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1.
Mediators Inflamm ; 2021: 2752265, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602857

RESUMO

Methods: The mice were randomly distributed into four groups: (a) control (CTRL) group, (b) ETEC group, (c) IQW-ETEC group, and (d) IRW-ETEC group. Villus length and crypt depth were measured after hematoxylin and eosin staining. The inflammatory reaction was analyzed via inflammatory cytokines (i.e., TNF-α, IL-1ß, IL-6, and IL-10) using the enzyme-linked immunosorbent assay (ELISA). The microbiota in the colon was sequenced using 16S ribosomal RNA. Results: The villus length decreased, the crypt depth decreased, and the expression of inflammatory cytokines (i.e., TNF-α, IL-1ß, IL-6, and IL-10) increased due to ETEC. In the IRW-ETEC and IQW-ETEC groups, the Shannon index decreased (P < 0.05). IQW and IRW increased the abundance of Firmicutes, Proteobacteria, Clostridiales, Lachnospiraceae, and Alloprevotella; contrastingly, it decreased the abundance of Epsilonproteobacteria, Erysipelotrichales, Prevotellaceae, and Flavobacteriaceae compared to the ETEC group (P <0.05). Conclusion: This study ascertained that the addition of IQW and IRW could alleviate jejunal inflammation and increase microbiota community diversity.

2.
Oxid Med Cell Longev ; 2021: 6867962, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594475

RESUMO

The purpose of this research is to explore the positive effects of Lactobacillus plantarum and Lactobacillus brevis on the tissue damage and microbial community in mice challenged by Enterotoxigenic Escherichia coli (ETEC). Twenty-four mice were divided into four groups randomly: the CON group, ETEC group, LP-ETEC group and LB-ETEC group. Our results demonstrated that, compared with the ETEC group, the LP-ETEC and LB-ETEC groups experienced less weight loss and morphological damage of the jejunum. We measured proinflammatory factors of colonic tissue and found that L. plantarum and L. brevis inhibited the expression of proinflammatory factors such as IL-ß, TNF-α, and IL-6 and promoted that of the tight junction protein such as claudin-1, occludin, and ZO-1. Additionally, L. plantarum and L. brevis altered the impact of ETEC on the intestinal microbial community of mice, significantly increased the abundance of probiotics such as Lactobacillus, and reduced that of pathogenic bacteria such as Proteobacteria, Clostridia, Epsilonproteobacteria, and Helicobacter. Therefore, we believe that L. plantarum and L. brevis can stabilize the intestinal microbiota and inhibit the growth of pathogenic bacteria, thus protecting mice from the gut inflammation induced by ETEC.

3.
Org Biomol Chem ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34636391

RESUMO

A visible-light-promoted radical cascade reaction of N-arylacrylamide and cyclobutanone oxime esters with sulfur dioxide insertion is established. Mainly through the exploration of the visible light wavelength, it is found that the light source has a certain influence on the formation of cyanoalkylsulfonylated oxindoles, furnishing a range of sulfones in good to excellent yields. This protocol presents good functional group compatibility and does not require transition metals, photosensitizers, external bases, or oxidants.

4.
ACS Omega ; 6(40): 25940-25949, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34660956

RESUMO

A novel metal catalyst-free and environmentally friendly method for the regioselective iodination of imidazo[1,2-α]pyridines at their C3 position is disclosed, which has a wide substrate scope and could be sustainable. This reaction proceeds through ultrasound acceleration in the presence of a green alcohol solvent. Compared with a conventional heating system, the reaction efficiency and the rate are significantly improved and the iodine atom economy is maximized using ultrasound techniques.

5.
ACS Omega ; 6(40): 26273-26281, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34660986

RESUMO

We report a novel, inexpensive double thiolation reagent that sulfurizes a broad range of imidazo[1,2-α]pyridines under mild conditions. Importantly, diethylaminosulfur trifluoride, as a common nucleophilic fluorinating reagent, was utilized as a novel thiolation reagent.

6.
PLoS Comput Biol ; 17(10): e1008794, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34669695

RESUMO

There has been a spate of interest in association networks in biological and medical research, for example, genetic interaction networks. In this paper, we propose a novel method, the extended joint hub graphical lasso (EDOHA), to estimate multiple related interaction networks for high dimensional omics data across multiple distinct classes. To be specific, we construct a convex penalized log likelihood optimization problem and solve it with an alternating direction method of multipliers (ADMM) algorithm. The proposed method can also be adapted to estimate interaction networks for high dimensional compositional data such as microbial interaction networks. The performance of the proposed method in the simulated studies shows that EDOHA has remarkable advantages in recognizing class-specific hubs than the existing comparable methods. We also present three applications of real datasets. Biological interpretations of our results confirm those of previous studies and offer a more comprehensive understanding of the underlying mechanism in disease.

7.
Front Mol Biosci ; 8: 686718, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589516

RESUMO

Outside a few affluent countries with adequate vaccination and screening coverage, cervical cancer remains the leading cause of cancer-related deaths in women in many countries. Currently, a major problem is that a substantial proportion of patients are already at an advanced cancer stage when diagnosed. There is increasing evidence that indicates the involvement of translationally controlled tumor protein 1 (TPT1) overexpression in cancer development, but little is known about its implication in cervical cancer. We assessed the levels of TPT1 in surgical tissue and sera of patients with cervicitis, cervical intraepithelial neoplasia III, and cervical cancer, as well as in normal and cancerous cervical cell lines. Gene sets, pathways, and functional protein interactions associated with TPT1 were identified using the TCGA data cohort of cervical cancer. We found that the TPT1 expression was significantly increased in cervical cancer tissue compared to all nonmalignant cervical tissues, including samples of cervicitis, cervical intraepithelial neoplasia III, and normal controls. Serum level of TPT1 was also increased in cervical cancer patients compared to healthy subjects. Furthermore, elevated TPT1 expression was significantly correlated with lymph node metastasis and a low differentiation degree of the cancer. In the cancerous tissues and cell lines, selective markers of PI3K/AKT/mTOR pathway over-activation, apoptosis repression, and EMT were detected, and their interaction with TPT1 was supported by biometrics analyses. Our results, for the first time, demonstrate a strong correlation of upregulated TPT1 expression with cervical cancer progression, suggesting that TPT1 might provide a potential biomarker for cervical cancer progression.

8.
Blood Adv ; 5(18): 3656-3667, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34470047

RESUMO

Proteasome inhibitors, such as bortezomib (BTZ), represent the key elements in chemotherapy regimens for multiple myeloma (MM), whereas acquired chemoresistance and ultimately relapse remain a major obstacle. In the current study, we screened differently expressed cytokines in bortezomib-resistant MM cells and found that Dickkopf-1 (DKK1) level was remarkably augmented, whereas CD138 level was significantly suppressed. DKK1 in vitro specifically enhanced the resistance of myeloma cells to bortezomib treatment, and excessive DKK1 drove CD138 downregulation via inhibition of canonical Wnt signaling. Notably, DKK1 mainly induced drug resistance in MM cells via the receptor of CKAP4. Mechanistically, CKAP4 transduced DKK1 signal and evoked NF-κB pathway through recruiting and preventing cullin associated and neddylation dissociated 1 from hampering the assembly of E3 ligase-mediated ubiquitination of IκBα. In addition, we found that interleukin-6 (IL-6) stimulated CKAP4 expression to generate drug resistance, and disturbance of DKK1-CKAP4 axis improved sensitivity to BTZ treatment of MM and attenuated bone destruction in a mouse model. Collectively, our study revealed the previously unidentified role of DKK1 in myeloma drug resistance via Wnt signaling dependent and independent manners, and clarified the importance of antagonism of DKK1-IL-6 loop in bone marrow microenvironment.

9.
Ann Clin Lab Sci ; 51(4): 494-502, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452887

RESUMO

OBJECTIVE: Gastric cancer is one of the most common gastrointestinal malignancies. miRNAs (microRNAs) have been reported to play a pivotal role in the tumorigenesis of gastric cancer. However, the role of miR-643 in gastric cancer is not fully understood. METHODS: The expression of miR-643 in gastric cancer cell lines was detected by qRT-PCR (quantitative reverse transcription PCR). Cell viability, apoptosis, migration, and invasion were assessed using the Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound scratch and Transwell assays, respectively. The target gene of miR-643 was predicted by bioinformatics analysis and validated using luciferase reporter assay. RESULTS: The expression level of miR-643 in gastric cancer cell lines was lower than in the normal gastric epithelium cell line (GES-1). Overexpression of miR-643 inhibited cell viability and colony formation but promoted cell apoptosis in gastric cancer. Transwell invasion assay and in vitro scratch assay evidenced that miR-643 overexpression inhibited gastric cancer cell migration and invasion. Bioinformatics analysis revealed that miR-643 could directly target TXNDC9 (Thioredoxin domain containing 9), and luciferase reporter assay validated this result. Further analysis showed that miR-643 mimics caused a significant reduction of TXNDC9 in gastric cancer cells. Moreover, TXNDC9 overexpression reversed the effects of miR-643 mimics on gastric cancer cell viability, invasion, and migration. CONCLUSION: miR-643 functions as a potential tumor suppressor in gastric cancer by inhibiting cell viability, colony formation, migration, and invasion via targeting TXNDC9, which provides a novel target for the diagnostic treatment of gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/patologia , Tiorredoxinas/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Transição Epitelial-Mesenquimal , Humanos , Invasividade Neoplásica , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tiorredoxinas/genética , Células Tumorais Cultivadas
10.
Biochem Biophys Res Commun ; 567: 9-16, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34130181

RESUMO

The circadian clock plays a critical role in synchronizing the inner molecular, metabolic and physiological processes to environmental cues that cycle with a period of 24 h. Non-24 h and shift schedules are commonly used in maritime operations, and both of which can disturb circadian rhythms. In this study, we first conducted an experiment in which the volunteers followed a 3-d rotary schedule with consecutive shift in sleep time (rotatory schedule), and analyzed the changes in salivary cortisol rhythms and blood variables. Next we conducted another experiment in which the volunteers followed an 8 h-on and 4-h off schedule (non-24-h schedule) to compare the changes in blood/serum variables. The rotatory schedule led to elevated levels of serum cortisol during the early stage, and the phase became delayed during the early and late stages. Interestingly, both of the schedules caused comprehensive changes in blood/serum biochemical variables and increased phosphate levels. Furthermore, transcriptomic analysis of the plasma miRNAs from the volunteers following the rotatory schedule identified a subset of serum miRNAs targeting genes involved in circadian rhythms, sleep homeostasis, phosphate transport and multiple important physiological processes. Overexpression of miRNAs targeting the phosphate transport associated genes, SLC20A1 and SLC20A2, showed altered expression due to rotary schedule resulted in attenuated cellular levels of phosphate, which might account for the changed levels in serum phosphate. These findings would further our understanding of the deleterious effects of shift schedules and help to optimize and enhance the performances and welfare of personnel working on similar schedules.

11.
Comput Methods Programs Biomed ; 208: 106193, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34107373

RESUMO

BACKGROUND AND OBJECTIVE: Recently, the COVID-19 epidemic has become more and more serious around the world, how to improve the image resolution of COVID-CT is a very important task. The network based on progressive upsampling for COVID-CT super-resolution increases the reconstruction error. This paper proposes a progressive back-projection network (PBPN) for COVID-CT super-resolution to solve this problem. METHODS: In this paper, we propose a progressive back-projection network (PBPN) for COVID-CT super-resolution. PBPN is divided into two stages, and each stage consists of back-projection, deep feature extraction and upscaling. We design an up-projection and down-projection residual module to minimize the reconstruction error and construct a residual attention module to extract deep features. In each stage, firstly, PBPN performs back-projection to extract shallow features by two up-projection and down-projection residual modules; then, PBPN extracts deep features from the shallow features by two residual attention modules; finally, PBPN upsamples the deep features through sub-pixel convolution. RESULTS: The proposed method achieves the improvements of about 0.14~0.47 dB/0.0012~0.0060 for × 2 scale factor, 0.02~0.08 dB/0.0024~0.0059 for × 3 scale factor, and 0.08~0.41 dB/ 0.0040~0.0147 for × 4 scale factor than state-of-the-art methods (Bicubic, SRCNN, FSRCNN, VDSR, LapSRN, DRCN and DSRN) in terms of PSNR/SSIM on benchmark datasets. CONCLUSIONS: The proposed mehtod obtains better performance for COVID-CT super-resolution and reconstructs high-quality high-resolution COVID-CT images that contain more details and edges.


Assuntos
COVID-19 , Processamento de Imagem Assistida por Computador , Algoritmos , Humanos , Redes Neurais de Computação , SARS-CoV-2 , Tomografia Computadorizada por Raios X
12.
Front Immunol ; 12: 640305, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868268

RESUMO

Epigallocatechin gallate (EGCG) has potent biological activity as well as strong antioxidant and anti-inflammatory effects. This study aims to explore the protective effect of EGCG on LPS-induced acute injury. We randomly divided 18 mice into three groups: CON, LPS, and EGCG-LPS. We gave the EGCG-LPS group gavage treatment with EGCG on day 8-15 and an intraperitoneal injection of LPS on day 16 to induce acute injury. The results showed that, compared with the LPS group, the bodyweight of the mice in the EGCG-LPS group increased significantly and effectively inhibited the morphological damage of the jejunum and liver. We measured liver tissue and found that the EGCG gavage treatment significantly inhibited the pro-inflammatory factors (TNF-α, IL-1ß, IL-6, MCP-1, MIP-2, IFN-γ) and oxidation indicators (MPO, NO, ALT, and AST) levels increase. The microbiological results showed that the EGCG gavage treatment reshaped the disturbance done to the intestinal microbial community in the mice by LPS, reversed the changes in the abundance ratio of Firmicutes/Bacteroidetes, and significantly reduced the abundance of Enterobacteriales. Finally, the serum metabolomics results showed that, when compared with the LPS group, the gavage treatment of EGCG significantly increased the concentration of sphingomyelin (d17:1/17:0), sphingomyelin (d16:1/20:0), and significantly reduced the content of trans-Hexadec-2-enoyl carnitine, and so on. Therefore, we believe that EGCG can protect mice from acute stress induced by LPS while stabilizing gut microbes in general, improving the metabolism of sphingolipids, and inhibiting the content of harmful metabolites.


Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Microbioma Gastrointestinal/efeitos dos fármacos , Sepse/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Animais , Catequina/farmacologia , Lipopolissacarídeos/toxicidade , Metabolômica , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Sepse/induzido quimicamente
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(3): 193-198, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33766225

RESUMO

Objective To investigate the effects of tolerogenic dendritic cells (tolDCs) induced by nuclear factor κB oligodeoxynucleotide decoy (NF-κB ODN decoy) on Th1 cells, Th2 cells, Th17 cells and regulatory T cells (Tregs) and the intervention effects on collagen-induced arthritis (CIA) rats. Methods SD female rats used to establish CIA rat models were divided into four groups, including a CIA model group, a bovine type II collagen-decoy-dendritic cell (Col2-decoy DC) treatment group, a blank control group, and a Col2-decoy DC control group. On the 20th days after the first immunization, the rats were injected with tolDCs via the tail vein, and the rats were sacrificed on the 7th weeks. The proportions of Th1 cells, Th2 cells, Th17 cells, and Tregs in the rat spleen were detected by flow cytometry. The ankle joint pathomorphological change was evaluated by HE staining, and the arthritis index (AI) was scored. Results Compared with the CIA model group, the Col2-decoy DC group had lower AI and milder ankle joint pathomorphological change. The percentages of Th1 cells and Th17 cells in the spleen CD4+ T cells decreased, while the percentages of Th2 cells and Tregs increased. Conclusion The treatment of tolDCs can alleviate the inflammation and arthropathy of CIA rats by reducing the proportion of Th1 and Th17 cells in CD4+ T cells.


Assuntos
Artrite Experimental , Animais , Artrite Experimental/terapia , Bovinos , Células Dendríticas , Feminino , Inflamação , Ratos , Células Th1 , Células Th17
14.
Front Cell Dev Biol ; 9: 625423, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33738283

RESUMO

Macrophages, which are functional plasticity cells, have the ability to phagocytize and digest foreign substances and acquire pro-(M1-like) or anti-inflammatory (M2-like) phenotypes according to their microenvironment. The large number of macrophages in the intestinal tract, play a significant role in maintaining the homeostasis of microorganisms on the surface of the intestinal mucosa and in the continuous renewal of intestinal epithelial cells. They are not only responsible for innate immunity, but also participate in the development of intestinal inflammation. A clear understanding of the function of macrophages, as well as their role in pathogens and inflammatory response, will delineate the next steps in the treatment of intestinal inflammatory diseases. In this review, we discuss the origin and development of macrophages and their role in the intestinal inflammatory response or infection. In addition, the effects of macrophages in the occurrence and development of inflammatory bowel disease (IBD), and their role in inducing fibrosis, activating T cells, reducing colitis, and treating intestinal inflammation were also reviewed in this paper.

15.
Nat Commun ; 12(1): 1022, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589584

RESUMO

Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Mieloma Múltiplo/tratamento farmacológico , Coativador 3 de Receptor Nuclear/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 4 , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Coativador 3 de Receptor Nuclear/antagonistas & inibidores , Coativador 3 de Receptor Nuclear/metabolismo , Inibidores de Proteassoma/farmacologia , Recidiva , Proteínas Repressoras/metabolismo , Transdução de Sinais , Análise de Sobrevida , Translocação Genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Sci China Life Sci ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33587264

RESUMO

Inflammatory bowel disease (IBD) is a chronic lifelong disease characterized by inflammation of the gastrointestinal tract. Although more and more treatment options serve IBD, there is still no cure. It is important to find an effective treatment for IBD. This study aims to investigate whether Lactobacillus plantarum (L. plantarum) could alleviate colitis induced by dextran sulfate sodium (DSS). Following the DSS challenge, L. plantarum on DSS-mediated inflammatory colon lesions in mice, and L. plantarum therapy heightened the relative abundance of the colon-resident Actinobacteria. Analysis of serum metabolomics also indicated that the content of MG (18:4 (6Z, 9Z, 12Z, 15Z)/0:0/0:0) was increased in response to L. plantarum therapy, and this was also the case for indolepyruvate and 1-hydroxyibuprofen. However, 13-oxooctadecadienoic acid (13-oxoODE) and indolylacryloylglycine content fell following the DSS challenge. Based on these results, the study elucidates the mitigatory effects of L. plantarum in colitis, which depend on its regulation of the colonic microbial community and its modification of serum metabolites. The results revealed that L. plantarum mitigated inflammatory colon lesions, reprogrammed the microbial community and altered the level of serum metabolites in a murine model challenged with DSS. The study may present a potential therapeutic strategy for colitis.

17.
Biodegradation ; 32(1): 99-112, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33481147

RESUMO

Perfluoroalkyl carboxylates (PFCAs) is toxic to the environment and human health. However, the degradation characteristics of fluorotelomer alcohols (FTOHs), precursors of PFACAs biodegradation, in the sludge during aerobic composting remain unclear. In this study, the degradation characteristics of 6:2 FTOH in sewage sludge by composting were researched and the influences of 6:2 FTOH on the composting process and microbial communities of the sludge were evaluated. After 52 days of composting, 6:2 FTOH retained only 0.73% of its original concentration, and its half-life was less than 1 d; 6:2 FTOH was degraded finally to perfluorohex unsaturated acid, perfluoropentanoic acid, 5:3 polyfluorinated acid (FTCA), 4:3 FTCA, and perfluorobutanoic acid through two pathways; and 6:2 FTCA and 6:2 fluorotel unsaturated acid were the intermediate products. Notably, dosing with 6:2 FTOH affected the composting process of sewage sludge. Additionally, 50 mg/kg 6:2 FTOH resulted in a decrease in the microbial richness and diversity of sludge compost. When compared with the compost without 6:2 FTOH, the proportion of Proteobacteria had increased, and the proportion of Firmicutes had decreased as the concentration of 6:2 FTOH increased. The negative effect of a dosage of 50 mg/kg 6:2 FTOH was more obvious than the effect of other treatments. This study expanded our understanding of the risk of sludge contaminated by 6:2 FTOH being used as a fertilizer after composting.


Assuntos
Compostagem , Esgotos , Álcoois , Biodegradação Ambiental , Ácidos Carboxílicos , Humanos
18.
Bioinformatics ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33416850

RESUMO

MOTIVATION: Many computational methods have been recently proposed to identify differentially abundant microbes related to a single disease; however, few studies have focused on large-scale microbe-disease association prediction using existing experimentally verified associations. This area has critical meanings. For example, it can help to rank and select potential candidate microbes for different diseases at-scale for downstream lab validation experiments and it utilizes existing evidence instead of the microbiome abundance data which usually costs money and time to generate. RESULTS: We construct a multiplex heterogeneous network (MHEN) using human microbe-disease association database, Disbiome, and other prior biological databases, and define the large-scale human microbe-disease association prediction as link prediction problems on MHEN. We develop an end-to-end graph convolutional neural network-based mining model NinimHMDA which can not only integrate different prior biological knowledge but also predict different types of microbe-disease associations (e.g. a microbe may be reduced or elevated under the impact of a disease) using one-time model training. To the best of our knowledge, this is the first method that targets on predicting different association types between microbes and diseases. Results from large-scale cross validation and case studies show that our model is highly competitive compared to other commonly used approaches. AVAILABILITY: The codes are available at Github https://github.com/yuanjing-ma/NinimHMDA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

19.
J Leukoc Biol ; 110(1): 9-20, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33404078

RESUMO

Excessive monocyte activation with the development of excessive or uncontrolled release of proinflammatory cytokines often results in host tissue injury and even death in patients with pneumonia caused by the 2019 novel coronavirus. However, the changes of cytokine profiles of coronavirus disease 2019 (COVID-19) patients, as well as the underlying mechanisms that are involved, remain unknown. Using a cytokine array containing 174 inflammation-related cytokines, we found significantly altered cytokine profiles in severe COVID-19 patients compared with those in mild patients or healthy controls, and identified leptin, CXCL-10, IL-6, IL-10, IL-12, and TNF-α as the top differentially expressed cytokines. Notably, leptin showed high consistency with CXCL-10 and TNF-α in predicting disease severity, and correlated with body mass index, decreased lymphocyte counts, and disease progression. Further analysis demonstrated that monocytes in severe patients with higher leptin levels were inclined toward M1 polarization. Mechanistic studies revealed that leptin synergistically up-regulated expression levels of inflammatory cytokines and surface markers with IL-6 in monocytes through STAT3 and NF-κB signaling pathways. Collectively, our results suggest that overweight COVID-19 patients were prone to have higher leptin levels, which further activated monocytes, resulting in amplified or dysregulated immune responses. Taken together, our findings argue that leptin correlates severity of COVID-19 and may indicate a possible mechanism by which overweight patients have a greater tendency to develop severe conditions.


Assuntos
COVID-19/patologia , Leptina/metabolismo , Monócitos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , COVID-19/virologia , Polaridade Celular , Criança , Citocinas/sangue , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Leptina/sangue , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , SARS-CoV-2/fisiologia , Fator de Transcrição STAT3 , Índice de Gravidade de Doença , Transdução de Sinais , Adulto Jovem
20.
Oncogene ; 40(7): 1231-1241, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33420361

RESUMO

Myeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Histona-Lisina N-Metiltransferase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mieloma Múltiplo/tratamento farmacológico , Proteínas Repressoras/genética , Cromatina/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Nitroimidazóis/farmacologia , Osteoblastos/efeitos dos fármacos , Osteólise/genética , Mostardas de Fosforamida/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
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