RESUMO
Three undescribed limonoids (1-3), named aglaians G-I, and one new natural product azedaralide (4), together with nine known analogues (5-13) were isolated from the branches and leaves of Aglaia lawii by RP C18 column, silica gel column, Sephadex LH-20 column chromatography and preparative HPLC. The structures of the new compounds were elucidated by IR, HRESIMS, 1D, 2D NMR, electronic circular dichroism (ECD) calculations and X-ray crystallography diffraction analysis. The results of bioassay showed that the compound 12 exhibited potential inhibitory activity against six human tumor cell lines (MDA-MB-231, MCF-7, Ln-cap, A549, HeLa and HepG-2) with IC50 values as 8.0-18.6â µM.
Assuntos
Aglaia , Antineoplásicos , Limoninas , Humanos , Aglaia/química , Limoninas/farmacologia , Limoninas/química , Estrutura Molecular , Linhagem Celular TumoralRESUMO
The phytochemical study of Peucedanum praeruptorum led to the isolation of twenty-five coumarins (1-25). Of which, (±) praeruptol A (±1), one pair of previous undescribed seco-coumarin enantiomers were obtained. Their structures were established according to HR-ESI-MS, NMR, X-ray single crystal diffraction analysis, as well as ECD calculation. All compounds were tested for anti-inflammatory activity in the RAW264.7 macrophage model, and eight compounds (7-10, and 13-16) exhibited significant inhibitory effects with IC50 values ranging from 9.48 to 34.66â µM. Among them, compound 7 showed the strongest inhibitory effect, which significantly suppressed the production of IL-6, IL-1ß, and TNF-α, as well as iNOS and COX-2 in a concentration-dependent manner. Further investigated results showed that compound 7 exerted an anti-inflammatory effect via the NF-κB signaling pathway.
Assuntos
Cumarínicos , NF-kappa B , NF-kappa B/metabolismo , Cumarínicos/farmacologia , Cumarínicos/metabolismo , Anti-Inflamatórios/farmacologia , Extratos Vegetais/química , Transdução de Sinais , Lipopolissacarídeos/farmacologiaRESUMO
Afterglow materials-based biological imaging has promising application prospects, due to negligible background. However, currently available afterglow materials mainly include inorganic materials as well as some organic nanoparticles, which are difficult to translate to the clinic, resulting from non-negligible metabolic toxicity and even leakage risk of inorganic heavy metals. Although building small organic molecules could solve such obstacles, organic small molecules with afterglow ability are extremely scarce, especially with a sufficient renal metabolic capacity. To address these issues, herein, we designed water-soluble zwitterion Cy5-NF with renal metabolic capacity and afterglow luminescence, which relied on an intramolecular cascade reaction between superoxide anion (O2â¢-, instead of 1O2) and Cy5-NF to release afterglow luminescence. Of note, compared with different reference contrast agents, zwitterion Cy5-NF not only had excellent afterglow properties but also had a rapid renal metabolism rate (half-life period, t1/2, around 10 min) and good biocompatibility. Unlike prior afterglow nanosystems possessing a large size, for the first time, zwitterion Cy5-NF has achieved the construction of water-soluble renal metabolic afterglow contrast agents, which showed higher sensitivity and signal-to-background ratio in afterglow imaging than fluorescence imaging for the kidney. Moreover, zwitterion Cy5-NF had a longer kidney retention time in renal-failure mice (t1/2 more than 15 min). More importantly, zwitterion Cy5-NF can be metabolized very quickly even in severe renal-failure mice (t1/2 around 25-30 min), which greatly improved biosecurity. Therefore, we are optimistic that the O2â¢--mediated afterglow mechanism-based water-soluble zwitterion Cy5-NF is very promising for clinical application, especially rapid detection of kidney failure.
Assuntos
Insuficiência Renal , Superóxidos , Animais , Camundongos , Água , Meios de ContrasteRESUMO
Global warming has profound impact on growth and development, and plants constantly adjust their internal circadian clock to cope with external environment. However, how clock-associated genes fine-tune thermoresponsive growth in plants is little understood. We found that loss-of-function mutation of REVEILLE5 (RVE5) reduces the expression of circadian gene EARLY FLOWERING 4 (ELF4) in Arabidopsis, and confers accelerated hypocotyl growth under warm-temperature conditions. Both RVE5 and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) accumulate at warm temperatures and bind to the same EE cis-element presented on ELF4 promoter, but the transcriptional repression activity of RVE5 is weaker than that of CCA1. The binding of CCA1 to ELF4 promoter is enhanced in the rve5-2 mutant at warm temperatures, and overexpression of ELF4 in the rve5-2 mutant background suppresses the rve5-2 mutant phenotype at warm temperatures. Therefore, the transcriptional repressor RVE5 finetunes ELF4 expression via competing at a cis-element with the stronger transcriptional repressor CCA1 at warm temperatures. Such a competition-attenuation mechanism provides a balancing system for modulating the level of ELF4 and thermoresponsive hypocotyl growth under warm-temperature conditions.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Relógios Circadianos , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Temperatura , Regulação da Expressão Gênica de Plantas , Arabidopsis/metabolismo , Hipocótilo , Relógios Circadianos/genética , Ritmo Circadiano/genéticaRESUMO
Global climate change has great impacts on plant growth and development, reducing crop productivity worldwide. Rice (Oryza sativa L.), one of the world's most important food crops, is susceptible to high-temperature stress from seedling stage to reproductive stage. In this review, we summarize recent advances in understanding the molecular mechanisms underlying heat stress responses in rice, including heat sensing and signalling, transcriptional regulation, transcript processing, protein translation, and post-translational regulation. We also highlight the irreversible effects of high temperature on reproduction and grain quality in rice. Finally, we discuss challenges and opportunities for future research on heat stress responses in rice.
Assuntos
Oryza , Oryza/fisiologia , Resposta ao Choque Térmico , Temperatura Alta , Reprodução , Grão ComestívelRESUMO
The present study aimed to explore the main active components and potential mechanisms of Panax notoginseng saponins(PNS) and osteopractic total flavone(OTF) in the treatment of osteoporosis(OP) through network pharmacology, molecular docking and in vitro cell experiments, which was expected to provide a theoretical basis for clinical applications. The blood-entering components of PNS and OTF were obtained from literature search and online database, and their potential targets were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The OP targets were obtained by means of searching Online Mendelian Inheritance in Man(OMIM) and GeneCards. The common targets of the drug and disease were screened by Venn. Cytoscape was used to construct a "drug-component-target-disease" network, and the core components were screened according to the node degree. The protein-protein interaction(PPI) network of the common targets was constructed by STRING and Cytoscape, and the core targets were screened according to the node degree. GO and KEGG enrichment analysis of potential therapeutic targets were carried out by R language. Molecular docking was used to determine the binding activity of some active components to key targets by AutoDock Vina. Finally, HIF-1 signaling pathway was selected for in vitro experimental verification according to the results of KEGG pathway analysis. Network pharmacology showed that there were 45 active components such as leachianone A, kurarinone, 20(R)-protopanaxatriol, 20(S)-protopanaxatriol, and kaempferol, and 103 therapeutic targets such as IL6, AKT1, TNF, VEGFA and MAPK3 involved. PI3K-AKT, HIF-1, TNF and other signaling pathways were enriched. Molecular docking revealed that the core components had good binding ability to the core targets. In vitro experiments found that PNS-OTF could up-regulate the mRNA expression levels of HIF-1α, VEGFA and Runx2, indicating that the mechanism of PNS-OTF in treating OP may be related to the activation of HIF-1 signaling pathway, and thus PNS-OTF played a role in promoting angiogenesis and osteogenic differentiation. In conclusion, this study predicted the core targets and pathways of PNS-OTF in treating OP based on network pharmacology and carried out in vitro experimental verification, which reflected the characteristics of multi-component, multi-target and multi-pathway synergy of PNS-OTF, and provided new ideas for the future clinical treatment of OP.
Assuntos
Farmacologia em Rede , Osteoporose , Humanos , Simulação de Acoplamento Molecular , Osteogênese , Fosfatidilinositol 3-Quinases , Bases de Dados GenéticasRESUMO
The chloroplast is essential for photosynthesis, plant growth and development. As semiautonomous organelles, the biogenesis and development of chloroplasts need to be well-regulated during plant growth and stress responses. Low or high ambient temperatures are adverse environmental stresses that affect crop growth and productivity. As sessile organisms, plants regulate the development and function of chloroplasts in a fluctuating temperature environment to maintain normal photosynthesis. This review focuses on the molecular mechanisms and regulatory factors required for chloroplast biogenesis and development under cold or heat stress conditions and highlights the importance of chloroplast gene transcription, RNA metabolism, ribosome function and protein homeostasis essential for chloroplast development under adverse temperature conditions.
Assuntos
Cloroplastos , Regulação da Expressão Gênica de Plantas , Cloroplastos/metabolismo , Fotossíntese/fisiologia , Plantas/genética , Plantas/metabolismo , TemperaturaRESUMO
BACKGROUND: Nanovaccines have shown the promising potential in controlling and eradicating the threat of infectious diseases worldwide. There has been a great need in developing a versatile strategy to conveniently construct diverse types of nanovaccines and induce potent immune responses. To that end, it is critical for obtaining a potent self-adjuvant platform to assemble with different types of antigens into nanovaccines. RESULTS: In this study, we identified a new natural polysaccharide from the rhizomes of Bletilla striata (PRBS), and used this polysaccharide as a platform to construct diverse types of nanovaccines with potent self-adjuvant property. In the construction process of SARS-CoV-2 nanovaccine, PRBS molecules and RBD protein antigens were assembled into ~ 300 nm nanoparticles by hydrogen bond. For HIV nanovaccine, hydrophobic effect dominantly drove the co-assembly between PRBS molecules and Env expression plasmid into ~ 350 nm nanospheres. Importantly, PRBS can potently activate the behaviors and functions of multiple immune cells such as macrophages, B cells and dendritic cells. Depending on PRBS-mediated immune activation, these self-adjuvant nanovaccines can elicit significantly stronger antigen-specific antibody and cellular responses in vivo, in comparison with their corresponding traditional vaccine forms. Moreover, we also revealed the construction models of PRBS-based nanovaccines by analyzing multiple assembly parameters such as bond energy, bond length and interaction sites. CONCLUSIONS: PRBS, a newly-identified natural polysaccharide which can co-assemble with different types of antigens and activate multiple critical immune cells, has presented a great potential as a versatile platform to develop potent self-adjuvant nanovaccines.
Assuntos
COVID-19 , Nanopartículas , Adjuvantes Imunológicos/química , COVID-19/prevenção & controle , Humanos , Imunidade , Nanopartículas/química , Polissacarídeos , SARS-CoV-2RESUMO
The circadian clock maintains the daily rhythms of plant growth and anticipates predictable ambient temperature cycles. The evening complex (EC), comprising EARLY FLOWERING 3 (ELF3), ELF4, and LUX ARRHYTHMO, plays an essential role in suppressing thermoresponsive hypocotyl growth by negatively regulating PHYTOCHROME INTERACTING FACTOR 4 (PIF4) activity and its downstream targets in Arabidopsis thaliana. However, how EC activity is attenuated by warm temperatures remains unclear. Here, we demonstrate that warm temperature-induced REVEILLE 7 (RVE7) fine-tunes thermoresponsive growth in Arabidopsis by repressing ELF4 expression. RVE7 transcript and RVE7 protein levels increased in response to warm temperatures. Under warm temperature conditions, an rve7 loss-of-function mutant had shorter hypocotyls, while overexpressing RVE7 promoted hypocotyl elongation. PIF4 accumulation and downstream transcriptional effects were reduced in the rve7 mutant but enhanced in RVE7 overexpression plants under warm conditions. RVE7 associates with the Evening Element in the ELF4 promoter and directly represses its transcription. ELF4 is epistatic to RVE7, and overexpressing ELF4 suppressed the phenotype of the RVE7 overexpression line under warm temperature conditions. Together, our results identify RVE7 as an important regulator of thermoresponsive growth that functions (in part) by controlling ELF4 transcription, highlighting the importance of ELF4 for thermomorphogenesis in plants.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Relógios Circadianos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Relógios Circadianos/genética , Ritmo Circadiano/genética , Regulação da Expressão Gênica de Plantas/genética , Hipocótilo/metabolismo , Temperatura , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
In the present study, antagonistic activity of bacterial strain BS-Z15, was evaluated against Verticillium dahlia. The fermented broth of BS-Z15 inhibited the growth of Verticillium dahliae. The genome of strain BS-Z15 had a total size of 4,068,702 base pairs and contained 4318 genes, of which 4196 are coding sequences and 122 are non-coding RNA. Among these genes, nine genomic islands, 86 tRNAs, 13 sRNAs, and one prophage was determined. With the help of annotation databases, most unigene functions were identified. At the same time, genomic comparison between BS-Z15 and 12 Bacillus members showed that the genes of BS-Z15 were closely related to the Bacillus group, and were conserved between the two groups, including most of the genes associated with fungal antagonism. BS-Z15 contains genes involved in a variety of antagonistic mechanisms, including genes encoding or synthesizing mycosubtilin, chitinases (but not CHIA and CHIB), glycoside hydrolases, iron nutrients, and antibiosis. However, it only contained the complete mycosubtilin- and bacilibactin-related operators in the reported main antifungal gene cluster of B. subtilis. Mycosubtilin and bacilibactin may be the main active antifungal substance. Besides, some genes could encode products related to biofilm production, which may be related to the colonization ability of the strain in plant rhizospheres. The complete genome of B. subtilis BS-Z15 provided new insights into the potential metabolites it produces related to its biocontrol activity.
Assuntos
Antibiose , Ascomicetos , Bacillus , Genoma Bacteriano , Microbiologia do Solo , Bacillus/genética , Genoma Bacteriano/genética , Gossypium/microbiologia , RizosferaRESUMO
The editorial group of the clinical practice guideline for postmenopausal osteoporosis(PMOP) with traditional Chinese medicine(TCM)(hereinafter referred to as "guideline") is composed of experts specialized in TCM orthopedics, TCM gynecology, clinical epidemiology, etc. The guideline was formulated through registration, collection and selection of clinical issues/outcome indicators, evidence retrieval and screening, preparation of systematic reviews, evaluation of evidence quality, formation of recommendations, drafting, and peer review. The syndromes and treatment of PMOP are elaborated in detail. Specifically, Liuwei Dihuang Pills and Zuogui Pills are recommended for PMOP with Yin deficiency in the liver and kidney, Qing'e Pills for PMOP with kidney deficiency and blood stasis, Yougui Pills and Jingui Shenqi Pills for PMOP with Yang deficiency in the spleen and kidney, and Er'xian Decoction for PMOP with Yin and Yang deficiency in the kidney. In addition, Duhuo Jisheng Decoction can be used to relieve pain. The commonly used Chinese patent medicines include Xianling Gubao Capsules, Qianggu Capsules, Jintiange Capsules, Gushukang Capsules, Hugu Capsules, Jinwu Gutong Capsules, and Guyuling Capsules. Acupuncture and moxibustion are also effective approaches for PMOP. The rehabilitation and daily management were carried out by exercise therapies such as Baduanjin(eight-section brocade), Wuqinxi(five-animal exercises), and Taijiquan(Tai Chi), Chinese medicine diet, health education, and fall prevention. The promotion and application of this guideline will facilitate the implementation of TCM prevention and treatment of PMOP, ensure the quality of life of PMOP patients, provide effective and safe TCM treatment measures for PMOP, and reduce the risk of fracture complications.
Assuntos
Medicamentos de Ervas Chinesas , Osteoporose Pós-Menopausa , Animais , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Medicina Tradicional Chinesa , Osteoporose Pós-Menopausa/tratamento farmacológico , Qualidade de Vida , Revisões Sistemáticas como Assunto , Deficiência da Energia YinRESUMO
PURPOSE: To determine the ability of nonperfusion, vessel density, and morphologic measurements using projection-resolved optical coherence tomography angiography to detect early retinal microvasculature impairments in diabetes mellitus. METHODS: A retrospective review was performed on Type 2 diabetes mellitus patients with no diabetic retinopathy (DR) or mild nonproliferative DR and age-matched controls imaged with optical coherence tomography angiography. Foveal avascular zone-related metrics and extrafoveal avascular area were measured in optical coherence tomography angiography images. Vessel density and fractal dimension were calculated with and without a skeletonization process. The vessel diameter index and vessel tortuosity were computed. The area under the receiver operating characteristic curve (AUC) estimated diagnostic performances. RESULTS: Dilated capillary diameter was observed in the deep capillary plexus in the diabetic groups. Vessel density and fractal dimension of skeletonized deep capillary plexus significantly and progressively decreased in the no DR and mild nonproliferative DR groups compared with controls. Superficial extrafoveal avascular area, vessel density, and fractal dimension of the skeletonized deep capillary plexus had the highest diagnostic performance to differentiate mild nonproliferative DR from control eyes, with AUCs of 0.885, 0.876, and 0.876, respectively. CONCLUSION: Vessel density and fractal dimension from the skeletonized deep capillary network may be the most sensitive for detecting early retinal capillary loss in diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Retinopatia Diabética/diagnóstico , Vasos Retinianos/patologia , Idoso , Área Sob a Curva , Diabetes Mellitus Tipo 2/fisiopatologia , Retinopatia Diabética/fisiopatologia , Diagnóstico Precoce , Feminino , Angiofluoresceinografia , Fóvea Central/irrigação sanguínea , Humanos , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Curva ROC , Vasos Retinianos/diagnóstico por imagem , Estudos Retrospectivos , Tomografia de Coerência ÓpticaRESUMO
The stems of Dryopteris crassirhizoma, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin ABBA is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin ABBA and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6%. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6⯵M), it was very exciting that dryocrassin ABBA and its analogues (b5 and e2) showed better NAs inhibitory activity against Anhui H7N9 with IC50 values of 3.6⯵M, 2.5⯵M and 1.6⯵M. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin ABBA and its analogues especially AB, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.
Assuntos
Antivirais/farmacologia , Compostos de Benzilideno/farmacologia , Cicloexanonas/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Subtipo H7N9 do Vírus da Influenza A/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Cicloexanonas/síntese química , Cicloexanonas/química , Relação Dose-Resposta a Droga , Dryopteris/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Subtipo H7N9 do Vírus da Influenza A/enzimologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: During the last decade buckwheat was reported to have positive health effects. The present study investigated a high-polyphenol buckwheat protein (Fagopyrum esculentum Moench) prepared by enzyme-assisted processing, together with its physicochemical properties, in vitro digestibility, and antioxidant activity. RESULTS: Buckwheat protein prepared from the synergistic enzymatic action of α-amylase and amyloglucosidase (E-BWP) had much higher polyphenol content than buckwheat protein prepared by isoelectric precipitation (I-BWP) or salt extraction (S-BWP). Rutin degraded during the process, giving quercetin. The protein constituents and amino acid composition of E-BWP were very similar to those of native buckwheat and were able to meet the WHO/FAO requirements for both children and adults. During in vitro digestion, E-BWP showed anti-digestive behavior with a nitrogen release that was lower than that of I-BWP or S-BWP. The positive effect of the polyphenol content of E-BWP resulted in a higher 1,1-diphenyl-2-picrylhydrazyl (DPPH) content and greater reducing activity. CONCLUSION: Buckwheat protein with high polyphenol content was successfully developed by enzyme-assisted processing. It had a well-balanced amino acid profile, antidigestive behavior, and high antioxidant activities. The results suggest that enzyme-assisted processing is promising in the production of polyphenol-enriched cereal protein, contributing higher functionality with good nutritional and antioxidant properties. © 2018 Society of Chemical Industry.
Assuntos
Antioxidantes/química , Fagopyrum/química , Fagopyrum/metabolismo , Glucana 1,4-alfa-Glucosidase/química , Proteínas de Plantas/química , Polifenóis/análise , alfa-Amilases/química , Antioxidantes/metabolismo , Biocatálise , Digestão , Manipulação de Alimentos , Humanos , Proteínas de Plantas/metabolismo , Polifenóis/metabolismo , Sementes/química , Sementes/metabolismoRESUMO
In this study, furbiprofen/hydroxypropyl-ß-cyclodextrin (HPßCD) inclusion complexes were prepared to improve the drug dissolution and facilitate its application in hydrophilic gels. Inclusion complexes were prepared using a supercritical fluid processing and a conventional optimized co-lypholization method was employed as a reference. The entrapment efficacy and drug loading of both methods were investigated. Evaluation of drug dissolution enhancement was conducted in deionized water as well as buffer solutions of different pH. Carbopol 940 gels of both flurbiprofen and flurbiprofen/HPßCD inclusion complexes, with or without penetration enhancers, were prepared and percutaneous permeation studies were performed using rat abdominal skin samples. Formation of flurbiprofen/HPßCD inclusion complexes was confirmed by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The results obtained showed that SCF processing produced a higher EE (81.91 ± 1.54%) and DL (6.96 ± 0.17%) compared with OCL with values of 69.11 ± 2.23% and 4.00 ± 1.01%, respectively. A marked instantaneous release of flurbiprofen/HPßCD inclusion complexes prepared by SCF processing (103.04 ± 2.66% cumulative release within 5 min, a 10-fold increase in comparison with flurbiprofen alone) was observed. In addition, this improvement in dissolution was shown to be pH-independent (the percentage cumulative release at pH 1.2, 4.5, 6.8 and 7.4 at 5 min was 95.19 ± 1.71, 101.75 ± 1.44, 105.37 ± 4.58 and 96.84 ± 0.56, respectively). Percutaneous permeability of flurbiprofen-in-HPßCD-in-gels could be significantly accelerated by turpentine oil and was related to the water content in the system. An in vivo pharmacokinetic study showed a 2-fold increase in Cmax and a shortened Tmax as well as a comparable relative bioavailability when compared with the commercial flurbiprofen Cataplasms (Zepolas®). With their superior dissolution, these flurbiprofen/HPßCD inclusion complexes prepared by SCF processing could provide improved applications for flurbiprofen.
Assuntos
Flurbiprofeno/química , Flurbiprofeno/farmacocinética , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Química Farmacêutica , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Varredura , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
OBJECTIVE: To study the clinical effect endoscopic realignment with drainage via a peel-away sheath in the treatment of urethral rupture. METHODS: We treated 21 urethral rupture patients by endoscopic realignment with drainage via a peel-away sheath using normal saline for irrigation under the normal nephroscope or Li Xun nephroscope, followed by analysis of the clinical results. RESULTS: The operation was successfully accomplished in 20 cases but failed in 1 and none experienced urinary extravasation. In the 14 cases of bulbar urethral rupture, the mean operation time was (5.1±1.6) min and the mean Foley catheter indwelling time was (26.0±5.1) d. Urethral stricture developed in 57.1% (8/14) of the cases after catheter removal, of which 1 was cured by internal urethrotomy and the other 7 by urethral sound dilation, with an average maximum urinary flow rate of (18.8±1.8) ml/s at 12 months after operation. In the 6 cases of posterior urethral rupture, the mean operation time was (15.8±7.5) min and the mean Foley catheter indwelling time was 8 weeks. Urethral stricture developed in all the 6 cases after catheter removal, of which 3 cases were cured by urethral dilation, 1 by internal urethrotomy, and 2 by open urethroplasty. The average maxium urinary flow rate of the 4 cases exempt from open surgery was (17.9±1.9) ml/s at 12 months after operation. CONCLUSIONS: Endoscopic realignment with drainage via a peel-away sheath can keep the operative field clear, avoid intraoperative rinse extravasation, shorten the operation time, improve the operation success rate, and achieve satisfactory early clinical outcomes in the treatment of either bulbar or posterior urethral rupture.
Assuntos
Drenagem , Endoscopia , Ruptura/cirurgia , Uretra/lesões , Remoção de Dispositivo , Humanos , Duração da Cirurgia , Resultado do Tratamento , Estreitamento Uretral/etiologia , Cateterismo UrinárioRESUMO
OBJECTIVE: To investigate the effect of FCGR3A polymorphisms on the antibody-dependent cell-mediated cytotoxicity (ADCC) activity induced by cetuximab against A549 cells. METHODS: A549 cell line was used as target cells and NKTm cells as effector cells. FCGR3A polymorphisms were detected by direct sequencing. The ADCC activity mediated by cetuximab was assessed by CCK-8 assay. RESULTS: Three genotypes of FCGR3A were detected:V/V,V/F,and F/F. The ADCC activity of NKTm cells with these three different genotypes mediated by cetuximab were significantly different (P=0.0015). NKTm cells with FCGR3A-158V/V genotypes had significantly higher ADCC activity than FCGR3A-V/F or F/F genotypes (P<0.01),whereas the ADCC activity between V/F and F/F genotype showed no statistical significance(P>0.05). CONCLUSION: FCGR3A polymorphisms have an impact on ADCC activity mediated by cetuximab in NKTm cells.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos , Polimorfismo Genético , Linhagem Celular Tumoral , Cetuximab , Genótipo , Humanos , Receptores de IgGRESUMO
OBJECTIVE: To investigate the role of epidermal growth factor receptor (EGFR) expression level in cetuximab cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) effect against A549 lung cancer cell line. METHODS: A549 cell line and NKTm cells were used as the target cell and the effector cell, respectively. pEGFR-EGFP plasmids were transfected into A549 cells by nucleofector method. EGFR expression levels were measured by immunohistochemistry. The ADCC activity induced by cetuximab was assessed by cell counting kit-8 assay. RESULTS: A549 cells transfected with pEGFR-EGFP plasmids expressed higher level of EGFR protein on membrane and were more sensitive to ADCC activity mediated by cetuximab (P<0.05). The inhibition rate of A549 cells showed no significant difference between transfection group and wild-type group when treated with cetuximab alone (P> 0.05). CONCLUSION: EGFR expression level influences the sensitivity of A549 lung cancer cell line to ADCC activity mediated by cetuximab but not to cetuximab alone.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Receptores ErbB/metabolismo , Neoplasias Pulmonares/patologia , Adenocarcinoma/patologia , Cetuximab , Humanos , Imuno-Histoquímica , Células Tumorais CultivadasRESUMO
The heterogeneity of hepatocellular carcinoma (HCC) and the complexity of the tumor microenvironment (TME) pose challenges to efficient drug delivery and the antitumor efficacy of combined or synergistic therapies. Herein, a metal-coordinated carrier-free nanodrug (named as USFe3+ LA NPs) was developed for ferroptosis-mediated multimodal synergistic anti-HCC. Natural product ursolic acid (UA) was incorporated to enhance the sensitivity of tumor cells to sorafenib (SRF). Surface decoration of cell penetration peptide and epithelial cell adhesion molecule aptamer facilitated the uptake of USFe3+ LA NPs by HepG2 cells. Meanwhile, Fe3+ ions could react with intracellular hydrogen peroxide, generating toxic hydroxyl radical (·OH) for chemodynamical therapy (CDT) and amplified ferroptosis by cystine/glutamate antiporter system (System Xc-), which promoted the consumption of glutathione (GSH) and inhibited the expression of glutathione peroxidase 4 (GPX4). Notably, these all-in-one nanodrugs could inhibit tumor metastasis and induced immunogenic cell death (ICD). Last but not least, the nanodrugs demonstrated favorable biocompatibility, augmenting the immune response against the programmed death-ligand 1 (PD-L1) by increasing cytotoxic T cell infiltration. In vivo studies revealed significant suppression of tumor growth and distant metastasis. Overall, our work introduced a novel strategy for applications of metal-coordinated co-assembled carrier-free nano-delivery system in HCC combination therapy, especially in the realms of cancer metastasis prevention and immunotherapy.
Assuntos
Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Neoplasias , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Preparações Farmacêuticas , Neoplasias Hepáticas/tratamento farmacológico , Terapia Combinada , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Meliasanines A-L, twelve previously unreported tirucallane-type triterpenoids, together with fifteen known ones, have been isolated from the stem bark of Melia toosendan. Their structures and absolute configurations were determined based on HRESIMS, and NMR, combined with calculated ECD and single-crystal X-ray diffraction analyses. Subsequently, all compounds except 10 were evaluated for their inhibitory effect on the production of nitric oxide induced by lipopolysaccharide in RAW264.7 macrophage cells. The results indicated that seven compounds (1, 13, 14, 16, 20, 22, and 23) exhibited significant NO inhibitory effects, with IC50 values ranging from 1.35 to 5.93 µM, which were more effective than the positive control indomethacin (IC50 = 13.18 µM). Moreover, the corresponding results of Western blot analysis revealed that meliasanine A (1) can significantly suppress the protein expression of inducible nitric oxide synthase and cyclooxygenase 2 in a concentration-dependent manner. The mechanism study suggested that meliasanine A exerts an anti-inflammatory effect via the nuclear factor-κB signaling pathway by suppressing phosphorylation of P65 and IκBα.