Diagnostic, monitoring, and prognostic value of combined detection of cerebrospinal fluid heparin-binding protein, interleukin-6, interleukin-10, and procalcitonin for post-neurosurgical intracranial infection.

OBJECTIVE: Intracranial infection is a common complication after neurosurgery and can increase the length of hospital stay, affect patient prognosis, and increase mortality. We aimed to investigate the value of the combined detection of cerebrospinal fluid (CSF) heparin-binding protein (HBP), interleukin-6 (IL-6), interleukin-10 (IL-10), and procalcitonin (PCT) for post-neurosurgical intracranial infection. METHODS: This study assessed the diagnostic values of CSF HBP, IL-6, IL-10, PCT levels, and combined assays for post-neurosurgical intracranial infection with the area under the receiver operating characteristic (ROC) curve by retrospectively analysing biomarkers of post-neurosurgical patients. RESULTS: The CSF HBP, IL-6, IL-10, and PCT levels were significantly higher in the infected group than the uninfected group and the control group (P < 0.001). The indicators in the groups with severe intracranial infections were significantly higher than those in the groups with mild intracranial infections (P < 0.001), and the groups with poor prognoses had significantly higher indexes than the groups with good prognoses. According to the ROC curve display, the AUC values of CSF HBP, IL-6, IL-10, and PCT were 0.977 (95 % CI 0.952-1.000), 0.973 (95 % CI 0.949-0.998), 0.884 (95 % CI 0.823-0.946), and 0.819 (95 % CI 0.733-0.904), respectively. The AUC of the combined test was 0.996 (95 % CI 0.989-1.000), which was higher than those of the four indicators alone. CONCLUSION: The combined detection can be an important indicator for the diagnosis and disease monitoring of post-neurosurgical intracranial infection.

Glutathione disrupts galectin-10 Charcot-Leyden crystal formation to possibly ameliorate eosinophil-based diseases such as asthma.

Charcot-Leyden crystals (CLCs) are the hallmark of many eosinophilic-based diseases, such as asthma. Here, we report that reduced glutathione (GSH) disrupts CLCs and inhibits crystallization of human galectin-10 (Gal-10). GSH has no effect on CLCs from monkeys ( Macaca fascicularis or M. mulatta), even though monkey Gal-10s contain Cys29 and Cys32. Interestingly, human Gal-10 contains another cysteine residue (Cys57). Because GSH cannot disrupt CLCs formed by the human Gal-10 variant C57A or inhibit its crystallization, the effects of GSH on human Gal-10 or CLCs most likely occur by chemical modification of Cys57. We further report the crystal structures of Gal-10 from M. fascicularis and M. mulatta, along with their ability to bind to lactose and inhibit erythrocyte agglutination. Structural comparison with human Gal-10 shows that Cys57 and Gln75 within the ligand binding site are responsible for the loss of lactose binding. Pull-down experiments and mass spectrometry show that human Gal-10 interacts with tubulin α-1B, with GSH, GTP and Mg 2+ stabilizing this interaction and colchicine inhibiting it. Overall, this study enhances our understanding of Gal-10 function and CLC formation and suggests that GSH may be used as a pharmaceutical agent to ameliorate CLC-induced diseases.

Structural basis for glucosylsucrose synthesis by a member of the α-1,2-glucosyltransferase family.

Glucosylsucroses are potentially useful as additives in cosmetic and pharmaceutical formulations. Although enzymatic synthesis of glucosylsucroses is the most efficient method for their production, the key enzyme that produces them has remained unknown. Here, we report that glucosylsucrose synthase from (TeGSS) catalyzes the synthesis of glucosylsucrose using sucrose and UDP-glucose as substrates. These saccharides are homologous to glucosylsucroses produced by sp. PCC 7120 (referred to as protein alr1000). When the ratio of UDP-glucose to sucrose is relatively high, TeGSS from cyanobacteria can hydrolyze excess UDP-glucose to UDP and glucose, indicating that sucrose provides a feedback mechanism for the control of glucosylsucrose synthesis. In the present study, we solved the crystal structure of TeGSS bound to UDP and sucrose. Our structure shows that the catalytic site contains a circular region that may allow glucosylsucroses with a right-hand helical structure to enter the catalytic site. Because active site residues Tyr18 and Arg179 are proximal to UDP and sucrose, we mutate these residues (., Y18F and R179A) and show that they exhibit very low activity, supporting their role as catalytic groups. Overall, our study provides insight into the catalytic mechanism of TeGSS.

Impacts of industrial agglomeration on industrial pollutant emissions: Evidence found in the Lanzhou-Xining urban agglomeration in western China.

Industrial agglomeration does not only promote economic and social prosperity of urban agglomeration, but also increases industrial pollution, which poses a health risk to the general public. The Lanzhou-Xining urban agglomeration in western China is characterized by industrial agglomeration and serious industrial pollution. Based on the county panel data of the Lanzhou-Xining urban agglomeration in western China from 2010 to 2018, a research of the impacts of industrial agglomeration on industrial pollutant emissions was conducted by using spatial analysis technology and spatial econometric analysis. The results indicate that industrial agglomeration is an important factor leading to an increase in industrial pollutant emissions. In addition, population density, economic level, and industrial structure are also important factors that lead to the increase in industrial pollutant emissions. However, technological level has led to the reduction in industrial pollutant emissions. Furthermore, industrial pollutant emissions are not only affected by the industrial agglomeration, population density, economic level, industrial structure, and technological level of the county but also by those same factors in the surrounding counties, owing to the spatial spillover effect. Joint development of green industries and control of industrial pollutant emissions is an inevitable result for the Lanzhou-Xining urban agglomeration in western China.

Actin binding to galectin-13/placental protein-13 occurs independently of the galectin canonical ligand-binding site.

The gene for galectin-13 (Gal-13, placental protein 13) is only present in primates, and its low expression level in maternal serum may promote preeclampsia. In the present study, we used pull-down experiments and biolayer interferometry to assess the interaction between Gal-13 and actin. These studies uncovered that human Gal-13 (hGal-13) and Saimiri boliviensis boliviensis (sGal-13) strongly bind to α- and ß-/γ-actin, with Ca2+ and adenosine triphosphate, significantly enhancing the interactions. This in turn suggests that h/sGal-13 may inhibit myosin-induced contraction when vascular smooth muscle cells undergo polarization. Here, we solved the crystal structure of sGal-13 bound to lactose and found that it exists as a monomer in contrast to hGal-13 which is a dimer. The distribution of sGal-13 in HeLa cells is similar to that of hGal-13, indicating that monomeric Gal-13 is the primary form in cells. Even though sGal-13 binds to actin, hGal-13 ligand-binding site mutants do not influence hGal-13/actin binding, whereas the monomeric mutant C136S/C138S binds to actin more strongly than the wild-type hGal-13. Overall, our study demonstrates that monomeric Gal-13 binds to actin, an interaction that is independent of the galectin canonical ligand-binding site.

lncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer.

Previous studies have reported that long noncoding RNAs (lncRNAs) have acted as new players during tumorigenesis. Metallothionein also plays an important role in tumor progression. It is mainly considered to be involved in the process of cell proliferation, oxidative stress, and multidrug resistance. However, the potential involvement of metallothionein-related lncRNAs in colon cancer remains poorly understood. In our study, we found that MT1M affected the expression of lncRNA STEAP3-AS1. STEAP3-AS1 is located in physical contiguity with STEAP3 and notably increased in colon cancer tissues and cell lines. STEAP3-AS1 expression was negatively associated with the expression of STEAP3. High levels of STEPA3-AS1 were associated with poor overall survival in colon cancer patients. In in vitro assays, STEAP3-AS1 knockdown could inhibit colon cancer cell proliferation and migration and arrest colon cancer cells at the G0-G1 phase. In tumorigenicity assays, STEAP3-AS1 knockdown could strongly inhibit tumor growth. Mechanistic investigations demonstrated that STEAP3-AS1 downregulation could increase the expression of cyclin-dependent kinase inhibitor 1C (CDKN1C) by STEAP3 upregulation. Overall, we identify the underlying role of MT1M-related lncRNA STEAP3-AS1 in colon cancer progression, which provides a novel strategy for colon cancer therapy.

DC-SIGN-LEF1/TCF1-miR-185 feedback loop promotes colorectal cancer invasion and metastasis.

DC-SIGN is previously focused on its physiologic and pathophysiologic roles in immune cells. Little is known about whether DC-SIGN is expressed in malignant epithelial cells and how DC-SIGN participates in tumor progression. Here we showed that DC-SIGN expression was increased in metastatic colorectal cancer (CRC) cell lines and patient tissues. The overall survival in CRC patients with positive DC-SIGN was remarkably reduced. Gain of DC-SIGN function facilitated the CRC metastases both in vitro and in vivo, and this effect was reversed by miR-185. DC-SIGN and Lyn interacted physically, and Lyn maintained the stability of DC-SIGN in cells. DC-SIGN activation recruited Lyn and p85 to form the DC-SIGN-Lyn-p85 complex, which promoted CRC metastasis by increasing PI3K/Akt/ß-catenin signaling in tyrosine kinase Lyn-dependent manner. Furthermore, activation of DC-SIGN promoted the transcription of MMP-9 and VEGF by increasing PI3K/Akt/ß-catenin signaling, and induced TCF1/LEF1-mediated suppression of miR-185. Our findings reveal the presence of the DC-SIGN-TCF1/LEF1-miR-185 loop in cancer cells with metastatic traits, implying that it may represent a new pathogenic mechanism of CRC metastasis. This character of the loop promises to provide new targets for blocking CRC invasive and metastatic activity.

DC-SIGN mediates gastric cancer progression by regulating the JAK2/STAT3 signaling pathway and affecting LncRNA RP11-181G12.2 expression.

BACKGROUND: The molecular mechanisms of gastric cancer (GC) development are very complicated. Recent studies revealed that DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein (DC-SIGNR) is involved in colon cancer and GC biological processes. However, the exact roles of DC-SIGN in GC remain unrevealed. METHODS: DC-SIGN overexpression and knockdown experiments were performed by using DC-SIGN shRNA or DC-SIGN plasmid to investigate the biological roles of DC-SIGN in proliferation, cell cycle progression, migration and invasion of GC cells in vitro. Furthermore, the lncRNA profiles of SGC-7901 cells with control shRNA and DC-SIGN shRNA were generated by using microarray analysis. Mechanistically, the relationship between DC-SIGN, RP11-181G12.2 and the JAK2/STAT3 signaling pathway was then investigated using qRT-PCR and western blot assays. Additionally, we analyzed DC-SIGN and RP11-181G12.2 expression levels in GC specimens based on the Cancer Genome Atlas database. RESULTS: In this study, the results showed that DC-SIGN was highly expressed in GC cells and significantly correlated with advanced clinical stage and lymphatic metastasis. Downregulation of DC-SIGN significantly inhibited the proliferation, cell cycle progression, migration and invasion of GC cells in vitro. The reverse results could partly be seen with the upregulation of DC-SIGN. Mechanistically, knockdown of DC-SIGN inactivated the JAK2/STAT3 signaling pathway, and overexpression of DC-SIGN activated the JAK2/STAT3 signaling pathway. In addition, through LncPath microarray analysis, we identified a lncRNA, RP11-181G12.2, that was significantly upregulated after knockdown of DC-SIGN; this was also confirmed by qRT-PCR. Furthermore, RP11-181G12.2 knockdown enhanced DC-SIGN expression in GC cells, further activating the JAK2/STAT3 signaling pathway. In contrast, DC-SIGN overexpression suppressed RP11-181G12.2 expression. CONCLUSIONS: Our study suggests that DC-SIGN might be involved in the progression of GC by regulating the JAK2/STAT3 signaling pathway and affecting lncRNA RP11-181G12.2 expression.

DC - SIGNR by influencing the lncRNA HNRNPKP2 upregulates the expression of CXCR4 in gastric cancer liver metastasis.

BACKGROUND: Profiling evidences of selectin demonstrate that they play an crucial role in cancer progression and metastasis. However, DC-SIGNR as a family member of selectin participates in gastric cancer liver metastasis remains unknown. METHODS: The serum level of DC-SIGNR was evaluated in gastric cancer patients by ELISA. Manipulation DC-SIGNR expression in BGC823 and SGC7901 cell lines was mediated by lentivirus. Investigation the biological effects of DC-SIGNR were verified by MTT, wounding and transwell in vitro and experiments on animals to confirm gastric cancer liver metastasis by IVIS. Insights of the mechanism were employed microarray and bioinformatic analysis. Further to confirm the results were conducted by qRT-PCR, western blot and by flow cytometry. RESULTS: DC-SIGNR serum level was significantly increased in gastric cancer patients compared with healthy group. Additionally, DC-SIGNR level was associated with an advanced pathological stage in gastric cancer patients. DC-SIGNR knockdown inhibited the proliferation, migration and invasion of gastric cancer cells in vitro and suppressed the liver metastasis in vivo. While, DC-SIGNR overexpression promoted cell proliferation, migration and invasion. In mechanism, HNRNPKP2 as a lncRNA was upregulated after DC-SIGNR knockdown. Importantly, STAT5A promoted HNRNPKP2 expression after knockdown DC-SIGNR. Furthermore after HNRNPKP2 depletion, the downstream target gene CXCR4 was downregulated. CONCLUSIONS: DC-SIGNR promoted gastric cancer liver metastasis mediated with HNRNPKP2 which expression was regulated by STAT5A. And HNRNPKP2 decreased the expression of downstream target gene CXCR4. These findings indicated potential therapeutic candidates for gastric cancer liver metastasis.

Novel roles of DC-SIGNR in colon cancer cell adhesion, migration, invasion, and liver metastasis.

BACKGROUND: Tumor metastasis is an essential cause of the poor prognosis of colon cancer. DC-SIGNR is a C-type lectin that is frequently found on human liver sinusoidal endothelial cells. LSECtin, which is a homologue of DC-SIGNR, has been demonstrated to participate in colon cancer liver metastasis. Due to the similarities in the expression pattern and structure of the two proteins, we speculated that DC-SIGNR could also be involved in this process. METHODS: Colon cancer cells were treated with the DC-SIGNR protein or control IgG, after which cell migration, invasion, and morphology were assayed. Xenograft mouse models were used to determine the role of DC-SIGNR in colon cancer liver metastasis in vivo. In addition, a human gene expression array was used to detect differential gene expression in colon cancer cells stimulated with the DC-SIGNR protein. The serum level of DC-SIGNR was examined in colon cancer patients by ELISA, and the significance of DC-SIGNR was determined. RESULTS: In our research, we investigated whether DC-SIGNR promotes colon cancer cell adhesion, migration, and invasion. Knocking down mouse DC-SIGNR decreased the liver metastatic potency of colon cancer cells and increased survival time. Expressing human DC-SIGNR enhanced colon cancer liver metastasis. Furthermore, DC-SIGNR conferred metastatic capability on cancer cells by upregulating various metallothionein isoforms. To validate the above results, we also found that the serum DC-SIGNR level was statistically higher in colon cancer patients with liver metastasis compared with those without metastasis. CONCLUSIONS: These results imply that DC-SIGNR may promote colon carcinoma hepatic metastasis and could serve as a promising therapeutic target for anticancer treatment.

Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family.

Colorectal cancer (CRC) is among the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for the development of new therapeutic approaches for the treatment of CRC. Accumulating evidence has revealed that niclosamide, an anthelminthic drug, exerts antitumor activity in several types of cancer, including colon cancer. However, the underlying molecular mechanisms responsible for the effects of this drug remain elusive. Previous studies have shown that the aberrant Notch signaling pathway contributes to the carcinogenesis of colon cancer. Herein, we examined the effects of niclosamide on the growth, migration and apoptosis of colon cancer cells, and the role of the Notch signaling pathway. By performing MTT, wound-healing and Transwell migration assays, we observed that niclosamide suppressed the growth and migration of colon cancer cells, and flow cytometry demonstrated that cell apoptosis was induced. This was associated with the decreased protein expression of Notch1, Notch2, Notch3 and Hey1, and the increased expression of the tumor suppressor microRNA (miR or miRNA)­200 family members (miR­200a, miR-200b, miR-200c, miR-141 and miR-429) that are typically downregulated in colon cancer. Collectively, these findings demonstrate that niclosamide potentially inhibits the progression of colon cancer by downregulating Notch signaling and by upregulating the miR-200 family members.

The history of China's maternal and child health care development.

The history of maternal and child health (MCH) development in China can be divided into six stages: before 1949 when the People's Republic of China was founded, traditional Chinese medicine shielded women's and children's health while modern medicine began to bud; 1949-1966, the MCH system was established and gradually improved; 1966-1976, the decade of the Cultural Revolution, the road to improve MCH twisted and turned along with the political instability; 1976-1990, especially after the "Reform" and "Opening Up", China's MCH care had been booming and the MCH status continued to improve with the rapid social and economic development; 1990-2008, with the booming economy, MCH care gained increasingly national and international attention. Through improving legislation and investment, China made great strides in the improvement of MCH. After 2009, the comprehensive health care reform laid an institutional basis for the development of MCH and promotion of health equity.

Conjugation of a nonspecific antiviral sapogenin with a specific HIV fusion inhibitor: a promising strategy for discovering new antiviral therapeutics.

Triterpene saponins are a major group of active components in natural products with nonspecific antiviral activities, while T20 peptide (enfuvirtide), which contains a helix zone-binding domain (HBD), is a gp41-specific HIV-1 fusion inhibitor. In this paper, we report the design, synthesis, and structure-activity relationship (SAR) of a group of hybrid molecules in which bioactive triterpene sapogenins were covalently attached to the HBD-containing peptides via click chemistry. We found that either the triterpenes or peptide part alone showed weak activity against HIV-1 Env-mediated cell-cell fusion, while the hybrids generated a strong cooperative effect. Among them, P26-BApc exhibited anti-HIV-1 activity against both T20-sensitive and -resistant HIV-1 strains and improved pharmacokinetic properties. These results suggest that this scaffold design is a promising strategy for developing new HIV-1 fusion inhibitors and possibly novel antiviral therapeutics against other viruses with class I fusion proteins.