The roles of adenosine signaling in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiple etiological factors. Immune disorder contributes to SLE development and is an important clinical manifestation of SLE patients. Immune dysfunction is characterized by abnormal of B cells, T cells, monocyte-macrophages and dendritic cells (DCs), in both quantity and quality. Adenosine is a critical factor for human immune homeostasis, which acts as an immunosuppressive signal and can prevent the hyperactivity of human immune system. Adenosine levels are significant decreased in serum from SLE patients. Adenosine level is regulated by the CD39, CD73 and adenosine deaminase (ADA). CD39/CD73/ADA catalyzed the cascade enzymatic reaction, which contained the adenosine generation and degradation. Adenosine affects the function of various immune cells via bind to the adenosine receptors, which are expressed on the cell surface. This review aims to export the changes of immune cells and adenosine signal pathway in SLE, as well as the effect of adenosine signal pathway in SLE development.

B7-H3 promotes proliferation and migration of lung cancer cells by modulating PI3K/AKT pathway via ENO1 activity.

Background: B7-H3 (CD276) is overexpressed in diverse malignant tumors and plays critical roles in tumorigenesis and metastasis. However, the mechanism of B7-H3 in lung cancer remains unclear. This study aimed to explore the mechanism of interaction between B7-H3 and α-enolase (ENO1) in lung cancer progression. Methods: Tumor Immune Estimation Resource 2.0 (TIMER 2.0) and Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) databases were used to analyze the B7-H3 messenger RNA (mRNA) expression levels in lung cancer. The Kaplan-Meier (KM) plotter was used to analyze the correlation between B7-H3 and prognosis. Immunoprecipitation and glutathione S-transferase (GST) pull-down were used to verify the B7-H3 and ENO1 interaction. Cell counting kit-8 (CCK-8) and wound healing assays were used to investigate the effect of B7-H3 on the lung cancer growth. Results: Based on the public databases, the analysis showed that B7-H3 mRNA expression levels were up-regulated and correlated with patient prognosis in lung cancer. By using B7-H3 gain and off cell model, we concluded that B7-H3 overexpression promoted proliferation and migration of SBC5 cells. Subsequently, we found that both B7-H3 and ENO1 knockdown could inhibit cell proliferation and migration, in the meanwhile, and the phosphorylation levels of PI3K-p85α, and AKT were significantly reduced. Interestingly, we determined that B7-H3 regulated ENO1 activity rather than changing its expression levels. Furthermore, we used an AP-III-a4 to block ENO1 activity in the experiments, which attenuated the roles of B7-H3 not only on phosphorylation levels of those molecules, but also on cell growth and migration. Conclusions: B7-H3 directly interacts with ENO1 in lung cancer cells. B7-H3 can promote proliferation and migration of lung cancer cells by modulating PI3K/AKT pathway via ENO1 activity.

Enhancing Neuroprotection in Mouse Model of Parkinson's Disease through Protein Nanosystem Conjugation with ApoE Peptide for miR-124 Delivery.

Parkinson's disease (PD) affects millions of people's lives worldwide. The main pathogenesis of PD is dopaminergic neuron necrosis and neuroinflammation mediated by activated microglia cells. In recent years, the anti-inflammatory ability and neuroprotective effects of miR-124 in PD models were well proved, but the in vivo delivery of miR-124 remains challenging. Herein, we report a protein nanosystem modified with a brain-targeting peptide ApoE that could efficiently deliver miR-124 across the blood-brain barrier (BBB). This nanosystem showed good cell viability on brain endothelial cells and microglia cells, and administration of this nanosystem significantly decreased the neuroinflammation and dopaminergic neuron loss, as well as recovered parts of neurobehavioral deficits. This ApoE peptide-based protein nanosystem holds great promise for the delivery of RNA therapeutics to the brain and for realizing neuron protection in PD treatment.

Down-regulation of DPP4 by TGFß1/miR29a-3p inhibited proliferation and promoted migration of ovarian cancer cells.

OBJECTIVE: To explore the DPP4 expression changes and functions in ovarian cancer (OV), as well as the regulation mechanism for DDP4. METHODS: GEPIA2, GSE18520, GSE26712 and UALCAN were used to analyze differences in DPP4 expression between OV tumors and control tissues. Serum DPP4 levels were measured by ELISA. The prognostic values of DPP4 were evaluated using a Kaplan-Meier (KM) plotter. Small interfering RNA was used for DPP4 knockdown in OVCAR-3 and SKOV-3 cells. CCK-8 and scratch healing assays were used to determine the cells' proliferation and migration abilities. Flow cytometry (FCM) was used to detect the cell cycle and apoptosis. A dual-luciferase assay was designed to confirm the regulatory effect of miR-29a-3p on DPP4. RESULTS: The expressions of DPP4 mRNA and protein were decreased in OV tumor tissues. Serum DPP4 levels decreased in OV patients. KM plotter analysis showed correlation between high DPP4 expression and a poor prognosis in OV patients. By targeting knockdown of DPP4, we found that OVCAR-3 and SKOV-3 cells' proliferation was inhibited, while cell's migration ability was significantly promoted. FCM analysis showed that DPP4 knockdown induced a decrease in the S phase. Furthermore, DPP4 was shown to be downregulated by miR-29a-3p and TGFß1 in OVCAR-3 cells, and miR-29a-3p expression was upregulated by TGFß1. The effects of miR-29a-3p and TGFß1 on OVCAR-3 cells' biological behaviors were consistent with DPP4 knockdown. CONCLUSION: DPP4 was downregulated in OV patients. DPP4 knockdown significantly inhibited OVCAR-3 and SKOV-3 cell proliferation and promoted cell migration. DDP4 can be downregulated by TGFß1 through the upregulation of miR-29a-3p in OV cells.

CD5L aggravates rheumatoid arthritis progression via promoting synovial fibroblasts proliferation and activity.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with progressive cartilage erosion and joint destruction. Synovial fibroblasts (SFs) play a crucial role in the pathogenesis of RA. This study aims to explore the function and mechanism of CD5L during RA progression. We examined the levels of CD5L in synovial tissues and SFs. The collagen-induced arthritis (CIA) rat models were used to investigate the effect of CD5L on RA progression. We also investigated the effects of exogenous CD5L on the behavior and activity of RA synovial fibroblasts (RASFs). Our results showed that CD5L expression was significantly upregulated in synovium of RA patients and CIA-rats. Histology and Micro-CT analysis showed that synovial inflammation and bone destruction were more severe in CD5L-treated CIA rats compared with control rats. Correspondingly, CD5L blockade alleviated bone damage and synovial inflammation in CIA-rats. The exogenous CD5L treatment promoted RASFs proliferation invasion and proinflammatory cytokine production. Knockdown of CD5L receptor by siRNA significantly reversed the effect of CD5L treatment on RASFs. Moreover, we observed that CD5L treatment potentiated PI3K/Akt signaling in the RASFs. The promoted effects of CD5L on IL-6 and IL-8 expression were significantly reversed by PI3K/Akt signaling inhibitor. In conclusion, CD5L promote RA disease progression via activating RASFs. CD5L blocking is a potential therapeutic approach for RA patients.

Role of CD5 molecular-like on hepatocellular carcinoma.

BACKGROUND: CD5L (CD5 molecular-like) plays an important role in lipid metabolism and immune regulation. This study aimed to investigate the roles of CD5L on liver hepatocellular carcinoma (LIHC). METHODS: We analyzed the CD5L mRNA expression and its potential prognostic value based on The Cancer Genome Atlas and Gene Expression Omnibus databases. Immunohistochemical analysis was used to investigate the CD5L levels in LIHC tissues. Serum CD5L levels in LIHC were detected by enzyme-linked immunosorbent assay. Cell Counting Kit-8 (CCK-8) assay was used to investigate the effect of CD5L treatment on HepG2 and QSG-7701 cell proliferation. CD5L expression correlated genes were exhumed based on the LinkedOmics. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses for CD5L associated genes were performed. The correlation between CD5L and tumor immune infiltration was analyzed by using Tumor Immune Estimation Resource (TIMER) 2.0. RESULTS: CD5L mRNA and protein levels were significantly decreased in LIHC tumor tissue compared with non-tumor control tissues. Moreover, serum CD5L levels were significantly lower in LIHC patients than that in healthy subjects. Gene Expression Profiling Interactive Analysis 2 and Kaplan-Meier plotter analysis showed that a high-CD5L expression was correlated with favorable overall survival in LIHC patients, except the LIHC patients with hepatitis virus. CCK-8 results showed that CD5L treatment significantly decreased HepG2 cell proliferation in a concentration-dependent manner, and CD5L treatment had no effect on the proliferation of non-tumor hepatocyte line QSG-7701. CD5L associated genes were enriched in the immune response biological process, and CD5L expression levels were positively correlated with the immune infiltrates of CD8 + T cell and M1 macrophage cells but negatively correlated with CD4 + T cells and M0 macrophage cell infiltration. CONCLUSIONS: Exogenous CD5L inhibits cell proliferation of hepatocellular carcinoma. CD5L may act as a role of prognostic marker.

Silencing of B7-H4 induces intracellular oxidative stress and inhibits cell viability of breast cancer cells via downregulating PRDX3.

Breast cancer (BC) is the most common malignancy in women worldwide, accounting for 15.5% of total cancer deaths. B7-H4 belongs to the B7 family members and plays an important role in the development of a variety of cancers, while Peroxiredoxin III (PRDX3) is an antioxidant protein found in mitochondria. Aberrant expression of B7-H4 or PRDX3 has been implicated in the tumorigenesis of various cancers. However, the functional roles of B7-H4 and PRDX3 in BC and the underlying mechanisms remain unclear. In this research, we found that silencing of B7-H4 by siRNA could lead to not only cell viability inhibition but also the downregulation of PRDX3 in MCF-7 and T47D cells. In order to reveal the roles of PRDX3 in the B7-H4 pathway, we firstly transfected siRNA specifically targeting PRDX3 into MCF-7 and T47D cells, and the results showed that silencing of PRDX3 also inhibited the viability of MCF-7 and T47D cells significantly, accompanied by the increase of reactive oxygen species (ROS) levels. Then we overexpressed the expression of PRDX3 by transfecting PRDX3 expression plasmids into B7-H4 knocking-down cells of MCF-7 and T47D. The results showed that compared with the control groups (MCF-7 or T47D/siNC+pcDNA3.1 vector), cell viabilities were significantly inhibited in RNAi groups (MCF-7 or T47D/siB7-H4+pcDNA3.1 vector), and mildly inhibited in revertant groups (MCF-7 or T47D/siB7-H4+pcDNA3.1 PRDX3), meanwhile, ROS levels significantly elevated in RNAi groups and had no significant changes in revertant groups. All these results indicate that silencing of B7-H4 increases intracellular ROS levels and affects cell viability by modulating the expression of PRDX3 in BC cells, which may provide a potential strategy and therapeutic target for the treatment of BC.

SPARC Overexpression Promotes Liver Cancer Cell Proliferation and Tumor Growth.

Background: Secreted protein acidic and rich in cysteine (SPARC) plays an important role in cancer development. The roles of SPARC in the liver hepatocellular carcinoma (LIHC) are unclear. Methods: GEPIA2 and UALCAN were used to analyze the SPARC mRNA expression levels in LIHC based on the TCGA database. The GEO database was used to verify the analysis results. Immunohistochemical (IHC) analysis was used to investigate the SPARC protein levels in LIHC tissues. The Kaplan-Meier (KM) plotter was used to analyze the correlation between SPARC and prognosis. The serum SPARC levels were measured by ELISA. CCK8 and murine xenograft models were used to investigate the effect of SPARC on the liver cancer growth in vitro and in vivo. SPARC-correlated genes were screened by LinkedOmics. Results: Based on the TCGA and GEO databases, the analysis showed that the SPARC mRNA expression levels were increased in tumor tissues and peripheral blood mononuclear cell (PBMC) from LIHC compared to normal controls. The IHC analysis showed an increased level of SPARC in LIHC tissues compared to adjacent non-tumor tissues. However, we found that the serum SPARC levels were lower in LIHC than those in healthy controls. The KM plotter showed that there was no significant correlation between the SPARC mRNA levels and overall survival. However, in sorafenib-treated LIHC patients, the high SPARC expression predicts favorable prognosis. Furthermore, the endogenous SPARC overexpression promotes liver cancer cell proliferation in vitro and tumor growth in vivo, while there was no significant effect of exogenous SPARC treatment on liver cancer cell proliferation. Function enrichment analysis of SPARC-correlated genes indicated a critical role of interaction with an extracellular matrix in SPARC-promoting cancer cell proliferation. Conclusion: SPARC mRNAs were increased in LIHC tumor tissues, and SPARC overexpression may promote the liver cancer growth. Further studies are needed to clarify the potential prognostic value of SPARC, both in tissues and in circulation.

IL-27 induces LL-37/CRAMP expression from intestinal epithelial cells: implications for immunotherapy of Clostridioides difficile infection.

Clostridioides difficile infection is currently the leading cause of nosocomial antibiotic-associated diarrhea and pseudomembranous colitis worldwide. Cathelicidins, a major group of natural antimicrobial peptides, have antimicrobial and immunomodulatory activities in Clostridioides difficile infection. Here, we have shown that cytokine IL-27 induced human cathelicidin antimicrobial peptide (LL-37) expression in primary human colonic epithelial cells. IL-27 receptor-deficient mice had impaired expression of cathelicidin-related antimicrobial peptide (CRAMP, mouse homolog for human LL-37) after Clostridioides difficile infection, and restoration of CRAMP improved Clostridium difficile clearance and reduced mortality in IL-27 receptor-deficient mice after Clostridioides difficile challenge. In clinical samples from 119 patients with Clostridioides difficile infection, elevated levels of IL-27 were positively correlated with LL-37 in the sera and stools. These findings suggest that IL-27 may be involved in host immunity against Clostridioides difficile infection via induction of LL-37/CRAMP. Therefore, IL-27-LL-37 axis may be a valuable pathway in the development of immune-based therapy.

Apoptosis inhibitor of macrophage/CD5L is associated with disease activity in rheumatoid arthritis.

OBJECTIVES: To investigate the association between apoptosis inhibitor of macrophage (AIM) and disease activity in patients with rheumatoid arthritis (RA). METHODS: In this study, concentrations of serum AIM in 110 RA patients, 38 patients with osteoarthritis (OA) and 50 sex- and age-matched control subjects were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum AIM concentrations in RA patients were dramatically higher than those from patients with OA or healthy controls. The levels of synovial fluid AIM displayed a significant increase as compared with OA patients. More importantly, AIM levels were significantly correlated with RA disease activity features such as ESR, CRP and DAS28. The predictive value of AIM on high disease activity was superior to those of CRP and ESR. A noteworthy correlation in our study was observed between the serum AIM levels and laboratory parameters, particularly serum lipids. Furthermore, serum AIM levels could be significantly down-regulated after effective integrative treatment. CONCLUSIONS: AIM may serve as a novel sensitive biomarker to assist disease activity assessment and monitor therapeutic effects in active RA patients.

Microbiota-driven interleukin-17 production provides immune protection against invasive candidiasis.

BACKGROUND: The intestinal microbiota plays a crucial role in human health, which could affect host immunity and the susceptibility to infectious diseases. However, the role of intestinal microbiota in the immunopathology of invasive candidiasis remains unknown. METHODS: In this work, an antibiotic cocktail was used to eliminate the intestinal microbiota of conventional-housed (CNV) C57/BL6 mice, and then both antibiotic-treated (ABX) mice and CNV mice were intravenously infected with Candida albicans to investigate their differential responses to infection. Furthermore, fecal microbiota transplantation (FMT) was applied to ABX mice in order to assess its effects on host immunity against invasive candidiasis after restoring the intestinal microbiota, and 16S ribosomal RNA gene sequencing was conducted on fecal samples from both uninfected ABX and CNV group of mice to analyze their microbiomes. RESULTS: We found that ABX mice displayed significantly increased weight loss, mortality, and organ damage during invasive candidiasis when compared with CNV mice, which could be alleviated by FMT. In addition, the level of IL-17A in ABX mice was significantly lower than that in the CNV group during invasive candidiasis. Treatment with recombinant IL-17A could improve the survival of ABX mice during invasive candidiasis. Besides, the microbial diversity of ABX mice was significantly reduced, and the intestinal microbiota structure of ABX mice was significantly deviated from the CNV mice. CONCLUSIONS: Our data revealed that intestinal microbiota plays a protective role in invasive candidiasis by enhancing IL-17A production in our model system.

Emergence of NDM-5-Producing Escherichia coli in a Teaching Hospital in Chongqing, China: IncF-Type Plasmids May Contribute to the Prevalence of bla NDM- 5.

The newly emerging NDM-5 confers increased antibiotic resistance and attracts extensive global attention, but the prevalence, dissemination mechanism, and clinical significance of NDM-5 among clinical Escherichia coli (E. coli) infections have not been thoroughly characterized to date. In the present study, 109 unique carbapenem-resistant E. coli (CR-EC) isolates were collected in Southwest China, from 2013 to 2017, among which 41 (37.61%) CR-EC isolates were identified as NDM-5-producers, with most isolates carrying the IncF-type plasmids. Molecular epidemiological studies revealed ST167 being the most common sequence type (ST). Moreover, we described the first report of a clinical CR-EC isolate co-harboring bla KPC- 2 and bla NDM- 5, which showed a higher level of resistance to carbapenems. In addition, bla NDM- 5 plasmid transformation and conjugation indicated that bla NDM- 5 itself did confer resistance to carbapenems. Complete sequencing of the bla NDM- 5-harboring IncF plasmid revealed highly conserved regions (ble MBL-trpF-tat) and some transposons around bla NDM- 5. Our findings revealed a new potential threat of NDM-5-postive CR-EC in mainland China and emphasized an urgent need to control their further spread.

Corrigendum to "Determinants of Mortality in Patients with Nosocomial Acinetobacter baumannii Bacteremia in Southwest China: A Five-Year Case-Control Study".

[This corrects the article DOI: 10.1155/2018/3150965.].

Elevated serum CXCL10 in patients with Clostridium difficile infection are associated with disease severity.

Clostridium difficile infection (CDI) is the primary cause of community- and health care-associated diarrhea. CXCL10, also known as IFN-γ-inducible protein of 10 (IP-10), is involved in various inflammatory diseases, but its role in CDI remains unknown. In this study, We determined the serum concentration of CXCL10 in 80 CDI patients and 76 sex & age-matched diarrhea patients by enzyme-linked immunosorbent assay (ELISA) and analyzed the correlation between CXCL10 levels and CDI disease severity parameters. Besides, we also measured the level of other cytokines and/or chemokines in CDI patients, such as IL-1ß, IL-6, TNF-α and CXCL9. We found that serum CXCL10 in CDI patients was significantly higher compared with those in non-C. difficile diarrhea patients, especially in the moderate disease. Elevated serum CXCL10 correlated positively and significantly with severity score index (SSI) score in all CDI patients. CXCL10 levels were also positively correlated with WBC count, creatinine and inflammatory cytokines including, IL-1ß, IL-6 and CXCL9, but negatively correlated with albumin. Furthermore, serum CXCL10 concentration could be significantly decreased after effective treatment of CDI. Therefore, the above results suggest that the up-regulated release of CXCL10 is important in the immunopathogenesis of CDI, and may be served as a potential alternative biomarker for the monitoring of CDI disease severity and therapeutic efficacy.

Determinants of Mortality in Patients with Nosocomial Acinetobacter baumannii Bacteremia in Southwest China: A Five-Year Case-Control Study.

PURPOSE: This study was aimed to identify the determinants of in-hospital mortality in Acinetobacter baumannii (A. baumannii) bacteremia and to assess impact of carbapenem resistance on mortality. METHODS: A five-year case-control study was conducted from January 2011 to December 2015 in a tertiary teaching hospital with 3200 beds, Southwest China. Clinical outcomes and potential determinants of mortality in patients with nosocomial A. baumannii bacteremia and carbapenem-resistant A. baumannii (CRAB) bacteremia were evaluated using Cox and logistic regression analyses. RESULTS: A total of 118 patients with nosocomial A. baumannii bacteremia were included. Seventy-one percent (84/118) of them had carbapenem-resistant A. baumannii (CRAB) bacteremia. The in-hospital mortality of nosocomial A. baumannii bacteremia was 21.2%, and the attributable in-hospital mortality rate due to CRAB was 21.5%. Significant difference of 30-day in-hospital mortality in the Kaplan-Meier curves was found between CRAB and CSAB groups (log-rank test, P=0.025). The Cox regression analysis showed that patients with CRAB bacteremia had 2.72 times higher risk for 30-day in-hospital mortality than did those with carbapenem-susceptible A. baumannii (CSAB) bacteremia (95% confidence intervals (CIs) 1.14-6.61, P=0.016). The logistic regression analysis reported that mechanical ventilation and respiratory tract as origin of bacteremia were independent predictors of mortality among patients with nosocomial A. baumannii bacteremia and CRAB bacteremia, while high APACHE II score on the day of bacteremia and multiple organ dysfunction syndromes (MODS) during hospitalization were independent predictors of mortality among patients with nosocomial A. baumannii bacteremia but not CRAB bacteremia. CONCLUSION: It was the severity of illness (high APACHE II score and MODS) not carbapenem resistance that highlighted the mortality of patients with nosocomial A. baumannii bacteremia. The impact of mechanical ventilation on mortality suggested that respiratory dysfunction might prime the poor outcome. Protection of respiratory function during the progression of nosocomial A. baumannii bacteremia should be given more importance. Early identification and intervention of patients with nosocomial A. baumannii bacteremia in critical ill conditions were advocated.

Clinical characteristics and predictors of mortality in patients with candidemia: a six-year retrospective study.

Although candidemia has been reported globally, little is known about the differences in candidemia episodes between ICU and surgical wards or the correlation between serum biomarkers and mortality from candidemia. A retrospective study of hospitalized patients with candidemia was conducted in southwest China. A total of 198 non-duplicate candidemia episodes were identified between January 2011 and December 2016. Candida albicans was the leading species causing candidemia (34.9%), and 78.8% of these isolates were susceptible to fluconazole. More than half of candidemic patients were hospitalized in surgical wards, but the incidence of these surgical patients was much lower than that of ICU patients. Compared with surgical patients, patients admitted to ICU were more frequently subjected to extensive invasive procedures, severe clinical presentations, and heavy exposure to antibiotics. In addition, the mortality in ICU was significantly higher than that in surgical wards. Multivariable analysis revealed that ascites, catheter-related candidemia, ICU admission, septic shock, and concomitant bacterial infection were independent factors associated with mortality. Moreover, we observed that high PCT and BDG levels as well as low PLT counts were also associated with mortality from candidemia. Better understanding of the specific predictors in different wards could facilitate the identification of high-risk candidates to receive early antifungal therapy, thus improving the outcomes of critically ill patients with candidemia.