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1.
Nature ; 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36450980

RESUMO

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

2.
Plant Biotechnol (Tokyo) ; 39(3): 251-257, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-36349228

RESUMO

Codonopsis pilosula, a traditional Chinese medicinal and edible plant, contains several bioactive components. However, the biosynthetic mechanism is unclear because of the difficulties associated with functional gene analysis. Therefore, it is important to establish an efficient genetic transformation system for gene function analysis. In this study, we established a highly efficient Agrobacterium-mediated callus genetic transformation system for C. pilosula using stems as explants. After being pre-cultured for 3 days, the explants were infected with Agrobacterium tumefaciens strain GV3101 harboring pCAMBIA1381-35S::GUS at an OD600 value of 0.3 for 15 min, followed by co-cultivation on MS induction medium for 1 day and delayed cultivation on medium supplemented with 250 mg l-1 cefotaxime sodium for 12 days. The transformed calli were selected on screening medium supplemented with 250 mg l-1 cefotaxime sodium and 2.0 mg l-1 hygromycin and further confirmed by PCR amplification of the GUS gene and histochemical GUS assay. Based on the optimal protocol, the induction and transformation efficiency of calli reached a maximum of 91.07%. The establishment of a genetic transformation system for C. pilosula calli lays the foundation for the functional analysis of genes related to bioactive components through genetic engineering technology.

3.
Int Microbiol ; 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352292

RESUMO

Fungi capable of producing fruit bodies are essential food and medicine resources. Despite recent advances in the study of microbial communities in mycorrhizospheres, little is known about the bacterial communities contained in fruit bodies. Using high-throughput sequencing, we investigated the bacterial communities in four species of mushrooms located on the alpine meadow and saline-alkali soil of the Qinghai-Tibet Plateau (QTP). Proteobacteria (51.7% on average) and Actinobacteria (28.2% on average) were the dominant phyla in all of the sampled fairy ring fruit bodies, and Acidobacteria (27.5% on average) and Proteobacteria (25.7% on average) dominated their adjacent soils. For the Agria. Bitorquis, Actinobacteria was the dominant phylum in its fruit body (67.5% on average) and adjacent soils (65.9% on average). The alpha diversity (i.e., Chao1, Shannon, Richness, and Simpson indexes) of the bacterial communities in the fruit bodies were significantly lower than those in the soil samples. All of the fungi shared more than half of their bacterial phyla and 16.2% of their total operational taxonomic units (OTUs) with their adjacent soil. Moreover, NH4+ and pH were the key factors associated with bacterial communities in the fruit bodies and soils, respectively. These results indicate that the fungi tend to create a unique niche that selects for specific members of the bacterial community. Using culture-dependent methods, we also isolated 27 bacterial species belonging to three phyla and five classes from fruit bodies and soils. The strains isolated will be useful for future research on interactions between mushroom-forming fungi and their bacterial endosymbionts.

4.
Front Pharmacol ; 13: 988245, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36330093

RESUMO

In recent years, with frequent reports of multi-drug resistant strains, bacteria antibiotic resistance has become an increasingly serious health problem worldwide. One of the most promising ways for combating bacterial infections and antibiotic resistance is development of quorum-sensing (QS) interfering drugs. In this study, the results show that 1,8-cineole inhibited the expression of QS as well as the virulence genes in Escherichia coli O101 (E. coli O101) with a 65% inhibition rate against luxS gene. Therefore, we hypothesized that 1,8-cineole may inhibit the biofilm formation and reduce the pathogenicity of E. coli O101 by inhibiting the expression of luxS gene. To confirm our hypotheses, a luxS gene deleted E. coli O101 was constructed. The results show that the biofilm formation, motility, structure and pathogenicity of E. coli O101 were significantly inhibited following deletion of the luxS gene. In addition, the transcript levels of QS and virulence genes of E. coli O101 were also significantly down-regulated. Interestingly, 1,8-cineole no longer had a significant inhibitory effect on the related phenotype and gene expression of E. coli O101 without luxS gene. In conclusion, the results show that 1,8-cineole can affect bacterial biofilm formation and pathogenicity by suppressing the expression of luxS gene in E. coli O101, which could provide a new perspective for dealing with the biofilm problem of pathogenic bacteria.

5.
Front Pharmacol ; 13: 1010593, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36330094

RESUMO

Fungal-infections are mostly due to fungi in an adhering, biofilm-mode of growth and not due to planktonically growing, suspended-fungi. 1, 8-cineole is a natural product, which has been shown to possess antifungal effect. However, the anti-biofilm effect and mechanism of 1,8-cineole against Fusarium solani species complex has not reported previously. In this study, we found that 1,8-cineole has a good antifungal activity against F. solani with an MIC value of 46.1 µg/ml. Notably, 1,8-cineole showed good anti-biofilm formation activity against F. solani via inhibiting cell adhesion, hypha formation and decreasing the secretion of extracellular matrix at the concentration of ≥5.76 µg/ml. In addition, transcriptome sequencing analysis results showed that F. solani species complex genes related to ECM, protein synthesis and energy metabolism were down-expressed in the biofilms formation process treated with 1,8-cineole. In conclusion, these results show that 1,8-cineole has good anti-biofilm formation activity against F. solani species complex, and it exerts its anti-biofilm formation activity by downregulating of ergosterol biosynthetic genes, inhibiting adhesion, hindering the synthesis of ECM and interfering mitochondrial activity. This study suggests that 1,8-cineole is a promising anti-biofilm agent against F. solani species complex.

6.
Sci Rep ; 12(1): 18723, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333392

RESUMO

The prediction of possibility and risk classification of collapse is an important issue in the process of highway construction in mountain area. Based on the principle of rough set and support vector machine, a landslide hazard prediction model was established. First of all, according to field investigation, an evaluation index system and a sample set of evaluation index data were established, the rough set decision table was constructed by preprocessing the original data based on the function classification of standard evaluation index, and then, the influence indexes of the collapse activity were reduced by rough set theory, and the main 9 indexes affecting the collapse activity as the key discriminant factors of support vector machine model, namely slope shape of slope, aspect of slope, slope of slope, height of slope, exposed structural face, stratum lithology, relationship between weakness face and free face, vegetation cover rate and weathering degree of rock were extracted. Then, taking the data of 13 post earthquake collapses in Yingxiu-Wolong highway of Hanchuan County measured by the authors in the field as training samples, the optimal model parameters were analyzed and calculated. When the penalty parameter [Formula: see text] is 8 and the kernel parameter [Formula: see text] is 0.5, the correct rate of cross-validation is 100%, and the model is optimal. At last, 4 other landslide data were tested, the discriminant results of the test sample data were compared with the results obtained by uncertainty measure and distance discriminant analysis. The results show that the discriminant results of the test sample data by RS-SVM were consistent with the results obtained by uncertainty measure and distance discriminant analysis, the accurate rate is 100%. The collapse hazard analysis model based on rough set and support vector machine can reduce the computation while ensuring the accuracy of evaluation, and better solve the small sample and nonlinear problems, can provide certain a good idea for collapse hazard evaluation in the future.

7.
Int J Pharm ; 628: 122277, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36241032

RESUMO

Co-localization of antigens and immunomodulators in the same antigen-presenting cells (APCs) can powerfully activate APCs and enhance immune responses. In this study, the immunomodulator resveratrol (Res) was encapsulated into quaternized chitosan (QCS) - coated liposomes for developing a new nanoparticle delivery system (QCS-Res-LP), and ovalbumin (OVA) was selected as a model antigen and adsorbed on the surface of QCS-Res-LP. The results showed that the particle size of QCS-Res-LP was 96.3 ± 3.52 nm; the PDI value was 0.280 ± 0.010; the Zeta potential was 9.59 ± 0.36 mV. QCS-Res-LP could encapsulate 76.22 ± 1.02 % resveratrol and adsorb 88.2 ± 16.3 % antigen. QCS-Res-LP effectively promoted the co-uptake of antigen and Res by dendritic cells (DCs) with 50-fold greater than resveratrol liposomes (Res-LP). QCS-Res-LP promoted expression levels of CD80, CD86, IL-2, and IL-12 in DCs. QCS-Res-LP did not cause hemolysis. The levels of ovalbumin-specific IgG antibodies and cytokines were significantly increased in mice vaccinated with ovalbumin-absorbed QCS-Res-LP, which induced a mixed Th1/Th2 immune response. In conclusion, these results demonstrated that QCS-coated liposomes enable the co-delivery of antigens and immunomodulators to induce strong and durable immune responses.


Assuntos
Quitosana , Lipossomos , Animais , Camundongos , Lipossomos/metabolismo , Quitosana/metabolismo , Resveratrol , Ovalbumina , Antígenos , Adjuvantes Imunológicos , Imunidade , Células Dendríticas
8.
Front Pharmacol ; 13: 953284, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36071830

RESUMO

Octadecanoic acid-3,4-tetrahydrofuran diester is a compound with acaricidal activity isolated and extracted from neem oil. In this study, a series of derivatives were obtained by structural modification of octadecanoic acid-3,4-tetrahydrofuran diester. The acaricidal activity of these derivatives indicated that introduction of benzyloxy substitution at the 2-position of the furan ring and the formation of a benzoate at the 3,4-position of the furan ring (benzoic acid-2-benzyloxy-3,4-tetrahydrofuran diester) could enhance the acaricidal activity. At concentration of 20, 10, and 5 mg/ml, the median lethal time (LT50) values of benzoic acid-2-benzyloxy-3,4-tetrahydrofuran diester were 16.138, 47.274, and 108.122 min, respectively. The LC50 value of benzoic acid-2-benzyloxy-3,4-tetrahydrofuran diester at 60 min was 5.342 mg/ml. Transmission electron microscopy showed that after treatment with benzoic acid-2-benzyloxy-3,4-tetrahydrofuran diester, the body structure of mites was destroyed; dermal organelles were dissolved; nuclear chromatin was ablated. Further, transcriptome sequencing analysis was used to get insight into the acaricidal mechanism of benzoic acid-2-benzyloxy-3,4-tetrahydrofuran diester. The results showed that its acaricidal mechanism is related to interfering "energy metabolism" in S. scabiei, including processes such as citric acid cycle, oxidative phosphorylation pathway and fatty acid metabolism. Additionally, through the activity detection of the mitochondrial complexes of S. scabiei, it was further verified that the acaricidal mechanism of benzoic acid-2-benzyloxy-3,4-tetrahydrofuran diester was related to the energy metabolism system of S. scabiei.

9.
Front Neuroinform ; 16: 937891, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120083

RESUMO

Objective: To explore the feasibility of a deep learning three-dimensional (3D) V-Net convolutional neural network to construct high-resolution computed tomography (HRCT)-based auditory ossicle structure recognition and segmentation models. Methods: The temporal bone HRCT images of 158 patients were collected retrospectively, and the malleus, incus, and stapes were manually segmented. The 3D V-Net and U-Net convolutional neural networks were selected as the deep learning methods for segmenting the auditory ossicles. The temporal bone images were randomized into a training set (126 cases), a test set (16 cases), and a validation set (16 cases). Taking the results of manual segmentation as a control, the segmentation results of each model were compared. Results: The Dice similarity coefficients (DSCs) of the malleus, incus, and stapes, which were automatically segmented with a 3D V-Net convolutional neural network and manually segmented from the HRCT images, were 0.920 ± 0.014, 0.925 ± 0.014, and 0.835 ± 0.035, respectively. The average surface distance (ASD) was 0.257 ± 0.054, 0.236 ± 0.047, and 0.258 ± 0.077, respectively. The Hausdorff distance (HD) 95 was 1.016 ± 0.080, 1.000 ± 0.000, and 1.027 ± 0.102, respectively. The DSCs of the malleus, incus, and stapes, which were automatically segmented using the 3D U-Net convolutional neural network and manually segmented from the HRCT images, were 0.876 ± 0.025, 0.889 ± 0.023, and 0.758 ± 0.044, respectively. The ASD was 0.439 ± 0.208, 0.361 ± 0.077, and 0.433 ± 0.108, respectively. The HD 95 was 1.361 ± 0.872, 1.174 ± 0.350, and 1.455 ± 0.618, respectively. As these results demonstrated, there was a statistically significant difference between the two groups (P < 0.001). Conclusion: The 3D V-Net convolutional neural network yielded automatic recognition and segmentation of the auditory ossicles and produced similar accuracy to manual segmentation results.

10.
Ecotoxicol Environ Saf ; 244: 114050, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36063614

RESUMO

Exposure to ammonia can cause convulsions, coma, and death. In this study, we investigate the effects of ammonia exposure on immunoregulatory and neuroendocrine changes in Takifugu rubripes. Fish were sampled at 0, 12, 24, 48, and 96 h following exposure to different ammonia concentrations (0, 5, 50, 100, and 150 mg/L). Our results showed that exposure to ammonia significantly reduced the concentrations of C3, C4, IgM, and LZM whereas the heat shock protein 70 and 90 levels significantly increased. In addition, the transcription levels of Mn-SOD, CAT, GRx, and GR in the liver were significantly upregulated following exposure to low ammonia concertation, however, downregulated with increased exposure time. These findings suggest that ammonia poisoning causes oxidative damage and suppresses plasma immunity. Ammonia exposure also resulted in the elevation and depletion of the T3 and T4 levels, respectively. Furthermore, ammonia stress induced an increase in the corticotrophin-releasing hormone, adrenocorticotropic hormone, and cortisol levels, and a decrease in dopamine, noradrenaline, and 5-hydroxytryptamine levels in the brain, illustrating that ammonia poisoning can disrupt the endocrine and neurotransmitter systems. Our results provide insights into the mechanisms underlying the neurotoxic effects of ammonia exposure, which helps to assess the ecological and environmental health risks of this contaminant in marine fish.


Assuntos
Amônia , Takifugu , Hormônio Adrenocorticotrópico/metabolismo , Amônia/metabolismo , Animais , Encéfalo/metabolismo , Dopamina/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Hidrocortisona/metabolismo , Imunidade , Imunoglobulina M/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Superóxido Dismutase/metabolismo , Takifugu/metabolismo , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo
11.
J Trace Elem Med Biol ; 74: 127060, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35987180

RESUMO

BACKGROUND: The role of iron biomarkers and iron intake in the susceptibility to lung cancer is unclear. The purpose of this study was to conduct a systematic review and meta-analysis, to assess the relationship between iron levels in the body or iron intake and the risk of lung cancer. METHOD: This review is registered with PROSPERO (number CRD 42020199776). PubMed, Web of Science, Scopus, Embase and Cochrane were used to search for studies assessing the relationship between iron and lung cancer, up to July 15, 2021. Qualitative and quantitative analysis was carried out to determine if there was a correlation between iron biomarkers/intakes and the risk of lung cancer. RESULT: Twenty articles were included. Pooled analyses demonstrated that serum ferritin concentrations and transferrin saturation (TSAT) were significantly higher in patients with lung cancer than in healthy controls (ferritin: standardized mean differences [SMD], 0.235, 95% confidence interval [CI], 0.129, 0.341, I2 = 32.1 %; TSAT: SMD, 0.07, 95 % CI, 0.018, 0.121, I2 = 0 %). In contrast, serum transferrin concentrations were significantly lower in patients with lung cancer than in healthy controls (SMD, -0.591, 95 % CI, -1.18, -0.003, I2 = 87.7 %). No significant effects of serum iron, lung tissue iron, bronchoalveolar lavage fluid (BALF) ferritin, or iron intake (total iron, dietary iron, heme iron, or non-heme iron) were found on lung cancer incidence. CONCLUSION: Among the different iron biomarkers analyzed, a trend in association was only detected with serum ferritin, TSAT and transferrin concentration and no associations were found between iron intakes and the risk of lung cancer. However, more prospective studies are needed to strengthen the current evidence.


Assuntos
Ferro na Dieta , Neoplasias Pulmonares , Biomarcadores , Ferritinas , Humanos , Ferro/metabolismo , Pulmão/metabolismo , Transferrina
12.
Fish Physiol Biochem ; 48(5): 1167-1181, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35941472

RESUMO

Tiger pufferfish (Takifugu rubripes) is one of Asia's most economically valuable aquaculture species. However, winter production of this species in North China is limited by low water temperature and unavailability of high-quality feed, resulting in high mortality and low profitability. Therefore, the aim of this study was to evaluate the effect of feeding frequency (F1: one daily meal; F2: two daily meals; F3: four daily meals; F4: continuous diurnal feeding using a belt feeder) on the growth performance, plasma biochemistry, digestive and antioxidant enzyme activities, and expression of appetite-related genes in T. rubripes (initial weight: 266.80 ± 12.32 g) cultured during winter (18.0 ± 1.0 °C) for 60 days. The results showed that fish in the F3 group had the highest final weight, weight gain rate, specific growth rate, survival rate, and best feed conversion ratio. Additionally, daily feed intake increased significantly with increasing feeding frequency. The protein efficiency and lipid efficiency ratios of fish in the F3 group were significantly higher than those of fish in the other groups. Furthermore, total cholesterol, triglycerides, and glucose levels increased with increasing feeding frequency, peaking in the F2 group and decreasing under higher feeding frequencies. The antioxidant (superoxide dismutase, catalase, glutathione, and glutathione peroxidase) and digestive (trypsin, amylase, and lipase) enzyme activities of fish in the F1 group were significantly higher than those of fish in the F3 and F4 groups. Additionally, there was a decrease in orexin expression with increasing feeding frequency. In contrast, the expression levels of tachykinin, cholecystokinin, and leptin increased with increasing feeding frequency, peaking in the F4 group. Overall, the findings of this study indicated that a feeding frequency of four meals per day was optimal for improved growth performance of pufferfish juveniles cultured during winter.


Assuntos
Antioxidantes , Takifugu , Animais , Takifugu/metabolismo , Catalase/genética , Catalase/metabolismo , Antioxidantes/metabolismo , Leptina/metabolismo , Orexinas/metabolismo , Orexinas/farmacologia , Apetite , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Tripsina/metabolismo , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Peixes/metabolismo , Triglicerídeos/metabolismo , Colesterol/metabolismo , Glutationa/metabolismo , Colecistocinina , Amilases/metabolismo , Lipase/metabolismo , Água/metabolismo , Glucose/metabolismo , Lipídeos/farmacologia
13.
Cancer Gene Ther ; 29(10): 1439-1451, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35388172

RESUMO

Increased vascular permeability facilitates metastasis. Cancer-secreted exosomes are emerging mediators of cancer-host crosstalk. Epstein-Barr virus (EBV), identified as the first human tumor-associated virus, plays a crucial role in metastatic tumors, especially in nasopharyngeal carcinoma (NPC). To date, whether and how exosomes from EBV-infected NPC cells affect vascular permeability remains unclear. Here, we show that exosomes from EBV-positive NPC cells, but not exosomes from EBV-negative NPC cells, destroy endothelial cell tight junction (TJ) proteins, which are natural barriers against metastasis, and promote endothelial-to-mesenchymal transition (EndMT) in endothelial cells. Proteomic analysis revealed that the level of HMGA2 protein was higher in exosomes derived from EBV-positive NPC cells compared with that in exosomes derived from EBV-negative NPC cells. Depletion of HMGA2 in exosomes derived from EBV-positive NPC cells attenuates endothelial cell dysfunction and tumor cell metastasis. In contrast, exosomes from HMGA2 overexpressing EBV-negative NPC cells promoted these processes. Furthermore, we showed that HMGA2 upregulates the expression of Snail, which contributes to TJ proteins reduction and EndMT in endothelial cells. Moreover, the level of HMGA2 in circulating exosomes is significantly higher in NPC patients with metastasis than in those without metastasis and healthy negative controls, and the level of HMGA2 in tumor cells is associated with TJ and EndMT protein expression in endothelial cells. Collectively, our findings suggest exosomal HMGA2 from EBV-positive NPC cells promotes tumor metastasis by targeting multiple endothelial TJ and promoting EndMT, which highlights secreted HMGA2 as a potential therapeutic target and a predictive marker for NPC metastasis.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Herpesvirus Humano 4/metabolismo , Humanos , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Proteômica
14.
BMC Plant Biol ; 22(1): 195, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35413790

RESUMO

BACKGROUND: The genus Swertia is of great medicinal importance and one of the most taxonomically challenging taxa within Gentianaceae, largely due to the morphological similarities of species within this genus and with its closely related genera. Previous molecular studies confirmed its polyphyly but suffered from low phylogenetic resolutions because only limited sequence loci were used. Thus, we conducted the structural, gene evolutionary, and phylogenetic analyses of 11 newly obtained plastomes of Swertia. Our result greatly improved the phylogenetic resolutions in Swertia, shed new light on the plastome evolution and phylogenetic relationships of this genus. RESULTS: The 11 Swertia plastomes together with the published seven species proved highly similar in overall size, structure, gene order, and content, but revealed some structural variations caused by the expansion and contraction of the IRb region into the LSC region, due to the heterogeneous length of the ψycf1. The gene rps16 was found to be in a state flux with pseudogenes or completely lost. Similar situation was also documented in other genera of Gentianaceae. This might imply loss of the gene in the common ancestor of Gentianaceae. The distribution plot of ENC vs. GC3 showed all these plastomes arranging very close in the Wright line with an expected ENC value (49-52%), suggesting the codon usage of Swertia was mainly constrained by a GC mutation bias. Most of the genes remained under the purifying selection, however, the cemA was identified under positive selection, possibly reflecting an adaptive response to low CO2 atmospheric conditions during the Late Miocene. Our phylogenomic analyses, based on 74 protein-coding genes (CDS), supported the polyphyly of Swertia with its close allies in the subtribe Swertiinae, presumably due to recent rapid radiation. The topology inferred from our phylogenetic analyses partly supported the current taxonomic treatment. Finally, several highly variable loci were identified, which can be used in future phylogenetic studies and accurate identification of medicinal genuineness of Swertia. CONCLUSIONS: Our study confirmed the polyphyly of Swertia and demonstrated the power of plastome phylogenomics in improvement of phylogenetic resolution, thus contributing to a better understanding of the evolutionary history of Swertia.


Assuntos
Genomas de Plastídeos , Gentianaceae , Swertia , Evolução Molecular , Gentianaceae/genética , Filogenia , Plastídeos/genética , Tibet
15.
J Spinal Cord Med ; : 1-9, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35353023

RESUMO

OBJECTIVES: Tropisetron is an alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonist and is a commonly used antiemetic clinically. α7nAChRs activation modulating nociception transmissions and cholinergic anti-inflammation may decrease neuropathic pain. This study was set to investigate the effects of tropisetron on neuropathic pain and neuroinflammation as well as the underlying mechanisms in rats. METHODS: Neuropathic pain behavior was assessed in rats using the paw mechanical withdrawal threshold and paw thermal withdrawal latency before and after the establishment of a spared nerve injury (SNI) pain model in rats treated with tropisetron treatment in the presence or absence of the α7nAChR antagonist methyllycaconitine (MLA) through intrathecal injection. Their spinal cords were then harvested for inflammatory cytokines, the α7nAChR, p38 mitogen-activated protein kinase (p-p38MAPK) and cAMP-response element binding protein (CREB) measurement. RESULTS: Tropisetron effectively alleviated mechanical allodynia and thermal hyperalgesia; decreased IL-6, IL-1ß and TNF-a; and down-regulated the phosphorylation of p38MAPK and CREB. Pre-treatment with MLA abolished these effects of tropisetron. CONCLUSION: Our data indicate that tropisetron alleviates neuropathic pain may through inhibition of the p38MAPK-CREB pathway via α7nAChR activation. Thus, tropisetron may be a potential new therapeutic strategy for chronic neuropathic pain.

16.
Endocrinology ; 163(4)2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35213720

RESUMO

Papillary thyroid cancer (PTC) remains the most common endocrine malignancy, despite marked achieves in recent decades, and the mechanisms underlying the pathogenesis and progression for PTC are incompletely elucidated. Accumulating evidence show that γ-glutamylcyclotransferase (GGCT), an enzyme participating in glutathione homeostasis and is elevated in multiple types of tumors, represents an attractive therapeutic target. Using bioinformatics, immunohistochemistry, qRT-PCR, and Western blot assays, we found that GGCT expression was upregulated in PTC and correlated with more aggressive clinicopathological characteristics and worse prognosis. GGCT knockdown inhibited the growth and metastasis ability of PTC cells both in vitro and in vivo and reduced the expression of mesenchymal markers (N-cadherin, CD44, MMP2, and MMP9) while increasing epithelial marker (E-cadherin) in PTC cells. We confirmed binding of microRNA-205-5p (miR-205-5p) on the 3'-UTR regions of GGCT by dual-luciferase reporter assay and RNA-RNA pull-down assay. Delivery of miR-205-5p reversed the pro-malignant capacity of GGCT both in vitro and in vivo. Lastly, we found that GGCT interacted with and stabilized CD44 in PTC cells by co-immunoprecipitation and immunohistochemistry assays. Our findings illustrate a novel signaling pathway, miR-205-5p/GGCT/CD44, that involves in the carcinogenesis and progression of PTC. Development of miR-205-mimics or GGCT inhibitors as potential therapeutics for PTC may have remarkable applications.


Assuntos
MicroRNAs , Neoplasias da Glândula Tireoide , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , gama-Glutamilciclotransferase/genética , gama-Glutamilciclotransferase/metabolismo
17.
Mol Cancer Res ; 20(1): 161-175, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34654722

RESUMO

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Linfangiogênese/genética , Metástase Linfática/fisiopatologia , Carcinoma Nasofaríngeo/fisiopatologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Microambiente Tumoral , Regulação para Cima
18.
Glia ; 70(2): 379-392, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34724258

RESUMO

Myelin sheath is an important structure to maintain functions of the nerves in central nervous system. Protein palmitoylation has been established as a sorting determinant for the transport of myelin-forming proteins to the myelin membrane, however, its function in the regulation of oligodendrocyte development remains unknown. Here, we show that an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC5, is involved in the control of oligodendrocyte development. Loss of Zdhhc5 in oligodendrocytes inhibits myelination and remyelination by reducing total myelinating oligodendrocyte population. STAT3 is the primary substrate for DHHC5 palmitoylation in oligodendrocytes. Zdhhc5 ablation reduces STAT3 palmitoylation and suppresses STAT3 phosphorylation and activation. As a result, the transcription of the myelin-related and anti-apoptosis genes is inhibited, leading to suppressed oligodendrocyte development and myelination. Our findings demonstrate a key role DHHC5 in controlling myelinogenesis.


Assuntos
Bainha de Mielina , Oligodendroglia , Células Cultivadas , Lipoilação , Bainha de Mielina/metabolismo , Neurogênese , Oligodendroglia/metabolismo
19.
Front Immunol ; 12: 783236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899747

RESUMO

Hepatocellular carcinoma (HCC), one of the most fatal malignancies in the world, is usually diagnosed in advanced stages due to late symptom manifestation with very limited therapeutic options, which leads to ineffective intervention and dismal prognosis. For a decade, tyrosine kinase inhibitors (TKIs) have offered an overall survival (OS) benefit when used in a first-line (sorafenib and lenvatinib) and second-line setting (regorafenib and cabozantinib) in advanced HCC, while long-term response remains unsatisfactory due to the onset of primary or acquired resistance. Recently, immunotherapy has emerged as a promising therapy in the treatment of several solid tumors, such as melanoma and non-small cell lung cancer. Moreover, as the occurrence of HCC is associated with immune tolerance and immunosurveillance escape, there is a potent rationale for employing immunotherapy in HCC. However, immunotherapy monotherapy, mainly including immune checkpoint inhibitors (ICIs) that target checkpoints programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and the cytotoxic T lymphocyte antigen-4 (CTLA-4), has a relatively low response rate. Thus, the multi-ICIs or the combination of immunotherapy with other therapies, like antiangiogenic drugs and locoregional therapies, has become a novel strategy to treat HCC. Combining different ICIs may have a synergistical effect attributed to the complementary effects of the two immune checkpoint pathways (CTLA-4 and PD-1/PD-L1 pathways). The incorporation of antiangiogenic drugs in ICIs can enhance antitumor immune responses via synergistically regulating the vasculature and the immune microenvironment of tumor. In addition, locoregional treatments can improve antitumor immunity by releasing the neoplasm antigens from killed tumor cells; in turn, this antitumor immune response can be intensified by immunotherapy. Therefore, the combination of locoregional treatments and immunotherapy may achieve greater efficacy through further synergistic effects for advanced HCC. This review aims to summarize the currently reported results and ongoing trials of the ICIs-based combination therapies for HCC to explore the rational combination strategies and further improve the survival of patients with HCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/terapia , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/métodos , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Ensaios Clínicos como Assunto , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fígado/imunologia , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Intervalo Livre de Progressão , Ablação por Radiofrequência/métodos , Radiocirurgia/métodos , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Evasão Tumoral/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
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