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1.
Methods Mol Biol ; 2225: 39-61, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108656

RESUMO

Vaccines are the most effective means to prevent infectious diseases, especially for viral infection. The key to an excellent antiviral vaccine is the ability to induce long-term protective immunity against a specific virus. Bacterial vaccine vectors have been used to impart protection against self, as well as heterologous antigens. One significant benefit of using live bacterial vaccine vectors is their ability to invade and colonize deep effector lymphoid tissues after mucosal delivery. The bacterium Salmonella is considered the best at this deep colonization. This is critically essential for inducing protective immunity. This chapter describes the methodology for developing genetically modified self-destructing Salmonella (GMS) vaccine delivery systems targeting influenza infection. Specifically, the methods covered include the procedures for the development of GMSs for protective antigen delivery to induce cellular immune responses and DNA vaccine delivery to induce systemic immunity against the influenza virus. These self-destructing GMS could be modified to provide effective biological containment for genetically engineered bacteria used for a diversity of purposes in addition to vaccines.

2.
Protein Expr Purif ; 178: 105782, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33122039

RESUMO

Streptococcus pneumoniae is a gram-positive bacterial pathogen causing invasive pneumonia, meningitis, otitis media, and bacteremia. Owing to the current pitfalls of polysaccharide and polysaccharide-conjugate vaccines, protein vaccines are considered promising candidates against pneumonia. Pneumococcal surface protein A (PspA) and pneumococcal surface adhesin A (PsaA) are virulence proteins showing good immunogenicity and protective effects against S. pneumoniae strains in mice. In this study, we expressed the fusion protein PsaA-PspA, which consists of PsaA and the N-terminal region of PspA family 1 and 2, in Escherichia coli. We describe a novel and effective method to purify PsaA-PspA using hydroxyapatite and two-step chromatography. After determining the optimal induction conditions and a series of purification steps, we obtained PsaA-PspA fusion protein with over 95% purity at a final yield of 22.44% from the starting cell lysate. The molecular weight of PsaA-PspA was approximately 83.6 kDa and its secondary structure was evaluated by circular dichroism. Immunization with the purified protein induced high levels of IgG antibodies in mice. Collectively, these results demonstrate that our purification method can effectively produce high-purity PsaA-PspA fusion protein with biological activity and chemical integrity, which can be widely applied to the purification of other PspA subclass proteins.

3.
Nat Commun ; 11(1): 5912, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219235

RESUMO

The physiological homeostasis of gut mucosal barrier is maintained by both genetic and environmental factors and its impairment leads to pathogenesis such as inflammatory bowel disease. A cytokine like molecule, FAM3D (mouse Fam3D), is highly expressed in mouse gastrointestinal tract. Here, we demonstrate that deficiency in Fam3D is associated with impaired integrity of colonic mucosa, increased epithelial hyper-proliferation, reduced anti-microbial peptide production and increased sensitivity to chemically induced colitis associated with high incidence of cancer. Pretreatment of Fam3D-/- mice with antibiotics significantly reduces the severity of chemically induced colitis and wild type (WT) mice co-housed with Fam3D-/- mice phenocopy Fam3D-deficiency showing increased sensitivity to colitis and skewed composition of fecal microbiota. An initial equilibrium of microbiota in cohoused WT and Fam3D-/- mice is followed by an increasing divergence of the bacterial composition after separation. These results demonstrate the essential role of Fam3D in colon homeostasis, protection against inflammation associated cancer and normal microbiota composition.

4.
Technol Cancer Res Treat ; 19: 1533033820970688, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33167799

RESUMO

PURPOSES: Minichromosome maintenance (MCM) proteins play an important role in replication and cell cycle progression. Even so, their expression and prognostic roles in cancer remain controversial. METHODS: To address this issue, the study investigated the roles of MCMs in the prognosis of GC by using ONCOMINE, GEPIA2, UALCAN, Cancer Cell Line Encyclopedia (CCLE), the Human Protein Atlas, Kaplan-Meier Plotter, cBioPortal, GeneMANIA, and DAVID databases. RESULTS: Over expressions of mRNA and cell lines were found in all members of the MCM family, and MCMs were found to be significantly associated with pathological tumor grades in GC patients. Besides, higher mRNA expressions of MCM1/5/7 were found to be significantly associated with shorter overall survival (OS) and progression-free survival (FP) in GC patients, while higher mRNA expression of MCM4/6/9 were connected with favorable OS and FP. Moreover, a high mutation rate of MCMs (68%) was also observed in GC patients. CONCLUSIONS: The results indicated that MCM1/5/7 were potential targets of precision therapy for patients with GC. And MCM4/6/9 were new biomarkers for the prognosis of GC. The results of the study will contribute to supplement the existing knowledge, and help to explore therapeutic targets and enhance the accuracy of prognosis for patients with GC.

5.
Inflammation ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33141376

RESUMO

This study aimed to investigate the effect of splenectomy on dexmedetomidine-activated cholinergic anti-inflammatory pathway-mediated alleviation of LPS-induced AKI. A mouse model of septic kidney injury was established in C57BL/6 mice. A total of 30 C57BL/6 mice were randomly divided into the control group, LPS group, dexmedetomidine + LPS group, splenectomy group, splenectomy + LPS group, and splenectomy + dexmedetomidine + LPS group. The pathological effects in kidney tissues in each group were analyzed by HE staining. Apoptosis in each group was examined by the TUNEL method. Cr and Cys-C levels in each group were measured by ELISA. The expression levels of IL-6, NF-κB p65, Caspase-3, the antiapoptotic protein Bcl-2, the proapoptotic protein Bax, and α7nAChR in each group were measured by qRT-PCR and Western blotting. Dexmedetomidine alone reduced apoptosis in kidney tissue; however, apoptosis was increased after splenectomy in mice treated with dexmedetomidine. Splenectomy reduced the production of proinflammatory cytokines in circulation and had a protective effect on the kidney. Splenectomy inhibited dexmedetomidine-mediated activation of the α7nAChR pathway. Dexmedetomidine effectively alleviated LPS-induced kidney injury, and splenectomy inhibited the anti-inflammatory, antiapoptotic, and renoprotective effects of dexmedetomidine. The kidney-spleen axis is mediated by the α7nAChR-NF-κB signaling pathway and is involved in the development of AKI.

6.
Matrix Biol ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33068727

RESUMO

Disturbed flow leads to increased inflammatory responses of endothelial cells (ECs) prone to atherogenic state. Currently, little is known about the physiological mechanisms protecting vasculature against disturbed flow-activated ECs leading to atherosclerosis. Understanding the protective mediators involved in EC activation could provide novel therapeutic strategies for atherosclerosis. The extracellular matrix microenvironment profoundly regulates cellular homeostasis. A non-EC resident ECM protein, cartilage oligomeric matrix protein (COMP), has diverse protective roles in the cardiovascular system. To determine whether COMP could protect against disturbed flow-activated EC and atherosclerosis, we compared oscillatory shear stress (OSS) induced EC activation coated with various ECM proteins. Purified COMP inhibited EC activation caused by OSS. EC activation was upregulated in the aortic arch where the flow is disturbed in COMP-/- mice as compared with wild-type mice under physiological conditions or pathologically in partially ligated mouse carotid arteries. Mechanistically, co-immunoprecipitation, mammalian two-hybrid and FRET assay results suggest that COMP bound directly to integrin α5 via its C-terminus. We next synthesized a COMP-derived peptidomimetics (CCPep24) mimicking a specific COMP-integrin α5 interaction and found that CCPep24 protected against EC activation and atherogenesis in vivo. This study extends our current understanding of how ECM and flow coordinately fine-tune EC homeostasis and reveals the potential therapeutic effect of COMP or COMP-derived peptidomimetics on blocking aberrant integrin α5 activation, inflammatory EC activation and atherosclerosis pathogenesis.

7.
Immunol Invest ; : 1-14, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33078652

RESUMO

Background: Influenza A viruses (IAVs) induce acute respiratory disease and cause severe epidemics and pandemics. Since IAVs exhibit antigenic variation and genome reassortment, the development of broad-spectrum influenza vaccines is crucial. The stem of the hemagglutinin (HA) is highly conserved across IAV strains and thus has been explored in broad-spectrum influenza vaccine studies. The present study aimed to identify viral epitopes capable of eliciting effective host immune responses, which can be explored for the development of broad-spectrum non-strain specific prophylactic options against IAV. Methods: In this study, a series of conserved linear sequences from the HA stem of IAV (H1N1) was recognized by sequence alignment and B/T-cell epitope prediction after being chemically coupled to the Keyhole Limpet Hemocyanin (KLH) protein. The predicted linear epitopes were identified by enzyme-linked immunosorbent assay (ELISA) after animal immunization and then fused with ferritin carriers. Results: Three predicted linear epitopes with relatively strong immunogenicity, P3, P6 and P8 were fused with ferritin carriers P3F, P6F and P8F, respectively to further improve their immunogenicity. Antibody titre of the sera of mice immunized with the recombinant immunogens revealed the elicitation of specific antibody-binding activities by the identified sequences. While hemagglutinin-inhibition activities were not detected in the antisera, neutralizing antibodies against the H1 and H3 virus subtypes were detected by the microneutralization assay. Conclusion: The linear epitopes fused with ferritin identified in this study can lay the foundation for future advancements in development of broad-spectrum subunit vaccine against IAV (H1N1), and give rise to the potential future applicability of ferritin-based antigen delivery nanoplatforms.

8.
Front Immunol ; 11: 526965, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013922

RESUMO

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory illness, particularly in infants, the elderly, and immunocompromised adults. There is no licensed commercial vaccine against RSV. Importantly, formalin-inactivated RSV vaccines mediate enhanced respiratory disease. RSV fusion (F) protein with pre-fusion conformation is a promising candidate subunit vaccine. However, some problems remain to be solved, such as low immunogenicity and humoral immunity bias. Adjuvants can effectively enhance and adjust vaccine immune responses. In this study, we formulated pre-fusion RSV-F protein with the adjuvants, Alhydrogel, MF59, AS03, AS02, and glycol chitosan (GCS). We then conducted head-to-head comparisons of vaccine-induced immune responses in BALB/c mice. All adjuvanted vaccines enhanced antigen-specific and neutralizing antibody titers and viral clearance and gave an order of adjuvant activity: AS02 > AS03, MF59 > GCS, and Alhydrogel. Among them, AS02 elicited the highest antibody expression, which persisted until week 18. Moreover, AS02 significantly enhanced Th1 type immune response in immunized mice. Mice in the AS02 group also showed faster recovery from viral attacks in challenge tests. Further transcriptome analysis revealed that AS02 regulates immune balance by activating TLR-4 and promotes Th1-type immune responses. These results suggest that AS02 may be an excellent candidate adjuvant for RSV-F subunit vaccines. This study also provides valuable information regarding the effect of other adjuvants on immune responses of RSV-F subunit vaccines.

9.
Avian Dis ; 64(3): 254-268, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33112952

RESUMO

A programmed self-destructive Salmonella vaccine delivery system was developed to facilitate efficient colonization in host tissues that allows release of the bacterial cell contents after lysis to stimulate mucosal, systemic, and cellular immunities against a diversity of pathogens. Adoption and modification of these technological improvements could form part of an integrated strategy for cost-effective control and prevention of infectious diseases, including those caused by parasitic pathogens. Avian coccidiosis is a common poultry disease caused by Eimeria. Coccidiosis has been controlled by medicating feed with anticoccidial drugs or administering vaccines containing low doses of virulent or attenuated Eimeria oocysts. Problems of drug resistance and nonuniform administration of these Eimeria resulting in variable immunity are prompting efforts to develop recombinant Eimeria vaccines. In this study, we designed, constructed, and evaluated a self-destructing recombinant attenuated Salmonella vaccine (RASV) lysis strain synthesizing the Eimeria tenella SO7 antigen. We showed that the RASV lysis strain χ11791(pYA5293) with a ΔsifA mutation enabling escape from the Salmonella-containing vesicle (or endosome) successfully colonized chicken lymphoid tissues and induced strong mucosal and cell-mediated immunities, which are critically important for protection against Eimeria challenge. The results from animal clinical trials show that this vaccine strain significantly increased food conversion efficiency and protection against weight gain depression after challenge with 105E. tenella oocysts with concomitant decreased oocyst output. More importantly, the programmed regulated lysis feature designed into this RASV strain promotes bacterial self-clearance from the host, lessening persistence of vaccine strains in vivo and survival if excreted, which is a critically important advantage in a vaccine for livestock animals. Our approach should provide a safe, cost-effective, and efficacious vaccine to control coccidiosis upon addition of additional protective Eimeria antigens. These improved RASVs can also be modified for use to control other parasitic diseases infecting other animal species.

10.
J Agric Food Chem ; 68(45): 12651-12660, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33107729

RESUMO

Naringin, a major flavonoid in citrus, has potential for preventing atherosclerosis. The presence in the colon of a large amount of naringin after oral intake might affect the gut microbiota. We investigated the role of gut microbiota remodeling in the alleviation of atherosclerosis by naringin. Naringin significantly alleviated atherosclerosis and lowered the serum and liver cholesterol levels by 24.04 and 28.37% in ApoE-/- mice fed with a high-fat diet. Nontarget metabolomics showed that naringin modulated the hepatic levels of cholesterol derivatives and bile acids. Naringin increased the excretion of bile acids and neutral sterols by 1.6- and 4.3-fold, respectively. The main potential pathway by which naringin alleviated atherosclerosis was the gut microbiota-liver-cholesterol axis. Naringin modulated the abundances of bile salt hydrolase- and 7α-dehydroxylase-producing bacteria, promoting bile acid synthesis from cholesterol by upregulating CYP7A1 via suppression of the FXR/FGF15 pathway. In addition, naringin facilitated reverse cholesterol transport by downregulating PCSK9/IDOL. The results provide insight into the atherosclerosis-alleviation mechanisms of citrus flavonoids and a scientific basis for the development of functional foods containing citrus flavonoids.

11.
Apoptosis ; 25(11-12): 853-863, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33068199

RESUMO

Blockade of hypoxia-caused nonmyocytes apoptosis helps improve survival and mitigate ventricular remodeling and dysfunction during the chronic stage of myocardial infarction. But tools affecting nonmyocyte apoptosis are very rare. Sphingosylphosphorylcholine (SPC), a naturally occurring bioactive sphingolipid in plasma, was proved to protect cardiomyocyte against apoptosis in an ischemic model in our previous study. Here, we showed that SPC also inhibited hypoxia-induced apoptosis in myofibroblasts, an important type of nonmyocytes in the heart. Calmodulin (CaM) is an identified receptor of SPC. We clarified that SPC inhibited myofibroblast apoptosis through CaM as evidenced by decreased cleaved caspase 3, PARP1 and condensed nucleus. Furthermore, the employment of inhibitor and agonist of p38 and STAT3 suggests that SPC inhibits myofibroblast apoptosis by regulating the phosphorylation of p38 and STAT3, and they act as downstream of CaM. The present work may provide new evidence on the regulation of myofibroblasts apoptosis by SPC and a novel target for heart remodeling after hypoxia.

12.
Nat Commun ; 11(1): 4857, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978402

RESUMO

Characterization of the dynamic conformational changes in membrane protein signaling complexes by nuclear magnetic resonance (NMR) spectroscopy remains challenging. Here we report the site-specific incorporation of 4-trimethylsilyl phenylalanine (TMSiPhe) into proteins, through genetic code expansion. Crystallographic analysis revealed structural changes that reshaped the TMSiPhe-specific amino-acyl tRNA synthetase active site to selectively accommodate the trimethylsilyl (TMSi) group. The unique up-field 1H-NMR chemical shift and the highly efficient incorporation of TMSiPhe enabled the characterization of multiple conformational states of a phospho-ß2 adrenergic receptor/ß-arrestin-1(ß-arr1) membrane protein signaling complex, using only 5 µM protein and 20 min of spectrum accumulation time. We further showed that extracellular ligands induced conformational changes located in the polar core or ERK interaction site of ß-arr1 via direct receptor transmembrane core interactions. These observations provided direct delineation and key mechanism insights that multiple receptor ligands were able to induce distinct functionally relevant conformational changes of arrestin.


Assuntos
Arrestina/química , Arrestina/genética , Arrestina/metabolismo , Ligantes , Espectroscopia de Prótons por Ressonância Magnética/métodos , Sítios de Ligação , Cristalografia por Raios X , Humanos , Modelos Moleculares , Fenilalanina , Ligação Proteica , Conformação Proteica , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , beta-Arrestina 1/química , beta-Arrestina 1/genética , beta-Arrestina 1/metabolismo
13.
Neural Plast ; 2020: 9260807, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908492

RESUMO

Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss. It is responsible for 2-5% of congenital deafness. WS is classified into four types depending on the clinical phenotypes. Currently, pathogenic mutation of PAX3, MITF, EDNRB, EDN3, SNAI2, or SOX10 can cause corresponding types of WS. Among them, SOX10 mutation is responsible for approximately 15% of type II WS or 50% of type IV WS. We report the case of a proband in a Chinese family who was diagnosed with WS type II. Whole exome sequencing (WES) of the proband detected a novel heterozygous spontaneous mutation: SOX10 c.246delC. According to analysis based on nucleic acid and amino acid sequences, this mutation may produce a truncated protein, with loss of the HMG structure domain. Therefore, this truncated protein may fail to activate the expression of the MITF gene, which regulates melanocytic development and plays a key role in WS. Our finding expands the database of SOX10 mutations associated with WS and provides more information regarding the molecular mechanism of WS.

14.
J Alzheimers Dis ; 77(4): 1717-1732, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32925038

RESUMO

BACKGROUND: Adjuvants are important components of vaccines and effectively enhance the immune response of specific antigens. However, the role of adjuvants or combinations of adjuvants in stimulating immunogenicity of the amyloid-ß (Aß) vaccine, as well as molecular mechanisms underlying such stimulation still remain unclear. A previous study of ours developed a norovirus P particle-based active Aß epitope vaccine, PP-3copy-Aß1-6-loop123, which stimulates a high titer of Aß-specific antibodies in mouse Alzheimer's disease (AD) models. OBJECTIVE: The most effective and safe adjuvant that maximizes the immunogenicity of our protein vaccine was determined. METHODS: We investigated four adjuvants (CpG, AS02, AS03, and MF59), and combinations of those, for capacity to enhance immunogenicity, and performed transcriptome analysis to explore mechanisms underlying the role of these in AD immunotherapy. RESULTS: Addition of the adjuvant, AS02, remarkably improved the immunogenicity of the PP-3copy-Aß1-6-loop123 vaccine without triggering an Aß-specific T-cell response. Combinations of adjuvants, particularly CpG +  AS02 and CpG + AS03, elicited a significantly elevated and prolonged Aß-specific antibody response. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that a combination of two adjuvants was more effective in activating immune-related pathways, thereby enhancing the immunogenicity of PP-3copy-Aß1-6-loop123. CONCLUSION: These findings demonstrated that adjuvants can be used as enhancers in AD protein vaccination, and that a combination of CpG and AS-related adjuvants may be a very effective adjuvant candidate suitable for further clinical trials of the PP-3copy-Aß1-6-loop123 vaccine. Our studies also revealed potential mechanisms underlying the stimulation of immune response of protein vaccines by adjuvants.

15.
Mol Med Rep ; 22(4): 3173-3182, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945447

RESUMO

In recent years, there have been major breakthroughs in immunotherapies for the treatment of cancer. However, different patients have different responses to immunotherapy. Numerous studies have shown that the accumulation of epigenetic abnormalities, such as DNA methylation, serve an important role in the immune response of lung adenocarcinoma (LUAD). To investigate the effects of DNA methylation on tumor immunity with survival and prognosis, relevant studies can be performed based on the regulatory mechanisms of RNA molecules. For example, long non­coding RNAs (lncRNAs), which regulate gene expression through epigenetic levels. By constructing an immune-associated competitive endogenous RNA (ceRNA) network, the present study identified the regulatory associations among 3 key immune­associations mRNAs, 2 microRNAs (miRs) and 29 lncRNAs that were closely associated with the prognosis of patients with LUAD. The molecular biology analysis indicated that hypomethylation of the 1101320­1104290 regions of chromosome 1 resulted in the low expression levels of LINC00337 and that LINC00337 may affect the expression levels of CHEK1 by competitively binding with human (has)­miR­373 and hsa­miR­195. Therefore, abnormal DNA methylation in lncRNA­associated regions caused their abnormal expression levels, which further affected the interactions between RNA molecules. The interactions between these RNA molecules may have regulatory effects on tumor immunity and the prognosis of patients with LUAD.

16.
Can J Gastroenterol Hepatol ; 2020: 5716981, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908852

RESUMO

Aims: The over-the-scope clip (OTSC) has recently emerged as a new endoscopic device for treating gastrointestinal bleeding, perforations, fistulas, and leaks. A modified OTSC device (full-thickness resection device, FTRD) has been widely used for endoscopic full-thickness resection. However, there is less experience regarding the indications and methods for OTSC removal. We aimed to summarize the existing methods and indications for OTSC removal. Methods: We searched PubMed, Cochrane Library, and ClinicalTrials.gov to identify relevant publications on OTSC removal. The details of OTSC removal, including the methods, indications, success rates, adverse events, and failure causes, were extracted and summarized. A meta-analysis of pooled success rates was conducted using STATA 15.0. Results: Eighteen articles were included. The reported methods for OTSC removal included (1) grasping forceps, (2) the Nd : YAG laser, (3) argon plasma coagulation, (4) the remOVE system, (5) endoscopic mucosal resection/endoscopic submucosal dissection, and (6) ice-cold saline solution. Indications for OTSC removal were (1) poor healing, (2) OTSC misplacement, (3) repeat biopsy/therapy or further treatment, (4) adverse events after OTSC implantation, (5) removal after recovery, and (6) patient wishes. The pooled success rate of OTSC removal was 89% in patients treated with the remOVE system. Minor bleeding, superficial thermal damage, and superficial mucosal tears were common adverse events. Mucosal overgrowth was the main cause of OTSC removal failure. Conclusions: The remOVE system is the best investigated method, with sufficient efficacy and safety for OTSC removal. This is the first systematic review of OTSC removal and provides significant guidance for clinical practice.

17.
Cell Mol Life Sci ; 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32734582

RESUMO

Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.

18.
Cancer Manag Res ; 12: 5831-5843, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765086

RESUMO

Background: Programmed death-ligand 1 (PD-L1) is a negative costimulatory molecule, and its main function is widely considered to be in the regulation of T cells. Tumor-associated macrophages (TAMs) are an important part of the tumor microenvironment, and they also play an important role in immunosuppression. However, the relationship between the expression of PD-L1 and TAMs in cervical carcinoma (CC) remains unclear. We detected the expression of PD-L1 and TAMs in tumor tissue to study the correlation between them. Methods: Immunohistochemical staining of PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) was performed in 120 cases of cervical squamous cell carcinoma. Logistic regression analysis was used to evaluate the predictors related to positive PD-L1 expression. We also apply the Kaplan-Meier method to study the recurrence-free and overall survival rate of CC patients. Results: The increase in PD-L1 expression in tumor cells (TC) was significantly correlated with the increase in CD163 density (r=0.8550, p<0.0001), while PD-L1 in the stroma was also significantly associated with the intratumoral density of CD68- or CD163-positive cells (CD68 p<0.0001; CD163 p=0.0009). The mean infiltration rates of CD68- and CD163-positive cells in PD-L1-positive TC were significantly higher than in PD-L1-negative TC (CD68 p=0.0095; CD163 p<0.0001). In multivariate logistic regression analyses, only the density of CD163-positive cells was correlated with the expression of PD-L1 in TC cells (OR 1.52; p=0.032). In prognostic analysis, PD-L1 more than 10% was significantly correlated with short RFS (HR=2.66; p=0.028). For CD163+ macrophage evaluation, the density above the median was also significantly correlated with RFS (HR=2.48; p=0.021). Conclusion: CD163+ M2-like macrophage infiltration is highly associated with PD-L1 expression in CC, suggesting that macrophage infiltration can serve as a potential therapeutic target.

19.
Risk Anal ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32790201

RESUMO

Protection motivation theory states individuals conduct threat and coping appraisals when deciding how to respond to perceived risks. However, that model does not adequately explain today's risk culture, where engaging in recommended behaviors may create a separate set of real or perceived secondary risks. We argue for and then demonstrate the need for a new model accounting for a secondary threat appraisal, which we call secondary risk theory. In an online experiment, 1,246 participants indicated their intention to take a vaccine after reading about the likelihood and severity of side effects. We manipulated likelihood and severity in a 2 × 2 between-subjects design and examined how well secondary risk theory predicts vaccination intention compared to protection motivation theory. Protection motivation theory performed better when the likelihood and severity of side effects were both low (R2 = 0.30) versus high (R2 = 0.15). In contrast, secondary risk theory performed similarly when the likelihood and severity of side effects were both low (R2 = 0.42) or high (R2 = 0.45). But the latter figure is a large improvement over protection motivation theory, suggesting the usefulness of secondary risk theory when individuals perceive a high secondary threat.

20.
Ecotoxicol Environ Saf ; 205: 111172, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846300

RESUMO

Following oil extraction in the wetland of the Yellow River Delta, heavy metal contamination of coastal saline-alkaline soil, especially with cadmium (Cd), has become a serious environmental problem in some regions. Biochar application has been proposed to remedy Cd-contaminated soil, but the remediation effect is related to preparation conditions of biochar (e.g., pyrolysis temperature and raw material) and soil properties. The invasive plant, Spartina alterniflora, produces a high amount of biomass, making it suitable for biochar production in coastal China. We investigated the effect of S. alterniflora-derived biochar (SDB) pyrolyzed at four temperatures (350, 450, 550, and 650 °C) crossed with three addition ratios (1, 5, and 10%) and control on Cd contamination of coastal saline-alkaline soil. Pyrolysis temperature affected pH, surface area, and functional groups of SDB. SDB markedly improved soil pH and soil organic matter, but the degree of improvement was affected by pyrolysis temperature and addition ratio. SDB significantly altered available Cd content in soil, but reduced it only at low pyrolysis temperatures (350 and 450 °C). Available Cd content had a positive correlation with soil pH (R2 = 0.298, P < 0.01), but was not related to salinity and soil organic matter content. Thus, SDB pyrolyzed at 350 °C with 5% addition was optimal for passivating Cd in coastal saline-alkaline soil, since available Cd content in soil decreased mostly (by 26.9%). These findings act as a reference for the development of an application strategy for SDB to ameliorate Cd-contaminated coastal saline-alkaline soil.


Assuntos
Cádmio/análise , Carvão Vegetal/química , Recuperação e Remediação Ambiental/métodos , Poaceae/química , Poluentes do Solo/análise , Solo/química , Álcalis/análise , Biomassa , China , Modelos Teóricos , Pirólise , Salinidade , Áreas Alagadas
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