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1.
Artigo em Inglês | MEDLINE | ID: mdl-33596170

RESUMO

To solve the low spatial and/or temporal resolution problem which the conventional hyperspectral cameras often suffer from, coded hyperspectral imaging systems have attracted more attention recently. Recovering a hyperspectral image (HSI) from its corresponding coded image is an ill-posed inverse problem, and learning accurate prior of HSI is essential to solve this inverse problem. In this paper, we present an effective convolutional neural network (CNN) based method for coded HSI reconstruction, which learns the deep prior from the external dataset as well as the internal information of input coded image. Specifically, we first develop a CNN-based reconstruction network to exploit spatial-spectral correlation of the HSI. Then, the reconstruction network is learned by leveraging an arbitrary external hyperspectral dataset to exploit the general spatial-spectral correlation under adversarial loss. Finally, we customize the network by internal learning with spatial-spectral constraint and total variation regularization for each coded image, which can make use of the internal imaging model to learn specific prior for current desirable image and effectively avoids overfitting. Experimental results using both synthetic data and real images show that our method outperforms the state-of-the-art methods on several popular coded hyperspectral imaging systems under both comprehensive quantitative metrics and perceptive quality.

2.
Sci Rep ; 11(1): 2957, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536496

RESUMO

In this study, we analyzed the complete mitochondrial genome (mitogenome) of Speiredonia retorta, which is a pest and a member of the Lepidoptera order. In total, the S. retorta mitogenome was found to contain 15,652 base pairs encoding 13 protein-coding genes (PCGs), 22 tRNAs, 2 rRNAs, as well as an adenine (A) + thymine (T)-rich region. These findings were consistent with the mitogenome composition of other lepidopterans, as we identified all 13 PCGs beginning at ATN codons. We also found that 11 PCGs terminated with canonical stop codons, whereas cox2 and nad4 exhibited incomplete termination codons. By analyzing the mitogenome of S. retorta using Bayesian inference (BI) and maximum likelihood (ML) models, we were able to further confirm that this species is a member of the Erebidae family.

3.
Int Immunopharmacol ; 93: 107378, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33529915

RESUMO

OBJECTIVE: This study was performed to test whether ATG16L1 rs2241880, rs6758317 and ATG16L2 rs11235604 polymorphisms were associated with RA and further examine the genetic interaction between ATG16L1 and ATG16L2 in RA among a Chinese population. METHODS: A total of 594 RA patients and 604 healthy controls were included, and the genetic polymorphisms were genotyped based on HI-SNP technology. RESULTS: Significant associations of ATG16L1 rs2241880 polymorphism with RA (T/T versus C/T + C/C, OR = 1.32, 95% CI 1.04-1.67, P = 0.02), cyclic citrullinated peptide (CCP)-positive RA (genotype comparison, P = 5.38 × 10-3; T/T versus C/T + C/C, OR = 1.45, 95% CI 1.12-1.87, P = 4.86 × 10-3) and rheumatoid factor (RF)-positive RA (genotype comparison, P = 0.03; T versus C, OR = 1.23, 95% CI 1.01-1.49, P = 0.04; T/T versus C/T + C/C, OR = 1.44, 95% CI 1.10-1.88, P = 7.62 × 10-3) were found. Significant genetic interaction between ATG16L1 rs2241880 and ATG16L2 rs11235604 was associated RA (P = 0.03), and significant genetic interaction between ATG16L1 rs6758317 and ATG16L2 rs11235604 was associated with RA (P = 7.57 × 10-3), CCP-positive RA (P = 0.01) and RF-positive RA (P = 0.01). Consistently, stratification analysis found that significant associations of RA with ATG16L1 rs2241880, rs6758317 polymorphisms were only detected among individuals carrying C/T genotype of the ATG16L2 rs11235604 polymorphism. CONCLUSIONS: Our results indicated that ATG16L1 rs2241880 polymorphism was associated with RA in Chinese population, and provided evidence for genetic interaction between ATG16L1 and ATG16L2 in determing the development of RA, highlighting the involvement of autophagy in the pathogenesis of RA.

4.
Biol Reprod ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33624742

RESUMO

The zona pellucida (ZP) plays vital roles in reproductive processes including oogenesis, fertilization and preimplantation development. Both human and rat ZP consist of four glycoproteins, called ZP1, ZP2, ZP3 and ZP4. Our previous research reported a novel Zp1 mutation in cases of human infertility, associated with an abnormal phenotype involving the absence of the zona pellucida. Here, we developed a homologous rat strain to investigate the pathogenic effect. The ovaries of homozygous (Zp1MT/MT) females possessed both growing and fully grown oocytes; the oocytes completely lacked a zona pellucida, but ZP1 was detectable inside the cytoplasm. Only 1-2 eggs were recovered from oviducts of superovulated Zp1MT/MT females, while ≈ 21 eggs were recovered from superovulated Zp1WT/WT females. The eggs of Zp1MT/MT females were not surrounded by a zona pellucida and lost their fertilization capacity in vitro. Zp1MT/MT females mated with wild-type males failed to become pregnant. Studies in 293 T cells showed that mutant Zp1 resulted in a truncated ZP1 protein, which might be intracellularly sequestered and interact with wild-type ZP3 or ZP4. Our results suggest that the Zp1 point mutation led to infertility and loss of the ZP in oocytes in rats.

5.
Curr Neuropharmacol ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430733

RESUMO

Chlorogenic acid (CGA) is a kind of traditional Chinese medicine, abundant in honeysuckle and eucommia, has a wide range of biological activities, and pharmacological effects. Previous studies have shown that CGA can regulate learning, memory, cognitive ability, coupled with improvement to anxiety, depression, and other post-traumatic stress disorder (PTSD)-like symptoms. This article explores the protective effects of CGA on neurons, through its anti-apoptotic effect, inhibition of neuroinflammation and oxidative stress, which may be the mechanisms of its improvement of PTSD-like symptoms. It may provide a new therapeutic strategy for the treatment of PTSD and its comorbidities.

6.
J Exp Clin Cancer Res ; 40(1): 8, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402215

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal malignancy, with an average 5-year survival rate of 9% (Siegel RL, Miller KD, Jemal A. Ca Cancer J Clin. 2019;69(1):7-34). The steady increase in mortality rate indicates limited efficacy of the conventional regimen. The heterogeneity of PDAC calls for personalized treatment in clinical practice, which requires the construction of a preclinical system for generating patient-derived models. Currently, the lack of high-quality preclinical models results in ineffective translation of novel targeted therapeutics. This review summarizes applications of commonly used models, discusses major difficulties in PDAC model construction and provides recommendations for integrating workflows for precision medicine.

7.
Nat Commun ; 12(1): 494, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479210

RESUMO

Mast cells are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the mast cell lineage-determining factors. However, it is unclear whether these lineage-determining factors regulate chromatin accessibility at mast cell enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of mast cell identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We find that the number and densities of GATA2- but not MITF-bound sites at the super-enhancers are several folds higher than that at the typical enhancers. Our studies reveal that GATA2 promotes robust gene transcription to maintain mast cell identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key mast cell genes.


Assuntos
Antígenos/metabolismo , Montagem e Desmontagem da Cromatina/genética , Elementos Facilitadores Genéticos/genética , Fator de Transcrição GATA2/genética , Mastócitos/metabolismo , Animais , Antígenos/imunologia , Linhagem da Célula/genética , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Feminino , Fator de Transcrição GATA2/metabolismo , Perfilação da Expressão Gênica/métodos , Masculino , Mastócitos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo
8.
Cancer Metastasis Rev ; 40(1): 245-272, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33423164

RESUMO

Pancreatic cancer (PC) is assumed to be an intimidating and deadly malignancy due to being the leading cause of cancer-led mortality, predominantly affecting males of older age. The overall (5 years) survival rate of PC is less than 9% and is anticipated to be aggravated in the future due to the lack of molecular acquaintance and diagnostic tools for its early detection. Multiple factors are involved in the course of PC development, including genetics, cigarette smoking, alcohol, family history, and aberrant epigenetic signatures of the epigenome. In this review, we will mainly focus on the genetic mutations and epigenetic signature of PC. Multiple tumor suppressor and oncogene mutations are involved in PC initiation, including K-RAS, p53, CDKN2A, and SMAD4. The mutational frequency of these genes ranges from 50 to 98% in PC. The nature of mutation diagnosis is mostly homozygous deletion, point mutation, and aberrant methylation. In addition to genetic modification, epigenetic alterations particularly aberrant hypermethylation and hypomethylation also predispose patients to PC. Hypermethylation is mostly involved in the downregulation of tumor suppressor genes and leads to PC, while multiple genes also represent a hypomethylation status in PC. Several renewable drugs and detection tools have been developed to cope with this aggressive malady, but all are futile, and surgical resection remains the only choice for prolonged survival if diagnosed before metastasis. However, the available therapeutic development is insufficient to cure PC. Therefore, novel approaches are a prerequisite to elucidating the genetic and epigenetic mechanisms underlying PC progression for healthier lifelong survival.

9.
BMC Cancer ; 21(1): 20, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402102

RESUMO

BACKGROUND: Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. METHODS: RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety. DISCUSSION: This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer. TRIAL REGISTRATION: Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.

10.
J Org Chem ; 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33423501

RESUMO

A highly chemoselective [2+1] annulation of α-alkylidene pyrazolones with α-bromonitroalkenes has been achieved under mild conditions. α-Alkylidene pyrazolones were unprecedentedly used as a C1 synthon to participate in annulation reactions, providing access to diverse vinylcyclopropane-based pyrazolone products. In addition, a spectrum of pharmaceutically interesting pyrazole-fused pyranone oximes could be rapidly obtained through a [2+1] annulation/rearrangement sequential process. Computational studies disclosed the origin of the observed chemoselectivity of the [2+1] cycloaddition.

11.
NMR Biomed ; 34(3): e4449, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33354829

RESUMO

The aim of this study was to establish reference values for middle-aged subjects and to investigate the age and gender dependence of liver diffusion MRI parameters. The IVIM type of liver diffusion scan was based on a single-shot spin-echo-type echo-planar sequence using a 1.5 T magnet with 16 b-values. Diffusion-derived vessel density (DDVD)(b0b2) or DDVD(b0b10) was the signal difference between b = 0 and b = 2 (or b = 10) s/mm2 images after removing visible vessels. IVIM analysis was performed with full fitting and segmented fitting, and with a threshold b-value of 60 or 200 s/mm2 , and fitting started from b = 2 s/mm2 . Thirty-one men (age range: 25-71 years) and 26 men (age: 22-69 years) had DDVD and IVIM analysis, respectively, while 37 women (age: 20-71 years) and 36 women (age: 20-71 years) had DDVD and IVIM analysis, respectively. DDVD results showed a significant age-related reduction for women. IVIM results for full fitting showed excellent agreement with those for segmented fitting using a threshold b of 60 s/mm2 , but this was less good for results with a threshold b of 200 s/mm2 . As age increased, female subjects' Dslow measure showed a significant reduction, while their PF and Dfast measures showed a significant increase. For the age group of 40-55 years, DDVD(b0b2), DDVD(b0b10), Dslow , PF and Dfast were 12.26 ± 3.90 au/pixel, 16.95 ± 5.45 au/pixel, 1.072 ± 0.067 (10-3 mm2 /s), 0.141 ± 0.025 and 61.0 ± 14.0 (10-3 mm2 /s) for men, and 13.35 ± 3.6 au/pixel, 17.20 ± 3.62 au/pixel, 1.069 ± 0.074 (10-3 mm2 /s), 0.119 ± 0.014 and 57.1 ± 13.2 (10-3 mm2 /s) for women, respectively. DDVD measure of this study suggest that aging is associated with a reduction in liver perfusion. There is a possibility that a lower Dslow measure is associated with artificially higher PF and Dfast measures, and that IVIM modeling of the perfusion component is constrained by the diffusion component.

12.
Huan Jing Ke Xue ; 42(1): 359-367, 2021 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-33372488

RESUMO

The bioaccessibility and health risks of heavy metals in soil-rice system of southwestern Fujian province were studied by combining a simple bioavailability extraction method (SBET) with a health risk assessment model. The results showed that some heavy metals in the agricultural soils and rice of southwestern Fujian province were enriched. The contents of Cd, Zn, Pb, and Cu were greater than the screening value of soil pollution risk for agricultural land (GB 15618-2018) by 32.4%, 15.5%, 14.1%, and 12.7% in the study areas, respectively. The accumulation ability of heavy metals was different and followed the approximately decreasing order of Cd > Zn > Cu > Ni > Hg > As > Cr > Pb. The bioaccessibility of heavy metals in soils and rice were quite different. The bioaccessibility of each heavy metal in rice was greater than the bioaccessibility of the heavy metals in soil, which indicated that the heavy metals in rice were more easily absorbed by the human body. The comprehensive non-carcinogenic risk index (HI) of heavy metals to adults and children was 2.71 and 4.06, respectively, indicating that there were non-carcinogenic risks. The comprehensive carcinogenic risk index (TCR) of heavy metals to adults and children was 1.42×10-3 and 5.28×10-4, respectively, indicating that there was a carcinogenic risk present. The non-carcinogenic risks were mainly due to As, while the carcinogenic risks were mainly contributed by Cd. The non-carcinogenic risk of children was higher than that of adults, while the carcinogenic risk of children was lower than that of adults. This result may be related to physiological characteristics, exposure period, and dietary intake. The dietary intake route may be the main pathway for heavy metals in the soil-rice system of southwest Fujian province to cause health risks. Therefore, more attention should be paid to the risks of dietary exposure in the risk management of heavy metals.


Assuntos
Metais Pesados , Oryza , Poluentes do Solo , Adulto , Criança , China , Monitoramento Ambiental , Humanos , Metais Pesados/análise , Medição de Risco , Solo , Poluentes do Solo/análise
13.
Sci Rep ; 10(1): 21026, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273556

RESUMO

Iron homeostasis is an essential biological process that ensures the tissue distribution of iron for various cellular processes. As the major producer of hepcidin, the liver is central to the regulation of iron metabolism. The liver is also home to many immune cells, which upon activation may greatly impact iron metabolism. Here, we focus on the role of invariant natural killer T (iNKT) cells, a subset of T lymphocytes that, in mice, is most abundant in the liver. Activation of iNKT cells with the prototypical glycosphingolipid antigen, α-galactosylceramide, resulted in immune cell proliferation and biphasic changes in iron metabolism. This involved an early phase characterized by hypoferremia, hepcidin induction and ferroportin suppression, and a second phase associated with strong suppression of hepcidin despite elevated levels of circulating and tissue iron. We further show that these changes in iron metabolism are fully dependent on iNKT cell activation. Finally, we demonstrate that the biphasic regulation of hepcidin is independent of NK and Kupffer cells, and is initially driven by the STAT3 inflammatory pathway, whereas the second phase is regulated by repression of the BMP/SMAD signaling pathway. These findings indicate that iNKT activation and the resulting cell proliferation influence iron homeostasis.

14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(6): 2028-2032, 2020 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-33283737

RESUMO

OBJECTIVE: To analyze the hematological characteristics of Hb Broomhill and Hb Hornchurch, and prenatal diagnosis should be carried out in two families. METHODS: RBC parameters and hemoglobin electrophoretogram were analyzed on the peripheral blood of all patients, and amniotic fluid was collected for prenatal diagnosis. PCR-Flow fluorescent hybridization and Sanger sequencing were performed for gene diagnosis of thalassemia. RESULTS: Three cases of Hb Broomhill were detected, including 2 cases with common SEA α-thalassemia, which was characterized by hypochromic microcytic mild anemia, the capillary electrophoregram revealed a tiny shoulder peak before the Hb A peak; 1 case was diagnosed as Hb Hornchurch combined with ß-thalassemia, which also showed mild anemia. Hemoglobin electrophoretogram showed an abnormal hemoglobin variant peak at Hb A2 zone. CONCLUSION: The carriers of Hb Broomhill and Hb Hornchurch do not have microcytic hypochromic anemia, which do not aggravate the hematological symptoms, such as anemia when being combined with thalassemia of the same type.

15.
Zhonghua Nan Ke Xue ; 26(7): 616-619, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-33377717

RESUMO

Objective: To analyze the efficiency of sperm donation by qualified donors and provide some experience for improving the success rate of sperm donation in human sperm banks. METHODS: This study included 440 qualified sperm donors in Chongqing Human Sperm Bank from April 2015 to June 2019. We analyzed the general information about the donors, the causes of failed sperm donation and the results of semen bacterial culture. RESULTS: Among the 440 qualified donors, 11 (2.50%) did not donate sperm, 28 (6.36%) were excluded because of frequent failures to donate, 397 (90.2%) completed all the procedures of sperm donation, and 4 (0.91%) failed to undergo HIV test six months after the last donation. The 397 donors that fulfilled the procedures donated sperm for 2 965 person-times, of which 2 159 (72.8%) were qualified and 806 (27.2%) unqualified for substandard semen quality (n = 684 ï¼»23.1%ï¼½), semen volume <2 ml (n = 33 ï¼»1.11%ï¼½), abnormal seminal liquefaction (n = 14 ï¼»0.47%ï¼½), or positive semen bacterial culture (n = 75 ï¼»2.53%ï¼½). CONCLUSIONS: Substandard semen quality is the main factor affecting the efficiency of sperm donation. The staff of the human sperm bank should pay adequate attention to the first reception of and communication with the donors, dispel their worries, enhance health care guidance, prevent pollution and improve the success rate of sperm donation.


Assuntos
Bancos de Esperma/estatística & dados numéricos , Obtenção de Tecidos e Órgãos , Humanos , Masculino , Análise do Sêmen , Espermatozoides , Doadores de Tecidos
16.
J Immunol ; 205(12): 3311-3318, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33188077

RESUMO

IL-13 plays a critical role in mediating many biological processes responsible for allergic inflammation. Mast cells express Il13 mRNA and produce IL-13 protein in response to antigenic stimulation. Enhancers are essential in promoting gene transcription and are thought to activate transcription by delivering essential accessory cofactors to the promoter to potentiate gene transcription. However, enhancers mediating Il13 have not been identified. Furthermore, which Il13 enhancers detect signals triggered by antigenic stimulation have not yet been defined. In this study, we identified potential mouse Il13 enhancers using histone modification monomethylation at lysine residue 4 on histone 3 (H3K4me1) chromatin immunoprecipitation sequencing and acetylation at lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing. We used Omni-assay for transposase-accessible chromatin sequencing to determine which accessible regions within the potential Il13 enhancers that responded to IgE receptor crosslinking. We also demonstrated that the transcription factor cluster consisting of the NFATC2, STAT5, GATA2, AP1, and RUNX1 binding sites at the proximal Il13 enhancer and the transcription factor cluster consisting of the EGR2 binding site at the distal Il13 E+6.5 enhancer are critical in sensing the signals triggered by antigenic stimulation. Those enhancers, which are responsive to antigenic stimulation and are constitutively active, cooperate to generate greater transcriptional outputs. Our study reveals a novel mechanism underlying how antigenic stimulation induces robust Il13 mRNA expression in mouse mast cells.

17.
Medicine (Baltimore) ; 99(45): e23122, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157990

RESUMO

INTRODUCTION: Hemorrhoidal disease is one of the most common and frequently occurring benign anorectal disorders, presented with bleeding and prolapsed, and surgery is the main and effective method for severe prolapsed hemorrhoids. Yet, the recurrence rate after procedure for prolapse and hemorrhoids (PPH) is significantly higher. To reduce the recurrence rate and protect the anus function, we try to carry out a randomized, controlled, prospective study to compare the efficacy and recurrence rate of tissue selecting technique (TST) with mega-window stapler (TST-MS) combined with anal canal epithelial preservation operation and PPH combined with external hemorrhoidectomy and inferior internal hemorrhoid ligation operation for the treatment of severe prolapsed hemorrhoids. METHODS: This study is a single-center, evaluator-blinded, randomized, controlled clinical trial. Participants meet the inclusion and exclusion criteria in this RCT will be randomly divided into treatment group (TST-MS combined with anal canal epithelial preservation operation group) and control group (PPH combined with external hemorrhoidectomy and inferior internal hemorrhoid ligation operation) in a 1:1 ratio according to a computer-generated randomization list. The outcomes of recurrence, anal function, intraoperative variables, and postoperative complications will be recorded at different follow-ups. CONCLUSION: The findings of the study will help to explore the efficacy and recurrence rate of TST-MS combined with anal canal epithelial preservation operation on the treatment of severe prolapsed hemorrhoids. TRIAL REGISTRATION: This study protocol was registered in open science framework (OSF). (Registration number: DOI 10.17605 / OSF.IO / 4JYNF).


Assuntos
Hemorroidectomia/métodos , Hemorroidas/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Prolapso Retal/cirurgia , Grampeamento Cirúrgico , Método Duplo-Cego , Hemorroidas/complicações , Humanos , Mucosa Intestinal , Ligadura/métodos , Tratamentos com Preservação do Órgão , Estudos Prospectivos , Prolapso Retal/etiologia , Índice de Gravidade de Doença , Grampeamento Cirúrgico/métodos
18.
Ann Transl Med ; 8(20): 1312, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33209892

RESUMO

Background: Osteoporosis is a systemic skeletal disorder and occurs frequently in postmenopausal women and older men. This study aimed to examine whether diosmetin (DIO) can relieve estrogen deficiency-induced osteoporosis and to explore the underlying mechanisms of this potential effect. Methods: Forty-nine Sprague-Dawley (SD) rats were divided into seven groups. Six groups underwent bilateral ovariectomy (OVX), while the sham group underwent ovarian exposure surgery. DIO and evodiamine were administered 3 days before surgery, and then subcutaneously every 3 days for 3 months in the following fashion: group I, DIO (100 mg/kg); group II, OVX; group III, OVX + DIO (50 mg/kg); group IV, OVX + DIO (100 mg/kg); group V, OVX + evodiamine (10 mg/kg) group; group VI, OVX + DIO (100 mg/kg) + evodiamine (10 mg/kg) group. Bone histopathological damage, bone loss, osteoclast production, and the expression level of transient receptor potential vanilloid 1 (TRPV1) were detected. Results: Compared with the sham group, the expression of bone resorption-related genes, osteoclast-associated receptor (OSCAR) (1.00%±0.16% versus 4.5%±0.28%, **, P<0.01) and tartrate-resistant acid phosphatase (TRAP) (2.0%±0.6% versus 18.00±1.2%, ***, P<0.001), was increased significantly. The protein level of osteogenic marker proteins, osterix (Osx) (1.0%±0.1% versus 0.03%±0.01%, **, P<0.01) and type 1 collagen (COL1A1) (1.0%±0.13% versus 0.13%±0.05%, **, P<0.01) was decreased significantly with the increase of TRPV1 (1.0%±0.15% versus 2.89%±0.28%, **, P<0.01) protein level. Notably, DIO can alleviate some abnormal symptoms related to osteoporosis. Conclusions: DIO can relieve typical osteoporosis symptoms in an OVX osteoporosis rat model. The underlying mechanism may be associated with the downregulation of TRPV1.

19.
Protein Expr Purif ; 179: 105796, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33221505

RESUMO

TREM2 has been identified by genomic analysis as a potential and novel target for the treatment of Alzheimer's disease. To enable structure-based screening of potential small molecule therapeutics, we sought to develop a robust crystallization platform for the TREM2 Ig-like domain. A systematic set of constructs containing the structural chaperone, maltose binding protein (MBP), fused to the Ig domain of TREM2, were evaluated in parallel expression and purification, followed by crystallization studies. Using protein crystallization and high-resolution diffraction as a readout, a MBP-TREM2 Ig fusion construct was identified that generates reproducible protein crystals diffracting at 2.0 Å, which makes it suitable for soaking of potential ligands. Importantly, analysis of crystal packing interfaces indicates that most of the surface of the TREM2 Ig domain is available for small molecule binding. A proof of concept co-crystallization study with a small library of fragments validated potential utility of this system for the discovery of new TREM2 therapeutics.

20.
Small ; 16(46): e2004240, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33107142

RESUMO

Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an increased level of anti-phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro-phagocytic nanoparticle (SNPACALR&aCD47 ) that concurrently carries CD47 antibody (aCD47) and a pro-phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPACALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell-surface CD47 and block the CD47-SIRPα pathway to inhibit the "don't eat me" signal. Tumor cell-targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an "eat me" signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti-tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti-phagocytic signals and activation of pro-phagocytic signals can be effective in macrophage-mediated cancer immunotherapy.

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