance (ε̅IR ≈ 97.2%), especially the ε̅IR value is much greater than that of the reported best porous polymer films. In outdoor environments under 750 mW cm-2 solar radiation, the dual-mode Janus film shows subambient cooling temperature of ≈8.8 °C and heating temperature reaching ≈39.3 °C, indicating excellent thermal management capacity. A wide temperature range is obtained only by flipping the dual-mode Janus film for thermal management. This work provides an advanced zero-energy-consumption human thermal management technique based on the high-performance dual-mode integrated Janus film material.

12.
Food Chem ; 410: 135418, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36652800

RESUMO

Polyguluronate (PG) is an acidic homopolymer of α-(1,4)-l-guluronate separated from alginate. In this study, PG was first grafted with soy protein isolate (SPI) through the Maillard reaction to obtain a new glycoprotein (SPI-PG). Then, this novel glycoprotein was used to prepare nanoparticles to encapsulate the resveratrol (RES). Our results showed that SPI-PG-RES had better pH stability, storage stability and ionic stability than SPI-RES. In vitro digestion experiments showed that the RES bioavailability of SPI-PG-RES was much higher than that of free RES and SPI-RES. Furthermore, the in vitro antioxidant capacity of SPI-PG-RES was much stronger than that of free RES and SPI-RES. In addition, SPI-PG-RES was more effective in preventing the symptoms of DSS-induced colitis than RES and SPI-RES. These results suggested that the protein nanoparticles prepared using SPI-PG were a stable and effective hydrophobic polyphenol carrier and could be applied to food-grade components in functional foods and nutritional supplements.

13.
Obes Surg ; 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36656451

RESUMO

BACKGROUND: To demonstrate the association of irisin levels with impaired glucose before and after laparoscopic sleeve gastrectomy (LSG) in patients with obesity. METHODS: Thirty-six patients with obesity undergoing LSG were included. We tested the irisin levels before and after LSG and conducted an evaluation of baseline irisin levels with elevated glucose as well as irisin changes with weight loss and its association with glucose control after LSG. RESULTS: Anthropometric measurements, body fat index, and metabolic parameters were significantly improved in 3 months following LSG (all p < 0.05). Baseline irisin levels were significantly higher in obesity with elevated fasting glucose than that with normal glucose (2.98 [2.37, 3.63] vs. 3.72 [3.06, 5.32], p = 0.031). After adjustment for sex, gender, and body mass index (BMI), obesity with higher irisin levels was prone to have impaired fasting glucose (OR = 2.499, 95% CI = 1.047-5.964). According to receiver operating characteristic curve analysis, the diagnostic accuracy and sensitivity of baseline irisin levels on impaired fasting glucose were 75% and 77.8%. Irisin levels decreased from 3.29 (2.67, 4.43) to 2.82 (2.41, 3.25) ng/mL (p = 0.009) after LSG. The decreases of weight, BMI, and FFA were more in irisin changes group (△irisin ≥ 0.5) than in no irisin changes group (△irisin < 0.5). And △irisin was negatively associated with postprandial glucose (PG) at 3 months after LSG (0.5 h-PG, r = - 0.478, p = 0.029; 2 h-PG, r = - 0.406, p = 0.017). CONCLUSIONS: Elevated baseline irisin levels indicated the impaired glucose in obesity. The decrease of irisin with weight loss provided more evidence for the contribution of serum irisin secretion by fat mass in obesity.

14.
Arch Virol ; 168(2): 60, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629974

RESUMO

The intron-based stabilization approach is a very useful strategy for construction of stable flavivirus infectious clones. SA14-14-2 is a highly attenuated Japanese encephalitis (JE) live vaccine strain that has been widely used in China since 1989. To develop safe and effective recombinant vaccines with SA14-14-2 as a backbone vector, we constructed the DNA-based infectious clone pCMW-JEV of SA14-14-2 using the intron-based stabilization approach and acquired the rescued virus rDJEV, which retained the biological properties of the parental virus. Unexpectedly, a rescued virus strain with altered virulence, designated rHV-DJEV, was accidentally acquired in one of the transfection experiments. rHV-DJEV showed up to 105-fold increased neurovirulence compared with the SA14-14-2 parental strain. Genome sequencing showed that the inserted introns were still present in the genome of rHV-DJEV. Therefore, we think that the intron-based stabilization approach should be used with caution in vaccine development and direct iDNA immunization.


Assuntos
Vírus da Encefalite Japonesa (Espécie) , Vacinas contra Encefalite Japonesa , Humanos , Sequência de Bases , Vírus da Encefalite Japonesa (Espécie)/genética , Encefalite Japonesa/prevenção & controle , Genoma Viral , Íntrons , Vacinas contra Encefalite Japonesa/genética , Vacinas Atenuadas/genética
15.
J Colloid Interface Sci ; 636: 184-193, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36634390

RESUMO

The electrocatalytic nitrogen reduction reaction (eNRR) to ammonia (NH3) has been recognized as an effective, carbon-neutral, and great-potential strategy for ammonia production. However, the conversion efficiency and selectivity of eNRR still face significant challenges due to the slow transfer kinetics and lack of effective N2 adsorption and activation sites in this process. Herein, we designed and fabricated defect-rich TiO2 nanosheets furnished with oxygen vacancies (OVs) and Au nanoparticles (Au/TiO2-x) as the electrocatalyst for efficient N2-fixing. The experimental results demonstrate that OVs act as active sites, which enable efficient chemisorption and activation of N2 molecules. The Au nanoparticles loaded on the OVs-rich TiO2 nanosheets not only accelerate charge transfer but also change the local electronic structure, thus enhancing N2 adsorption and activation. In this work, the optimal Au/TiO2-x electrocatalyst displays a considerable NH3 yield activity of 12.5 µg h-1 mgcat.-1 and a faradaic efficiency (FE) of 10.2 % at -0.40 V vs reversible hydrogen electrode (RHE). More importantly, the Au/TiO2-x exhibits a stable N2-fixing activity in cycling and it persists even after 80 h of consecutive electrolysis. Density functional theory (DFT) calculations reveal that the OVs serve as the active sites in TiO2, while Au nanoparticles are crucial for improving N2 chemisorption and lowering the reaction energy barrier by facilitating the charge transfer for eNRR with a distal hydrogenation pathway. This research offers a rational catalytic site design for modulating charge transfer of active sites on metal-supported defective catalysts to boost N2 electroreduction to NH3.

16.
Chem Commun (Camb) ; 59(5): 615-618, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36533586

RESUMO

We report here our findings on the diverse reaction results of sulfones and alcohols. In the presence of NiCl2/P(t-Bu)3 and under a N2 atmosphere, α-C-alkylation of sulfones with alcohols occurs through a borrowing-hydrogen mechanism; when the reaction was carried out in the open air without nickel, the product was not the predicted α,ß-unsaturated sulfone, but the ß-alkenyl sulfone, which is a useful building block in organic synthesis.

17.
Chem Biodivers ; 20(1): e202200871, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36529680

RESUMO

Seven benzophenanthridine alkaloids (1-7) were obtained from the 75 % EtOH extract of Eomecon chionantha, and exhibited moderate biological activity against MCF-7 cells. 8,12-dimethoxysanguinarine (1, DSG) strongly decreased the cell viability of MCF-7 cell lines with an IC50 value of 7.12 µΜ. Based on RNA-sequencing measure and KEGG pathway enrichment analysis results, the significant differentially expressed genes (DEGs) were associated with Pathways in Cancer and PI3 K-AKT signaling pathways in DSG treated group. The potential molecular regulatory mechanisms underlying the effect of DSG induces necroptosis in MCF-7 cells via molecular docking, TEM analysis, and ROS measurement. Besides, DEGs of bone metastasis-related genes such as PI3 K, IGF1R, Notch, and Wnt mRNA were significantly downregulated in the DSG-treated group on MCF-7 cells. DSG might be selected as a bone metastasis proteins inhibitor of IL-1ß, IL-6, IκBα, IGF1R, Notch, NF-κB, PTHrp, PI3 K, PKB/AKT, PTEN, TNF-α, and Wnt via molecular docking. DSG suppressed bone metastasis by regulating the expression levels of IL-1ß, IL-6, PTH, CROSS, TP1NP, and OSTEOC on MCF-7 cells using ELISA measurement. Thus, our findings reveal that DSG could be a lead compound for suppressing tumor cells to bone metastasis in breast cancer cells.


Assuntos
Alcaloides , Antineoplásicos , Humanos , Células MCF-7 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Benzofenantridinas/farmacologia , Interleucina-6 , Simulação de Acoplamento Molecular , Alcaloides/farmacologia , Antineoplásicos/farmacologia
18.
Genomics ; 115(1): 110540, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36563917

RESUMO

Non-coding RNAs (ncRNAs) induced competing endogenous RNAs (ceRNA) play crucial roles in various biological process by regulating target gene expression. However, the studies of ceRNA networks in the regulation of ovarian ovulation processing of chicken remains deficient compared to that in mammals. Our present study revealed that circEML1 was differential expressed in hen's ovarian tissues at different ages (15 W/20 W/30 W/68 W) and identified as a loop structure from EML1 pre-mRNA, which promoted the expressions of CYP19A1/StAR and E2/P4 secretion in follicular granulosa cells (GCs). Furthermore, circEML1 could serve as a sponge of gga-miR-449a and also found that IGF2BP3 was targeted by gga-miR-449a to co-participate in the steroidogenesis, which possibly act the regulatory role via mTOR/p38MAPK pathways. Meanwhile, in the rescue experiment, gga-miR-449a could reverse the promoting role of circEML1 to IGF2BP3 and steroidogenesis. Eventually, this study suggested that circEML1/gga-miR-449a/IGF2BP3 axis exerted an important role in the steroidogenesis in GCs of chicken.


Assuntos
Galinhas , MicroRNAs , Animais , Feminino , Galinhas/genética , Galinhas/metabolismo , Células da Granulosa , Mamíferos/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Ovário/metabolismo , Esteroides/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo
19.
Eur J Med Chem ; 247: 115013, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36566714

RESUMO

Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in multiple hormone related cancers, such as breast and prostate cancer, and is correlated with tumor development and aggressiveness. As a phase I biotransformation enzyme, AKR1C3 catalyzes the metabolic processes that lead to resistance to anthracyclines, the "gold standard" for breast cancer treatment. Novel approaches to restore the chemotherapy sensitivity of breast cancer are urgently required. Herein, we developed a new class of AKR1C3 inhibitors that demonstrated potent inhibitory activity and exquisite selectivity for closely related isoforms. The best derivative 27 (S19-1035) exhibits an IC50 value of 3.04 nM for AKR1C3 and >3289-fold selectivity over other isoforms. We determined the co-crystal structures of AKR1C3 with three of the inhibitors, providing a solid foundation for further structure-based drug optimization. Co-administration of these AKR1C3 inhibitors significantly reversed the doxorubicin (DOX) resistance in a resistant breast cancer cell line. Therefore, the novel AKR1C3 specific inhibitors developed in this work may serve as effective adjuvants to overcome DOX resistance in breast cancer treatment.


Assuntos
Neoplasias da Mama , Masculino , Humanos , Neoplasias da Mama/tratamento farmacológico , Preparações Farmacêuticas , Hidroxiprostaglandina Desidrogenases/química , Hidroxiprostaglandina Desidrogenases/metabolismo , 3-Hidroxiesteroide Desidrogenases/metabolismo , Membro C3 da Família 1 de alfa-Ceto Redutase , Antibióticos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química
20.
Brain Res ; 1798: 148132, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341903

RESUMO

Ischemic stroke is the leading cause of death and disability worldwide. The activation of gamma-aminobutyric acid A (GABAA) receptors can attenuate cerebral ischemia-reperfusion injury (CI/RI). Boropinol-B, originally isolated from Boronia pinnata Sm. (Rutaceae), has been proved the ability to activate GABAA receptors synergistically. However, whether boropinol-B has neuroprotection in CI/RI remains unknown. Here we reported the neuroprotective effect of boropinol-B on CI/RI and its underlying mechanism, focusing on inhibiting inflammation and apoptosis. The oxygen and glucose deprivation and reperfusion (OGD/R) cell model showed that boropinol-B could improve cell viability, mitigate cell injury, and inhibit apoptosis. In rats, the transient ischemic model was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. Our results indicated that boropinol-B improved neurological scores, reduced cerebral infarction and neuronal necrosis of rats 24 h after ischemia, and prolonged median survival time after continuous administration for 14 days. Furthermore, we found that boropinol-B inhibited the over-activation of microglia and astrocytes, reduced the release of pro-inflammatory factors, and down-regulated the expression of matrix metalloproteinases-3/9, thus alleviating cerebral edema and blood-brain barrier dysfunction. Also, it suppressed apoptosis by increasing Bcl-2 expression and decreasing the expression of Bax, Active Caspase-3, and Cytochrome C. In conclusion, boropinol-B demonstrated anti-inflammatory and anti-apoptotic properties that contributed to the neuroprotective effect against CI/RI, suggesting that it may be an up-and-coming drug candidate to treat ischemic stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Ratos , Animais , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Apoptose , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ácido gama-Aminobutírico/farmacologia
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