Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 589
Filtrar
1.
Fish Shellfish Immunol ; 125: 65-73, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35533975

RESUMO

This study aims to investigate the effects of glycerol monolaurate (GML) on growth performance, non-specific immunity, antioxidant capacity and intestinal microflora in Chinese mitten crabs. The crabs were randomly arranged to three experimental diets groups containing 0 (control group), 1000 mg/kg GML (GML1000 group), and 2000 mg/kg GML (GML2000 group), respectively. After 8 weeks of breeding, results showed a better growth performance in GML2000 group, with a higher PWG, SGR and lower FCR (P < 0.05). Meanwhile, in GML2000 group the activities of phenoloxidase, alkaline phosphatase, acid phosphatase and lysozyme in hemolymph were increased (P < 0.05), also the activities of hemolymph and hepatopancreas superoxide dismutase (SOD) and glutathione peroxidase (GPx) were increased in hepatopancreas (P < 0.05). While malondialdehyde (MDA) concentrations were lower significantly (P < 0.05) both in GML1000 and GML2000 groups. Furthermore, the mRNA expression of TLR1, TLR2, which related to the Toll pathway were increased (P < 0.05). Supplementation of 2000 mg/kg GML up-regulated the expression of ALF and LZM (P < 0.05), and down-regulated the expression of caspase-3 (P < 0.05). The abundance of Firmicutes increased in GML2000 group (P < 0.05), and Shewanella was significantly increased (P < 0.05) in both GML1000 and GML2000 groups. In conclusion, dietary supplemented with GML enhanced the growth performance and antioxidant capacity, enhanced hemolymph immune enzymes activities and antimicrobial peptides expression through regulating the proPO system and Toll pathway, and improved gut microflora in Chinese mitten crabs.

2.
Eur J Med Chem ; 236: 114311, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35385803

RESUMO

TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 µM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.

3.
Hum Pathol ; 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35427637

RESUMO

Ovarian serous neoplasms are thought to arise from the fallopian tube or from the ovarian surface epithelium. The possibility of a third pathway - involving the mesenchymal-epithelial transition and mimicking the formation of the Müllerian duct, arose from observations gathered from our routine cases. The purpose of this study is to determine the association of precursors in the ovarian stroma with different types of ovarian serous neoplasms. Three hundred benign (25), borderline (63), and malignant ovarian serous neoplasms [40 low grade serous carcinomas (LGSCas) and 172 high grade serous carcinomas (HGSCas)] were reviewed. Clinicopathologic features analyzed included: patient's age, tumor size, stage, histologic pattern, and possible precursors in the ovarian parenchyma (endosalpingiosis, inverted macropapillae, polyploid giant cancer cells, and simple cysts). All benign and borderline cases showed continuity with benign serous cysts or endosalpingiosis. In LGSCas, continuity with serous cysts was found in 29 (72%) of 40 cases, and inverted macropapillae were found in 12 (30%) of 40 cases. In untreated HGSCas, there was continuity with simple cysts in 42% of cases. In addition, these HGSCas contained polyploid giant cancer cells in 20% of cases. There were no different features in the ovaries in cases with or without serous tubal intraepithelial carcinoma (STIC). Our study shows that in a subset of cases, ovarian serous neoplasms and the Müllerian duct develop in similar fashion, originating from epithelial cells derived from the mesothelium, or occur de-novo from structures derived from mesenchymal-epithelial transition.

4.
Chemosphere ; 300: 134599, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35427662

RESUMO

The mass production and application of graphene have gradually expanded from academic research to industrial applications, which will inevitably lead to graphene entering the soil actively and passively. Therefore, the relationship between graphene and the pedosphere has attracted a lot of attention in the last decade. The most important question is whether graphene will harm soil health. Fortunately, the evidence is that graphene can alter soil physicochemical properties and microbial communities to some extent, but not dramatically. On this basis, the role of graphene in soil has been investigated in all directions. This review summarizes the literature on the relationship between graphene and soils. Topics include remediation and sensing of soil using graphene materials, the effects of graphene on soil, and the effects of graphene in soil on plant growth. At the same time, this review also uses bibliometrics to review the history of the topic. The number of papers published each year, participating countries, participating institutions and important articles were analyzed in detail. Finally, based on the published literature, we described the future perspectives of graphene and the pedosphere.

5.
Bioorg Chem ; 123: 105780, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35395448

RESUMO

Swietelinins A - C (1-3) and swieteliacates F - R (4-16), sixteen new limonoids and 18 known limonoids (17-34) were isolated from Swietenia macrophylla. The absolute configurations of these compounds were defined by using a combination of electronic circular dichroism data analysis and single-crystal X-ray diffraction data. Swieteliacate J (10) is the first limonoid possessing an unusual 8ß, 9ß-epoxy ring system. All of the compounds were tested for cytotoxicity against four human tumor cell lines (SMMC-7721, SW620, A549, and A375). Compounds 10, 11, and 19 exhibited selectively moderate cytotoxicity against four tumor cell lines, especially 19 exhibited significant cytotoxic effects against A375 with IC50 an value of 9.8 µM and was more active than the positive control, dacarbazine with an IC50 value of 22.4 µM. Compound 19 effectively induced apoptosis of A375, which was associated with G2/M-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 19 significantly induced A375 cell apoptosis in a dose-dependent manner.


Assuntos
Limoninas , Melanoma , Meliaceae , Apoptose , Linhagem Celular Tumoral , Humanos , Limoninas/química , Limoninas/farmacologia , Meliaceae/química
6.
J Med Chem ; 65(7): 5760-5799, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35333526

RESUMO

Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).


Assuntos
Antineoplásicos , Proteínas Nucleares , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Domínios Proteicos , Fatores de Transcrição
7.
ChemMedChem ; : e202100778, 2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-35274459

RESUMO

Although the farnesoid X receptor (FXR) has been regarded as a promising drug target for metabolic diseases as well as anti-inflammatory, antitumor and antiviral actions, the antagonism by FXR ligands are still underrepresented in current FXR targeted therapies. In this study, we discovered selective FXR antagonists through structure optimization from the polyoxygenated chalcone scaffold. The selective antagonist 6 p [2-methoxy-2'-hydroxy-4'-(4''-methoxy-4''-oxo-E-crotonyl) chalcone] is not only inhibitory toward non-small-cell lung cancer (NSCLC) cell proliferation in an FXR-dependent manner, but is also active in metastasis models. Taken together, this chalcone-based FXR antagonist has the potential for the targeted therapy of NSCLC in which FXR is highly expressed.

8.
Front Immunol ; 13: 824664, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35251004

RESUMO

Rhamnolipid (RL) is a glycolipid biosurfactant and exhibits the following outstanding characteristics: strong antibacterial properties, low toxicity, and high biodegradability. The present research was conducted to explore the protective effects and mechanisms of rhamnolipids as an alternative to antibiotics in LPS (lipopolysaccharide)-challenged broilers. 16S rRNA gene sequencing and metabolomics were used for analyzing the cecal microbial composition and serum metabolites. Dietary antibiotics and RLS supplementation decreased the weight loss rate, enhanced serum immunoglobulin levels, reduced serum diamine oxidase and D-lactate acid concentration, and improved the symptoms of intestinal bleeding and villus height, when broilers were challenged with LPS. The addition of RLS in the diet enhanced serum interleukin-4 and interleukin-10 contents and reduced serum interleukin-6 and tumor necrosis factor-α levels in LPS-challenged broilers compared with the antibiotics group. Spearman's correlation analysis revealed that RLS may alleviate LPS-induced inflammatory responses through altering the 6-methoxymellein level in broilers. The genus Bacteroides may contribute to the decreased weight loss rate via regulating the serum lysoPC [20:5(5Z,8Z,11Z,14Z,17Z)] secretion. RLS alleviates LPS-induced intestinal injury, enhances the growth and immunity, ameliorates intestinal microflora, and improves serum metabolites in LPS-challenged broilers. RLS exhibited better protective effect than antibiotic supplementation in the diet of LPS-challenged broilers. These findings provide potential regulation strategies and novel insights for RLS enhancing its protective effect in LPS-challenged broilers.


Assuntos
Galinhas , Lipopolissacarídeos , Ração Animal/análise , Animais , Antibacterianos/farmacologia , Suplementos Nutricionais/análise , Glicolipídeos/metabolismo , Glicolipídeos/farmacologia , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/toxicidade , RNA Ribossômico 16S/genética , Perda de Peso
9.
iScience ; 25(3): 103923, 2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35252817

RESUMO

Bulk and single-cell RNA sequencing do not provide full characterization of tissue spatial diversity in cancer samples, and currently available in situ techniques (multiplex immunohistochemistry and imaging mass cytometry) allow for only limited analysis of a small number of targets. The current study represents the first comprehensive approach to spatial transcriptomics of high-grade serous ovarian carcinoma using intact tumor tissue. We selected a small cohort of patients with highly annotated high-grade serous ovarian carcinoma, categorized them by response to neoadjuvant chemotherapy (poor or excellent), and analyzed pre-treatment tumor tissue specimens. Our study uncovered extensive differences in tumor composition between the poor responders and excellent responders to chemotherapy, related to cell cluster organization and localization. This in-depth characterization of high-grade serous ovarian carcinoma tumor tissue from poor and excellent responders showed that spatial interactions between cell clusters may influence chemo-responsiveness more than cluster composition alone.

10.
Front Nutr ; 9: 848532, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308272

RESUMO

The consumption of bamboo leaf flavonoids (BLFs) as novel dietary antioxidants has increased owing to their beneficial biological and pharmacological functions. This study assessed the in vivo effects of BLFs on antioxidant capacity, as well as caecal microbiota, serum metabolome, and health status. The Gallus gallus domesticus model and the oral administration approach were used with four treatment groups (basal diet, basal diet with 20 mg bacitracin/kg, basal diet with 50 mg BLF/kg, and basal diet with 250 mg BLF/kg). Ultra-high-performance liquid chromatography triple-quadrupole mass spectrometry analysis indicated that vitexin, fumaric acid, orientin, isoorientin, and p-coumaric acid were the predominant BLF components. From days 1 to 21, BLF increased the average daily gain and decreased the feed:gain of broilers. Moreover, BLF enhanced the serum antioxidant capacity and immune responses. Further, 16S rRNA sequencing showed that BLF modulated the caecal microbial community structure, which was dominated by Betaproteobacteriales, Erysipelatoclostridium, Parasutterella, Lewinella, Lactobacillus, and Candidatus Stoquefichus in BLF broilers. Among the 22 identified serum metabolites in BLF broilers, sphinganine, indole-3-acetaldehyde retinol, choline, 4-methylthio-2-oxobutanoic acid, and L-phenylalanine were recognised as biomarkers. In summary, BLFs appeared to modulate the caecal microbiome, alter the serum metabolome, and indirectly improve antioxidant capacity and health status.

11.
Front Vet Sci ; 9: 846649, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35265699

RESUMO

We aimed to study the effects of dietary Bacillus coagulans (B. coagulans) and Lactobacillus plantarum (L. plantarum) on broilers challenged by Escherichia coli lipopolysaccharide (LPS). One-day-old Cobb 500 chicks (360) were divided randomly into three treatment groups for 47 days: no supplementation (control, CON), B. coagulans supplementation (BC), and L. plantarum supplementation (LA). Broilers were routinely fed for 42 days and intraperitoneally injected with 500 µg LPS per kg body weight at 43, 45, and 47 days of age, respectively. Samples were collected 3 h after the last injection. At 1-21 days of age, the ADG in the BC and LA groups was higher than that in the CON group, and the feed to gain ratio (F/G) in the BC group was significantly decreased (P < 0.05). Compared with that in CON birds, the ADG was increased and the F/G was decreased in the BC and LA birds at 22-42 and 1-42 days of age, respectively (P < 0.05). After LPS stimulation, the endotoxin (ET), diamine oxidase (DAO), and D-lactic acid (D-LA) levels in the BC group were lower than those in the CON group (P < 0.05). The IgY, IgA, and IgM contents in the BC group and the IgY and IgM contents in the LA group were higher than those in the CON group (P < 0.05). The pro-inflammatory factor and interferon-ß (IFN-ß) contents (P < 0.05) decreased, and the anti-inflammatory factor content in the serum (P < 0.05) increased in the BC and LA groups. Compared with the CON and LA treatments, the BC treatment increased the concentrations of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), and decreased that of malondialdehyde (MDA) (P < 0.05). In contrast with the CON treatment, the BC and LA treatments increased the abundance of Ruminococcaceae and reduced that of Desulfovibrio (P < 0.05). Moreover, BC increased the abundance of beneficial bacteria. Overall, supplementation with B. coagulans and L. plantarum promoted the growth of broilers, improved their immunity and antioxidant capacity, and alleviated the LPS-stimulated inflammatory response by regulating the intestinal flora.

12.
Artigo em Inglês | MEDLINE | ID: mdl-35124186

RESUMO

Basal metabolic rate (BMR) has been shown to be a highly phenotypic flexibility trait within species. A significant proportion of an individual's energy budget is accounted for by BMR, hence among-individual variation in this trait may affect other energetic processes, as well as fitness. In this study, we measured BMR, organ mass, mitochondrial respiration capacities and cytochrome c oxidase (COX) activities in muscle and liver and circulating levels of plasma triiodothyronine (T3) in Chinese bulbuls (Pycnonotus sinensis) and Eurasian tree sparrows (Passer montanus). Our results showed that heart and kidney mass was positively correlated with BMR in Chinese bulbuls, whereas liver and kidney mass was positively correlated with BMR in Eurasian tree sparrows. Regarding metabolic biochemical markers of tissues, state 4 respiration and COX activity in the muscles of the Chinese bulbuls was correlated with BMR, while state 4 respiration in the muscle and liver was correlated with BMR in Eurasian tree sparrows. T3 was significantly and positively correlated with BMR in Chinese bulbuls and Eurasian tree sparrows. Consistent with the above results, our findings suggest that T3 levels play an important role in modulating BMR in Chinese bulbuls and Eurasian tree sparrows. Moreover, individual variation in BMR can be explained partly by morphological and physiological mechanisms.


Assuntos
Metabolismo Basal , Pardais , Animais , Fígado , Músculos , Tri-Iodotironina
13.
Opt Lett ; 47(3): 553-556, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35103669

RESUMO

An optical element has been invented to generate a zero-order quasi-Bessel beam with a certain distance to the element, which does not exist in the zero-order quasi-Bessel beam by using a traditional axicon. The cross section of designed element is an isosceles triangle whose equal sides are circumscribed by two semi-ellipses. Using a well-developed three-dimensional (3D)-printing technique, we have fabricated a series of elements working at terahertz (THz) frequency. Both simulated and experimental results clearly show that there is a certain distance between the generated quasi-Bessel beam and this element. A physical analysis based on geometric optics theory is performed to explain the obtained results. Because it is a refractive transmitted optical element, we propose that it can be also realized at another frequency band if the relevant processing techniques are available.

14.
J Clin Exp Dent ; 14(2): e205-e210, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35173905

RESUMO

In order to clarify the prognosis of intentional replantation used for palatogingival groove treatment for long-term follow-up observation, the case of a patient with a maxillary lateral incisor with palatogingival groove was investigated. The intentional replantation was carried out to preserve the tooth. The periodontal pocket and the apical bone defect were almost completely repaired at 12-month follow-up. However, the infection was reoccurred after 25-month follow-up examinations. The infected tooth was extracted, of which the root was investigated by histological analysis. Therefore, the reason of the replant failure and the pathways of bacterial infection was investigated. Key words:Palatogingival groove, intentional tooth replantation, bacterial infection, maxillary lateral incisor.

15.
Sensors (Basel) ; 22(3)2022 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-35161571

RESUMO

Outdoor fall detection, in the context of accidents, such as falling from heights or in water, is a research area that has not received as much attention as other automated surveillance areas. Gathering sufficient data for developing deep-learning models for such applications has also proven to be not a straight-forward task. Normally, footage of volunteer people falling is used for providing data, but that can be a complicated and dangerous process. In this paper, we propose an application for thermal images of a low-cost rubber doll falling in a harbor, for simulating real emergencies. We achieve thermal signatures similar to a human on different parts of the doll's body. The change of these thermal signatures over time is measured, and its stability is verified. We demonstrate that, even with the size and weight differences of the doll, the produced videos of falls have a similar motion and appearance to what is expected from real people. We show that the captured thermal doll data can be used for the real-world application of pedestrian detection by running the captured data through a state-of-the-art object detector trained on real people. An average confidence score of 0.730 is achieved, compared to a confidence score of 0.761 when using footage of real people falling. The captured fall sequences using the doll can be used as a substitute to sequences of people.


Assuntos
Acidentes por Quedas , Emergências , Humanos
16.
Int J Nanomedicine ; 17: 17-29, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35023917

RESUMO

BACKGROUND: Compared with the healthy condition, osteoporotic bone defects are often accompanied by poor osteogenesis and excessive reactive oxygen species (ROS), which pose serious challenges to bone augmentation and repair by normal resorbable guided bone regeneration (GBR) membrane. PURPOSE: Polaprezinc (PZ) was loaded into polycaprolactone/gelatin (PG) hybrid electrospun nanofibers to fabricate a GBR membrane with antioxidant and osteogenesis ability. METHODS: A series of physicochemical characterization were performed by scanning electron microscopy, Fourier-transform infrared spectroscopy, and water contact angle measurement. In addition to membrane degradation and PZ release detection, membranes were tested for cell viability, differentiation, and protein expression in MC3T3-E1 cells by CCK8, alkaline phosphatase activity, mineralization, and Western blotting assays. The membrane osteogenic capacity in cranial bone defects was studied by micro-CT in vivo. RESULTS: PZ was successfully doped into the PCL/GEL nanofibers to form a hydrophilic GBR membrane. The cumulative release of PZ was closely related to the membrane degradation behavior. PG/0.4%PZ membranes produced the best protective effect on cell proliferation/differentiation under oxidative stress microenvironment; however, the PG/0.8%PZ membrane was cytotoxic. Western blotting demonstrated that the PZ-loaded membrane upregulated the Nrf2/HO-1/SOD1 signaling molecules in a concentration-dependent manner. In addition, micro-CT results showed an abundant formation of new bones in the PG/0.4%PZ group compared to the PG group. CONCLUSION: PZ-loaded degradable PG membranes (especially PG/0.4%PZ) have great potential to accelerate bone regeneration in oxidative stress-related diseases.


Assuntos
Nanofibras , Osteoporose , Antioxidantes/farmacologia , Regeneração Óssea , Carnosina/análogos & derivados , Proliferação de Células , Humanos , Compostos Organometálicos , Osteogênese , Osteoporose/tratamento farmacológico , Poliésteres , Tecidos Suporte , Compostos de Zinco
17.
Cell Rep ; 38(4): 110301, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35081345

RESUMO

Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy.


Assuntos
Proteína Substrato Associada a Crk/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Células Endoteliais/metabolismo , Neoplasias Ovarianas/patologia , Inibidores da Angiogênese/farmacocinética , Animais , Bevacizumab/farmacologia , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Opt Lett ; 47(2): 238-241, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35030576

RESUMO

We have implemented a terahertz (THz) ptychographic technique using a long-distance diffraction-free beam (DFB) instead of traditional low-energy pinhole-defined illumination as the probe. The DFB generating system containing two lens-axicon doublets is very easily realized. Measured transverse intensities of such a DFB display an Airy-pattern-like distribution. Based on the well-developed extended ptychographic iterative engine, we simultaneously reconstruct a phase object and the DFB probe with both simulated and real data. Further calculation shows that the DFB has abundant spatial high-frequency components that guarantee high coherence of the illuminating probe beam in our THz ptychographic system. In addition, we firmly believe that the proposed approach can be easily transplanted to the ptychography at other frequency bands as both lens and axicon are very common optical elements.

19.
Bioorg Chem ; 120: 105639, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35093691

RESUMO

Dengue virus, belonging to a genus Flavivirus, caused public health problem in recent years. One controversial vaccine of DENV was approved and there is no antiviral for the clinic treatment of DENV, therefore, efficient antivirals to DENV are of great medical significance. In this study, we conducted the design, synthesis, cell-based and target-based activity evaluation of 28 compounds based on indoline structural skeleton against DENV infection. Among them, 13 active compounds against DENV infection were discovered and their structure-activity relationship (SAR) was summarized. In this study, indoline carbohydrazine has derived more active compounds than indoline carboamide. It is discovered that TBS group exhibits a good pharmacophore to enhance anti-DENV activity. Further exploration indicated that post-treatment acts as effective time of addition and compound 15 targeting the post-entry stages of DENV2 viral life cycle. SPR imaging results support there are strong interaction of 13 and 15 with RdRp and compounds 13 and 15 reduce RdRp enzymatic activity, revealing that RdRp of DENV NS5 is the drug target for these series of compounds. Molecular docking deciphered the relationship of the structural feature with the putative binding mode by 13 and 15 with RdRp domain of DENV2 NS5 by hydrogen bonds and hydrophobic interactions to establish the fitted low energy conformation. Future studies will focus on designing more potent inhibitors for the treatment and prevention of dengue virus replication and infection, and understanding the more profound underlying structural features of inhibitors and drug action of the mechanism.

20.
Poult Sci ; 101(3): 101664, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35066382

RESUMO

The protective effects and underlying molecular mechanisms of sodium selenite (SS) and selenomethionine (SM) against chronic oxidative stress-induced duodenum and jejunum tight junction (TJ) network disturbance and growth inhibition of broilers were investigated in the current experiment. At the age of 1 d, 720 Lingnan Yellow broiler chicks were allocated to 4 experimental diets (with 6 replicates per diet and 30 birds per replicate) and offered either a control diet (fluorine [F] 23 mg/kg, control [CoN] group) or test diets (800 mg/kg F, high F [HF] group; 800 mg/kg F+0.15 mg selenium [Se]/kg as SS [SS group] or SM [SM group]) for 56 d. The results showed that HF group could induce chronic oxidative stress and subsequently increased (P < 0.05) proinflammatory cytokines levels of duodenum and jejunum in comparison with the CoN group. Increased proinflammatory cytokines levels of HF group promoted myosin light chain kinase (MLCK) transcription, thus leading to a decrease (P < 0.05) in TJ proteins expression of duodenum and jejunum when compared with the CoN group. A reduction of TJ proteins expression destroyed the TJ structures in the HF group, which in turn increased intestinal mucosal permeability of duodenum and jejunum and ultimately induced growth inhibition of broilers. Dietary Se supplementation could ameliorate HF-induced duodenum and jejunum TJ network impairment and growth retardation of broilers, potentially by increasing (P < 0.05) the glutathione peroxidase and thioredoxin reductase activities, reducing (P < 0.05) the reactive oxygen species and malondialdehyde levels, regulating the secretion of proinflammatory cytokines, and mediating the transcription level of MLCK in the duodenum and jejunum. Additionally, our data also suggested that the protective effects of SM were superior to those of SS. This study will provide a theoretical basis for developing SM into an efficient protective agent for intestinal mucosal barrier in poultry.


Assuntos
Selênio , Ração Animal/análise , Animais , Galinhas/fisiologia , Dieta/veterinária , Suplementos Nutricionais , Duodeno/metabolismo , Flúor/metabolismo , Flúor/farmacologia , Jejuno/metabolismo , Estresse Oxidativo , Selênio/metabolismo , Selênio/farmacologia , Junções Íntimas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...