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1.
Anal Chem ; 91(19): 12587-12595, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31496223

RESUMO

Glioblastoma is a highly malignant brain tumor with poor prognosis and survival rate because of a lack of effective diagnostic methods. Hydrocyanines are a type of reactive oxygen species (ROS)-responsive fluorescent probes, allowing for distinguishing tumor cells from normal cells based on their different intracellular levels of ROS. However, their diagnostic applications for glioblastoma have been limited because of the inability to discriminate between tumor cells and other tissues with high ROS production, leading to high false-positive diagnosis. Therefore, tumor-responsive and -specific hydrocyanines with cooperative targeting ability have great potential for improving the diagnosis and treatment of glioblastoma. Integrin αvß3 plays a critical role in the progression and angiogenesis of glioblastoma and has become a promising target for diagnosing glioblastoma. Herein, we identify a specific peptide ligand for integrin αvß3, Arg-Trp-(d-Arg)-Asn-Arg (RWrNR), which shows high binding affinity to human glioblastoma U87MG cells. Importantly, hydro-Cy5-RWrNR conjugation allowed for distinguishing U87MG cells from normal cells in response to intracellular ROS. Particularly, hydro-Cy5-RWrNR could not only selectively accumulate in orthotopic U87MG tumor with minimal background fluorescence but also effectively discriminate between glioblastoma and inflammatory tissues for the first time, leading to detection of glioblastoma in vivo with high target-to-background ratios and minimal background fluorescence. Therefore, hydro-Cy5-RWrNR is the first integrin αvß3-specific hydrocyanine probe and has great potential in precise tumor diagnosis because of its cooperative targeting of integrin αvß3 and ROS.

2.
Biomaterials ; 223: 119471, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31525693

RESUMO

Prostate cancer is one of the most commonly diagnosed cancers in men, leading to a high mortality rate due to a lack of effective anticancer treatment. Current anticancer chemotherapeutics are often administrated at suboptimal doses because of nonspecific toxicities to normal tissues, resulting in the eventual failure of therapy as well as the development of drug resistance and metastatic disease. Therefore, ligand-targeted therapeutics have the great potential of improving the selective anticancer toxicity. Integrins ß3 (αvß3 and αIIbß3) are an important cell adhesion molecular family, overexpressed on both cell membrane and perinuclear region of prostate cancer cells, and play a key role in the progression and metastasis of prostate cancer, making them an attractive target for anticancer therapy. However, their clinical impacts have been limited due to lack of specific ligands. Here, for the first time, we have identified a peptide Arginine-Tryptophan-(D-Arginine)-Asparagine-Arginine as an integrins ß3 specific ligand, named B3int, which shows superior selectivity to integrins ß3 over other integrin subunits. B3int has high affinity to integrins ß3 with a Kd value of 0.2 nM, which is 7-fold higher than c-RGDyK (1.4 nM), a well-established integrin αvß3 ligand. In addition, B3int shows high specificity for integrins ß3, and can selectively target integrin ß3 overexpressed cancer cells in vitro and in vivo. Most importantly, B3int-modified liposomes (B3int-LS-DOX) can selectively deliver DOX not only into prostate cancer cells, but into nucleus via targeting integrins ß3, thereby significantly improving anticancer effects in 2D prostate cancer cells and 3D tumor spheroids. Particularly, B3int-LS-DOX effectively inhibits tumor growth with an effective dose of as low as 1.5 mg/kg, which is 3.3-fold less than c-RGDyK-LS-DOX (5 mg/kg), indicating that integrins ß3 specific therapy is a promising anticancer strategy which can greatly improve the anticancer therapeutic index. In summary, we have identified B3int as the first integrins ß3 specific ligand with high affinity and specificity, and holds a great potential of improving the diagnosis and treatment for integrins ß3-overexpressed cancers.

3.
Mol Cell Endocrinol ; 496: 110518, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344393

RESUMO

Neuromedin U (NMU) shows circadian expression in the rat pars tuberalis (PT), and is known to be suppressed by melatonin. Here we examined the involvement of adenosine in the regulation of Nmu expression. We found that the rat PT expressed adenosine receptor A2b and that an adenosine receptor agonist, NECA, stimulated Nmu expression in brain slice cultures. In vitro promoter assays revealed that NECA stimulated Nmu promoter activity via a cAMP response element (CRE) in the presence of adenosine receptor A2b. NECA also increased the levels of phosphorylated CRE-binding protein. These findings suggest that adenosine stimulates Nmu expression by activating the cAMP signaling pathway through adenosine receptor A2b in the rat PT. This is the first report to demonstrate that Nmu expression in the PT is regulated by adenosine, which acts as an intravital central metabolic signal, in addition to melatonin, which acts as an external photoperiodic environmental signal.

4.
Acta Biochim Biophys Sin (Shanghai) ; 51(8): 845-855, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31287492

RESUMO

Autoimmune ovarian disease (AOD) is considered to be a major cause of premature ovarian failure (POF). The immunomodulatory properties of human amniotic epithelial cells (hAECs) have been studied in many disease models. We previously reported that hAECs restored ovarian function in chemotherapy-induced POF mice, but the immunomodulatory mechanism of hAECs is still unclear. To investigate the effect of hAECs on recipient mice, especially on regulatory Treg cells, hAECs and hAEC-conditioned medium (hAEC-CM) were intravenously injected into AOD mice immunized with zona pellucida protein 3 peptides (pZP3). Ovarian function was evaluated through estrous cycle, hormone secretion, follicle development, and cell apoptosis analysis. Immune cells including CD3, CD4, CD8 and Treg cells in the spleens were tested by flow cytometry. To elucidate the effect of hAEC-CM on macrophage function, inflammation model in vitro was established in RAW264.7 cells induced by lipopolysaccharide (LPS). hAECs and hAEC-CM regulated estrous cycles, promoted follicle development, ameliorated cell apoptosis and fibrosis in ovaries of AOD mice. In addition, hAECs significantly reversed the decrease of pZP3-induced Treg cells in the spleens. In vitro, hAEC-CM significantly inhibited the inflammatory reaction induced by LPS in RAW264.7 cells via up-regulating the expression of M2 macrophage genes. Further study demonstrated that hAEC-secreted transforming growth factor-beta and macrophage inhibitory factor played important roles in the macrophage polarization and migration under inflammatory stimulation. Taken together, hAECs restored ovarian function by up-regulating Treg cells in the spleens and reduced the inflammatory reaction via modulating the activated macrophage function in a paracrine manner in the ovaries of AOD mice.

5.
Brain Behav Immun ; 81: 630-645, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351185

RESUMO

Neuroinflammation has been involved in pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disease characterized neuropathologically by progressive dopaminergic neuronal loss in the substantia nigra (SN). We recently have shown that helper T (Th)17 cells facilitate dopaminergic neuronal loss in vitro. Herein, we demonstrated that interleukin (IL)-17A, a proinflammatory cytokine produced mainly by Th17 cells, contributed to PD pathogenesis depending on microglia. Mouse and rat models for PD were prepared by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or striatal injection of 1-methyl-4-phenylpyridinium (MPP+), respectively. Both in MPTP-treated mice and MPP+-treated rats, blood-brain barrier (BBB) was disrupted and IL-17A level increased in the SN but not in cortex. Effector T (Teff) cells that were adoptively transferred via tail veins infiltrated into the brain of PD mice but not into that of normal mice. The Teff cell transfer aggravated nigrostriatal dopaminergic neurodegeneration, microglial activation and motor impairment. Contrarily, IL-17A deficiency alleviated BBB disruption, dopaminergic neurodegeneration, microglial activation and motor impairment. Anti-IL-17A-neutralizing antibody that was injected into lateral cerebral ventricle in PD rats ameliorated the manifestations mentioned above. IL-17A activated microglia but did not directly affect dopaminergic neuronal survival in vitro. IL-17A exacerbated dopaminergic neuronal loss only in the presence of microglia, and silencing IL-17A receptor gene in microglia abolished the IL-17A effect. IL-17A-treated microglial medium that contained higher concentration of tumor necrosis factor (TNF)-α facilitated dopaminergic neuronal death. Further, TNF-α-neutralizing antibody attenuated MPP+-induced neurotoxicity. The findings suggest that IL-17A accelerates neurodegeneration in PD depending on microglial activation and at least partly TNF-α release.

6.
Mol Pharm ; 16(9): 3977-3984, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31306580

RESUMO

Integrin αvß3 is a cell adhesion molecule involved in the progression and invasion of glioblastoma, making it an attractive target for the diagnosis of glioblastoma. Although some integrin αvß3 specific ligands, such as RGD and its mimetic peptides (Cilengitide), have been devoted in detecting glioblastoma, their clinical practices have been limited due to low specificity and affinity. Herein, we have identified a linear peptide RWrNK, containing an unnatural d-arginine (r), as the integrin αvß3-specific ligand. RWrNK shows high binding affinity to integrin αvß3 with a Kd value of 1.6 nM, which is 2-fold higher than Cilengitide (3.2 nM), a well-established integrin αvß3 ligand. In addition, RWrNK can not only rapidly transport in human glioblastoma U87MG cells but effectively label U87MG tumor spheroids, compared to Cilengitide, indicating that it possesses an ability to sensitively detect glioblastoma. Importantly, RWrNK can pass through blood-brain tumor barrier (BBTB) and selectively accumulate in orthotopic U87MG tumor within 2 h, allowing for imaging glioblastoma in vivo with high sensitivity and specificity. Overall, RWrNK has the great potential in theranostic applications for glioblastoma, in consideration of its high specificity and affinity for integrin αvß3.

7.
Free Radic Biol Med ; 141: 67-83, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31153974

RESUMO

Endoplasmic reticulum stress (ERS) has been implicated in obesity-associated cardiac remodeling and dysfunction. Inactive rhomboid protein 2 (iRhom2), also known as Rhbdf2, is an inactive member of the rhomboid intramembrane proteinase family, playing an essential role in regulating inflammation. Nevertheless, the role of ERS-meditated iRhom2 pathway in metabolic stress-induced cardiomyopathy remains unknown. In the study, we showed that 4-PBA, as an essential ERS inhibitor, significantly alleviated high fat diet (HFD)-induced metabolic disorder and cardiac dysfunction in mice. Additionally, lipid deposition in heart tissues was prevented by 4-PBA in HFD-challenged mice. Moreover, 4-PBA blunted the expression of iRhom2, TACE, TNFR2 and phosphorylated NF-κB to prevent HFD-induced expression of inflammatory factors. Further, 4-PBA restrained HFD-triggered oxidative stress by promoting Nrf-2 signaling. Importantly, 4-PBA markedly suppressed cardiac ERS in HFD mice. The anti-inflammation, anti-ERS and anti-oxidant effects of 4-PBA were verified in palmitate (PAL)-incubated macrophages and cardiomyocytes. In addition, promoting ERS could obviously enhance iRhom2 signaling in vitro. Intriguingly, our data demonstrated that PAL-induced iRhom2 up-regulation apparently promoted macrophage to generate inflammatory factors that could promote cardiomyocyte inflammation and lipid accumulation. Finally, interventions by adding fisetin or metformin significantly abrogated metabolic stress-induced cardiomyopathy through the mechanisms mentioned above. In conclusion, this study provided a novel mechanism for metabolic stress-induced cardiomyopathy pathogenesis. Therapeutic strategy to restrain ROS/ERS/iRhom2 signaling pathway could be developed to prevent myocardial inflammation and lipid deposition, consequently alleviating obesity-induced cardiomyopathy.

8.
BMC Surg ; 19(1): 54, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138196

RESUMO

BACKGROUND: Appendicitis in elderly patients is associated with increased risk of postoperative complications. The choice between laparoscopy and open appendectomy remains controversial in treating elderly patients with appendicitis. METHODS: Comprehensive search of literature of MEDLINE, Embase, Cochrane Library and ClinicalTrials was done in January 2019. Studies compared laparoscopy and open appendectomy for elderly patients with appendicitis were screened and selected. Postoperative mortality, complications, wound infection, intra-abdominal abscess and operating time, length of hospital stay were extracted and analyzed. The Review Manage 5.3 was used for data analysis. RESULTS: Twelve studies with 126,237 patients in laparoscopy group and 213,201 patients in open group. Postoperative mortality was significantly lower following laparoscopy (OR, 0.33; 95% CI, 0.28 to 0.39). Postoperative complication and wound infection were reduced following laparoscopy ((OR, 0.65 95% CI, 0.62 to 0.67; OR,0.27, 95% CI, 0.22 to 0.32). Intra-abdominal abscess was similar between LA and OA (OR,0.44;95% CI, 0.19 to 1.03). Duration of surgery was longer following laparoscopy and length of hospital stay was shorter following laparoscopy (MD, 7.25, 95% CI, 3.13 to 11.36; MD,-2.72, 95% CI,-3.31 to - 2.13). CONCLUSIONS: Not only laparoscopy is safe and feasible, but also it is related with decreased rates of mortality, post-operative morbidity and shorter hospitalization.


Assuntos
Apendicectomia/métodos , Apendicite/cirurgia , Laparoscopia/métodos , Abscesso Abdominal/epidemiologia , Abscesso Abdominal/cirurgia , Idoso , Apendicectomia/efeitos adversos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Laparoscopia/efeitos adversos , Tempo de Internação , Masculino , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Infecção dos Ferimentos/epidemiologia
9.
Plant Cell Physiol ; 60(7): 1619-1629, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31073591

RESUMO

Although exogenous applications of gibberellins (GAs) delay tomato ripening, the regulatory mechanisms of GAs in the process have never been well recognized. Here, we report that the concentration of endogenous GAs is declined before the increase of ethylene production in mature-green to breaker stage fruits. We further demonstrate that reductions in GA levels via overexpression of a GA catabolism gene SlGA2ox1 specifically in fruit tissues lead to early ripening. Consistently, we have also observed that application of a GA biosynthetic inhibitor, prohexadione-calcium, at the mature-green stage accelerates fruit ripening, while exogenous GA3 application delays the process. Furthermore, we demonstrate that ethylene biosynthetic gene expressions and ethylene production are activated prematurely in GA-deficient fruits but delayed/reduced in exogenous GA3-treated WT fruits. We also show that the GA deficiency-mediated activation of ethylene biosynthesis is due to the activation of the ripening regulator genes RIN, NOR and CNR. In conclusion, our results demonstrate that GAs play a negative role in tomato fruit ripening.


Assuntos
Frutas/crescimento & desenvolvimento , Giberelinas/fisiologia , Lycopersicon esculentum/crescimento & desenvolvimento , Reguladores de Crescimento de Planta/fisiologia , Etilenos/biossíntese , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas/fisiologia , Genes de Plantas/fisiologia
10.
Food Funct ; 10(5): 2970-2985, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31074472

RESUMO

Obesity-related renal disease is related to caloric excess promoting deleterious cellular responses. However, a full understanding of the molecular mechanisms involved in progressive kidney disease, as well as a therapeutic strategy, is still absent. Fisetin (FIS), as a natural flavonoid, possesses various bioactivities in a number of disease models. However, its role in obesity-associated kidney injury is still unclear and requires elucidation. In our study, an obesity animal model was established using C57BL/6 mice fed with a normal chow diet (NCD) or high fat diet (HFD) for 16 weeks with or without FIS administration (20, 40 or 80 mg kg-1). Our results indicated that chronic HFD feeding led to a significant body weight gain in mice compared to the normal control group, accompanied by a marked insulin resistance and glucose intolerance, whereas FIS treatment exerted prominently protective effects. In addition, FIS significantly attenuated HFD-induced histological alterations in renal tissue samples. Moreover, FIS treatment down-regulated expression of kidney injury molecule-1 (KIM-1), and up-regulated nephrin and podocin expression levels in the kidneys of HFD-fed mice, improving their renal dysfunction. After HFD feeding, mice treated with FIS exhibited a decrease in phosphorylated IRS1Ser307, and an increase in phosphorylated glycogen synthase kinase 1 (IRS1Tyr608), AKT, forkhead box protein O1 (FOXO1) and glycogen synthase kinase (GSK)-3ß. Furthermore, FIS administration markedly restrained the inflammatory response in the kidneys of HFD-challenged mice, as evidenced by the reduced pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-1ß and IL-18, which was attributed to the blockage of nuclear factor κB (NF-κB) signaling. Importantly, FIS-treated obese mice exerted a remarkable decrease in RIP3 expressions in the kidneys compared to obese mice in the absence of FIS, along with an evident reduction in the NOD-like receptor protein 3 (NLRP3), an apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1. The protective effects of FIS against HFD-induced renal injury were verified in vitro using palmitate (PAL)-treated HK2 cells, an immortalized proximal tubule epithelial cell line from the adult human kidney. In summary, our results supported the notion that FIS functions as a promising agent to improve insulin resistance and inflammatory response against metabolic stress-induced renal injury.

11.
Int J Oncol ; 55(1): 179-190, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059002

RESUMO

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic tumors. Cancer spheroid culture is a widely used model to study cancer stem cells. Previous studies have demonstrated the effectiveness of cytokine­induced killer (CIK) cell­based therapies against cancer and cancer stem cells. However, it is not clear how EOC spheroid cells respond to CIK­mediated cellular lysis, and the mechanisms involved have never been reported before. A flow cytometry­based method was used to evaluate the anti­cancer effects of CIK cells against adherent A2780 cells and A2780 spheroids. To demonstrate the association between hypoxia inducible factor­1α (HIF1A) and intercellular adhesion molecule­1 (ICAM­1), two HIF1A short hairpin RNA (shRNA) stable transfected cell lines were established. Furthermore, the protein expression levels of hypoxia/HIF1A­associated signaling pathways were evaluated, including transforming growth factor­ß1 (TGF­ß1)/mothers against decapentaplegic homologs (SMADs) and nuclear factor­κB (NF­κB) signaling pathways, comparing A2780 adherent cells and cancer spheroids. Flow cytometry revealed that A2780 spheroid cells were more resistant to CIK­mediated cellular lysis, which was partially reversed by an anti­ICAM­1 antibody. HIF1A was significantly upregulated in A2780 spheroids compared with adherent cells. Using HIF1A shRNA stable transfected cell lines and cobalt chloride, it was revealed that hypoxia/HIF1A contributed to downregulation of ICAM­1 in A2780 spheroid cells and adherent cells. Furthermore, hypoxia/HIF1A­associated signaling pathways, TGF­ß1/SMADs and NF­κB, were activated in A2780 spheroid cells by using western blotting. The findings indicate that EOC stem­like cells resist the CIK­mediated cellular lysis via HIF1A­mediated downregulation of ICAM­1, which may be instructive for optimizing and enhancing CIK­based therapies.

12.
Planta ; 250(1): 145-162, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30949762

RESUMO

MAIN CONCLUSION: The possible molecular mechanisms regulating strawberry fruit ripening were revealed by plant hormone quantification, exogenous hormone application, and RNA-sequencing. Fruit ripening involves a complex interplay among plant hormones. Strawberry is a model for studies on non-climacteric fruit ripening. However, the knowledge on how plant hormones are involved in strawberry ripening is still limited. To understand hormonal actions in the ripening process, we performed genome-wide transcriptome and hormonal analysis for the five major hormones (abscisic acid and catabolites, auxins, cytokinins, gibberellins, and ethylene) in achenes and receptacles (flesh) at different ripening stages of the woodland strawberry Fragaria vesca. Our results demonstrate that the pre-turning stage (a stage with white flesh and red achenes defined in this study) is the transition stage from immature to ripe fruits. The combinatorial analyses of hormone content, transcriptome data, and exogenous hormone treatment indicate that auxin is synthesized predominantly in achenes, while abscisic acid (ABA), bioactive free base cytokinins, gibberellins, and ethylene are mainly produced in receptacles. Furthermore, gibberellin may delay ripening, while ethylene and cytokinin are likely involved at later stages of the ripening process. Our results also provide additional evidence that ABA promotes ripening, while auxin delays it. Although our hormone analysis demonstrates that the total auxin in receptacles remains relatively low and unchanged during ripening, our experimental evidence further indicates that ABA likely enhances expression of the endoplasmic reticulum-localized auxin efflux carrier PIN-LIKES, which may subsequently reduce the auxin level in nucleus. This study provides a global picture for hormonal regulation of non-climacteric strawberry fruit ripening and also evidence for a possible mechanism of ABA and auxin interaction in the ripening process.


Assuntos
Fragaria/genética , Regulação da Expressão Gênica de Plantas , Reguladores de Crescimento de Planta/metabolismo , Proteínas de Plantas/metabolismo , Transcriptoma , Ácido Abscísico/análise , Ácido Abscísico/metabolismo , Citocininas/análise , Citocininas/metabolismo , Etilenos/análise , Etilenos/metabolismo , Fragaria/fisiologia , Frutas/genética , Frutas/fisiologia , Giberelinas/análise , Giberelinas/metabolismo , Ácidos Indolacéticos/análise , Ácidos Indolacéticos/metabolismo , Reguladores de Crescimento de Planta/análise , Proteínas de Plantas/genética
13.
Mol Ther Nucleic Acids ; 16: 407-418, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-31022607

RESUMO

Premature ovarian failure (POF) is one of the most common complications among female patients with tumors treated with chemotherapy and requires advanced treatment strategies. Human amniotic epithelial cell (hAEC)-based therapy mediates tissue regeneration in a variety of diseases, and increasing evidence suggests that the therapeutic efficacy of hAECs mainly depends on paracrine action. This study aimed to identify exosomes derived from hAECs and explored the therapeutic potential in ovaries damaged by chemotherapy and the underlying molecular mechanism. hAEC-derived exosomes exhibited a cup- or sphere-shaped morphology with a mean diameter of 100 nm and were positive for Alix, CD63, and CD9. hAEC exosomes increased the number of follicles and improved ovarian function in POF mice. During the early stage of transplantation, hAEC exosomes significantly inhibited granulosa cell apoptosis, protected the ovarian vasculature from damage, and were involved in maintaining the number of primordial follicles in the injured ovaries. Enriched microRNAs (miRNAs) existed in hAEC exosomes, and target genes were enriched in phosphatidylinositol signaling and apoptosis pathways. Studies in vitro demonstrated that hAEC exosomes inhibited chemotherapy-induced granulosa cell apoptosis via transferring functional miRNAs, such as miR-1246. Our findings demonstrate that hAEC-derived exosomes have the potential to restore ovarian function in chemotherapy-induced POF mice by transferring miRNAs.

14.
Angew Chem Int Ed Engl ; 58(18): 5925-5929, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30843636

RESUMO

A hybrid thia-norhexaphyrin comprising a directly linked N-confused pyrrole and thiophene unit (1) revealed unique macrocycle transformations to afford multiply inner-annulated aromatic macrocycles. Oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone triggered a cleavage of the C-S bond of the thiophene unit, accompanied with skeletal rearrangement to afford unique π-conjugated products: a thiopyrrolo-pentaphyrin embedded with a pyrrolo[1,2]isothiazole (2), a sulfur-free pentaphyrin incorporating an indolizine moiety (3), and a thiopyranyltriphyrinoid containing a 2H-thiopyran unit (4). Furthermore, 2 underwent desulfurization reactions to afford a fused pentaphyrin containing a pyrrolizine moiety (5) under mild conditions. Using expanded porphyrin scaffolds, oxidative thiophene cleavage and desulfurization of the hitherto unknown N-confused core-modified macrocycles would be a practical approach for developing unique polypyrrolic aromatic macrocycles.

15.
Talanta ; 198: 472-479, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30876589

RESUMO

Listeria monocytogenes (Listeria) is a facultative pathogenic bacterium, and a sensitive method for specific detection of Listeria is considered of clinically significant. However, current approaches for identifying Listeria are time consuming or tentative, and especially, cannot identify bacterial viability and antibiotic efficacy, which are critical in establishing a treatment recipe. Herein, we have developed a nitroreductase (NTR) responsive fluorescent probe (NRFP) with a fluorescence off-on feature, which could rapidly detect Listeria in vitro and in vivo with high specificity and sensitivity. NRFP showed a selective response to NTRs over other biological reductants, and could detect NTRs as low as 12.5 ng/mL. Furthermore, NRFP responded rapidly to NTRs within 10 min, enabling it real-time monitoring NTR production. Most importantly, NRFP could not only distinguish Listeria from other bacteria in vitro and in vivo for the first time, but could provide valuable information about Listeria desired for healthcare professionals, such as the presence and viability. Particularly, NRFP could real-time monitor antimicrobial effects in vivo, thereby identifying effective antibiotics for Listeria infections. Overall, NRFP appears to be an ideal imaging probe for Listeria, and possesses great potentials in diagnostic and therapeutic applications.


Assuntos
Corantes Fluorescentes/química , Listeria/isolamento & purificação , Nitrorredutases/metabolismo , Fluorescência , Corantes Fluorescentes/metabolismo
16.
J Am Chem Soc ; 141(13): 5294-5302, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30849868

RESUMO

Expanded porphyrins have been attracting increasing attention owing to their unique optical and electrochemical properties as well as switchable aromaticity. Toward material applications, regioselective functionalization of the expanded porphyrins at their periphery is indeed challenging due to the presence of multiple reactive sites. Herein, a set of regioselective halogenated isomers (L5-Br-A/B/C) of neo-confused isosmaragdyrin (L5) are synthesized by a combination of the halogenation reaction of L5 and sequential macrocycle-to-macrocycle transformation reactions of its halogenated isomers. On this basis, the regioselectively functionalized isosmaragdyrins are utilized as building blocks for constructing multichromophoric porphyrinoids, specifically, heterodyads L5-ZnP-A/B/C, in which a common zinc porphyrin is linked at three different pyrrolic positions of isosmaragdyrins, respectively, by Sonogashira coupling reactions. The highly efficient energy cascade from porphyrin to isosmaragdyrin is elucidated using steady-state/time-resolved spectroscopies and theoretical calculations. Notably, the energy transfer processes from the porphyrin to the isosmaragdyrin moieties as well as the excitation energy transfer rates in L5-ZnP-A/B/C are highly dependent on the linking sites by through-bond and Förster-type resonance energy transfer mechanisms. The site-selective functionalization and subsequent construction of a set of heterodyads of the expanded porphyrinoid would provide opportunities for developing new materials for optoelectronic applications.

17.
Food Funct ; 10(3): 1302-1316, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30793717

RESUMO

Increasing evidence indicates that high-fat diet (HFD) is a predisposing factor for metabolic syndrome-associated systemic inflammation and nonalcoholic fatty liver disease (NAFLD). Tumor necrosis factor-α/receptor-interacting protein kinase 3 (TNF-α/RIPK3) axis has recently become regarded as an important regulator and contributor in many inflammation-related diseases. Fisetin (Fn) is a bioactive flavonoid polyphenol with anti-inflammatory and anti-tumor activity. Lately it has gained increasing attention due to its potential advantages in prevention of tumors, metabolic disorders, neuroinflammation and chronic liver injury. However, its role in NAFLD is still not fully understood. Thus, we studied whether prolonged HFD causes TNF-α/RIPK3 activation-associated hepatic steatosis, further evaluating the protective effects of Fn in HFD-fed mice. As expected, HFD promotes metabolic syndrome and pro-inflammatory cytokine generation in serum, enhances liver inflammatory infiltration-related lipid accumulation by increase of TNF-α/RIPK3 activation, ultimately resulting in development of nonalcoholic steatohepatitis. In contrast to this, dietary Fn intervention could suppress metabolic disorder and HFD-triggered hepatic function loss, downregulate TNF-α/RIPK3 signaling-associated hepatic inflammation, balance lipid metabolism-related gene expression, and finally inhibit lipid accumulation and steatohepatitis. Hence, Fn restrains HFD-induced hepatic inflammation and lipid deposition by downregulating metabolic disorder and excessive liver inflammation-associated TNF-α/RIPK3 axis activation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Flavonoides/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
18.
Int Immunopharmacol ; 67: 378-385, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30584967

RESUMO

INTRODUCTION: Newly published results of clinical trials has demonstrated immune checkpoint inhibitors as robust antitumor agents for urothelial carcinoma patients. However, searching for predictive biomarkers is still on the way. Previous clinical trials used PD-L1 as biomarkers, however, whether it can predict the objective response rate and overall survival is controversial. This is the first and latest study to pool the newest data in order the evaluate PD-L1 biomarker. RESULT: Nine studies were included and 1,436 urothelial carcinoma patients were included. We evaluated PD-L1 biomarker for atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab treatments. Patients with higher PD-L1 expression have significantly higher objective response rate compared with the lower ones. PD-L1 predicted the one year overall survival of PD-L1 inhibitors but not PD-1 inhibitors. Only one year overall survival of durvalumab was significantly associated with PD-L1 expression. CONCLUSION: PD-L1 can be used as a biomarker for objective response rate, while PD-L1 cannot predict the overall survival.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Neoplasias da Bexiga Urinária/sangue , Antígeno B7-H1/genética , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos
19.
J Cell Mol Med ; 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30394665

RESUMO

Long noncoding RNAs (lncRNAs) have been proved to play important roles in carcinogenesis and development of numerous cancers, but their biological functions in bladder cancer remain largely unknown. In this study, a novel lncRNA termed GAS6-AS2 were primary identified, and its roles as well as mechanisms in regulating proliferation and metastasis of bladder cancer cells were investigated. Clinically, GAS6-AS2 was significantly up-regulated in bladder cancer tissues and positively correlated with tumour stages and poor prognosis. Moreover, expression of GAS6-AS2 was also increased in bladder cancer cells compared with normal bladder cells. Further investigating the roles of GAS6-AS2, we found GAS6-AS2 regulated proliferation and proliferative activity of bladder cancer cells via inducing G1 phase arrest. What's more, we found that GAS6-AS2 contributed to metastatic abilities of cells. In mechanism, GAS6-AS2 could function as a competitive endogenous RNA (ceRNA) via direct sponging miR-298, which further regulating the expression of CDK9. Finally, we also proved that GAS6-AS2 knockdown suppressed tumour growth and metastasis in vivo. In conclusion, our study proved that GAS6-AS2 could function as a ceRNA and promote the proliferation and metastasis of bladder cancer cells, which provided a novel prognostic marker for bladder cancer patients in clinic.

20.
Genome Biol ; 19(1): 181, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30382931

RESUMO

BACKGROUND: Filamentous plant pathogen genomes often display a bipartite architecture with gene-sparse, repeat-rich compartments serving as a cradle for adaptive evolution. The extent to which this two-speed genome architecture is associated with genome-wide DNA modifications is unknown. RESULTS: We show that the oomycetes Phytophthora infestans and Phytophthora sojae possess functional adenine N6-methylation (6mA) methyltransferases that modulate patterns of 6mA marks across the genome. In contrast, 5-methylcytosine could not be detected in these species. Methylated DNA IP sequencing (MeDIP-seq) of each species reveals 6mA is depleted around the transcription start sites (TSSs) and is associated with lowly expressed genes, particularly transposable elements. Genes occupying the gene-sparse regions have higher levels of 6mA in both genomes, possibly implicating the methylome in adaptive evolution. All six putative adenine methyltransferases from P. infestans and P. sojae, except PsDAMT2, display robust enzymatic activities. Surprisingly, single knockouts in P. sojae significantly reduce in vivo 6mA levels, indicating that the three enzymes are not fully redundant. MeDIP-seq of the psdamt3 mutant reveals uneven 6mA methylation reduction across genes, suggesting that PsDAMT3 may have a preference for gene body methylation after the TSS. Furthermore, transposable elements such as DNA elements are more active in the psdamt3 mutant. A large number of genes, particularly those from the adaptive genomic compartment, are differentially expressed. CONCLUSIONS: Our findings provide evidence that 6mA modification is potentially an epigenetic mark in Phytophthora genomes, and complex patterns of 6mA methylation may be associated with adaptive evolution in these important plant pathogens.

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