Advances in molecular agents targeting toll-like receptor 4 signaling pathways for potential treatment of sepsis.

Sepsis is a systemic inflammatory response syndrome caused by an infection. Toll-like receptor 4 (TLR4) is activated by endogenous molecules released by injured or necrotic tissues. Additionally, TLR4 is remarkably sensitive to infection of various bacteria and can rapidly stimulate host defense responses. The TLR4 signaling pathway plays an important role in sepsis by activating the inflammatory response. Accordingly, as part of efforts to improve the inflammatory response and survival rate of patients with sepsis, several drugs have been developed to regulate the inflammatory signaling pathways mediated by TLR4. Inhibition of TLR4 signal transduction can be directed toward either TLR4 directly or other proteins in the TLR4 signaling pathway. Here, we review the advances in the development of small-molecule agents and peptides targeting regulation of the TLR4 signaling pathway, which are characterized according to their structural characteristics as polyphenols, terpenoids, steroids, antibiotics, anthraquinones, inorganic compounds, and others. Therefore, regulating the expression of the TLR4 signaling pathway and modulating its effects has broad prospects as a target for the treatment of lung, liver, kidneys, and other important organs injury in sepsis.

Advances in thiosemicarbazone metal complexes as anti-lung cancer agents.

The great success of cisplatin as a chemotherapeutic agent considerably increased research efforts in inorganic biochemistry to identify more metallic drugs having the potential of treating lung cancer. Metal coordination centres, which exhibit a wide range of coordination numbers and geometries, various oxidised and reduced states and the inherent ligand properties offer pharmaceutical chemists a plethora of drug structures. Owing to the presence of C=N and C=S bonds in a thiosemicarbazone Schiff base, N and S atoms in its hybrid orbital has lone pair of electrons, which can generate metal complexes with different stabilities with most metal elements under certain conditions. Such ligands and complexes play key roles in the treatment of anti-lung cancer. Research regarding metallic anti-lung cancer has advanced considerably, but there remain several challenges. In this review, we discuss the potential of thiosemicarbazone Schiff base complexes as anti-lung cancer drugs, their anti-cancer activities and the most likely action mechanisms involving the recent families of copper, nickel, platinum, ruthenium and other complexes.

STAT3-induced NCK1 elevation promotes migration of triple-negative breast cancer cells via regulating ERK1/2 signaling.

BACKGROUND: Noncatalytic region of tyrosine kinase 1 (NCK1) plays a key role in extracellular matrix degradation, which is required for the metastasis of triple-negative breast cancer (TNBC). However, the role NCK1 plays in the metastatic progression of TNBC is unknown. METHODS AND RESULTS: Based on online databases, NCK1 was found to be highly expressed in TNBC as compared to normal breast-like subjects, which was also confirmed using TNBC cells and a tissue microarray. NCK1 expression gradually decreased with increased tumor stage. High NCK1 expression displayed a poor prognosis in lymph node-positive metastatic TNBC patients, but not in lymph node-negative patients. Using transwell assays and immunoblotting, we confirmed that NCK1 overexpression promoted, while NCK1 downregulation inhibited migration capabilities, as well as the expression of matrix metalloproteinases (MMP2/9), uridylyl phosphate adenosine, and plasminogen activator inhibitor-1 in TNBC cells. Mechanistically, NCK1 upregulation mediated the activation of MMP2/9 through ERK1/2 activity. Signal transducer and activator of transcription 3 (STAT3) was positively correlated with NCK1. STAT3 could directly bind to the promoter region of NCK1 to promote its expression and was accompanied by the elevation of MMP2/9 and ERK1/2 signaling, which were partially abolished by the knockdown of NCK1 in TNBC cells. CONCLUSIONS: NCK1 may serve as a diagnostic and prognostic marker of metastatic TNBC. STAT3 upregulation promoted the expression of NCK1, which subsequently induced the migration and activity of MMPs in a ERK1/2 signaling-dependent manner in TNBC cells. NCK1 is a promising target for improving TNBC migration.

Identification of Significant Genes in Lung Cancer of Nonsmoking Women via Bioinformatics Analysis.

BACKGROUND: The aim of this study was to identify potential key genes, proteins, and associated interaction networks for the development of lung cancer in nonsmoking women through a bioinformatics approach. METHODS: We used the GSE19804 dataset, which includes 60 lung cancer and corresponding paracancerous tissue samples from nonsmoking women, to perform the work. The GSE19804 microarray was downloaded from the GEO database and differentially expressed genes were identified using the limma package analysis in R software, with the screening criteria of p value < 0.01 and ∣log2 fold change (FC) | >2. RESULTS: A total of 169 DEGs including 130 upregulated genes and 39 downregulated were selected. Gene Ontology and KEGG pathway analysis were performed using the DAVID website, and protein-protein interaction (PPI) networks were constructed and the hub gene module was screened through STING and Cytoscape. CONCLUSIONS: We obtained five key genes such as GREM1, MMP11, SPP1, FOSB, and IL33 which were strongly associated with lung cancer in nonsmoking women, which improved understanding and could serve as new therapeutic targets, but their functionality needs further experimental verification.

The global, regional, and national burden of kidney cancer and attributable risk factor analysis from 1990 to 2017.

BACKGROUND: Kidney cancer's incidence and mortality vary in different regions and countries. To compare and interpret kidney cancer's burden and change trends in the globe and in different countries, we conducted this study to report the global kidney cancer burden and attributable risk factors. METHODS: Data about kidney cancer's incidence, death, disability-adjusted life-year (DALY) were extracted from the Global Burden of Diseases 2017. Besides, social-demographic index (SDI) values were adopted to investigate the correlation between kidney cancer's burden and social development degrees. RESULTS: In the globe, the incidence case of kidney cancer increased sharply from 207.31*103 in 1990 to 393.04*103 in 2017. High SDI countries had the highest kidney cancer's burden with a decreased trend in incidence rate. On the contrary, the incidence rate was rapidly increased in low-middle SDI countries, although their burden of kidney cancer kept relatively low. At the same time, the deaths of kidney cancer increased from 68.14*103 to 138.53*103, and the kidney cancer-related DALYs increased from 1915.49*103 in 1990 to 3284.32*103 in 2017. Then, we searched the GBD database for kidney cancer-related risk factor. The high body-mass index and smoking were the main factors contributing to kidney cancer-related mortality. CONCLUSIONS: Generally, from 1990 to 2017, the incidence rate in developed countries had gone down from the historic peak values while the incidence rate was still on the rise in developing counties. Given the aging trend in the globe, it is necessary to appeal to the public to decrease the exposure of kidney cancer-associated risk factors.

Blocking TGF-ß Signaling To Enhance The Efficacy Of Immune Checkpoint Inhibitor.

During malignant transformation, a growing body of mutations accumulate in cancer cells which not only drive cancer progression but also endow cancer cells with high immunogenicity. However, because one or multiple steps in cancer-immunity cycle are impaired, anti-cancer immune response is too weak to effectively clear cancer cells. Therefore, how to restore robust immune response to malignant cells is a hot research topic in cancer therapeutics field. In the last decade, based on the deeper understanding of cancer immunity, great signs of progress have been made in cancer immunotherapies especially immune checkpoint inhibitors (ICIs). ICIs could block negative immune co-stimulatory pathways and reactivate tumor-infiltrating lymphocytes (TILs) from exhausted status. ICIs exhibit potent anti-cancer effect and have been approved for the treatment of numerous cancer types. Parallel with durable and effective tumor control, the actual response rate of ICIs is unsatisfactory. Although a subset of patients benefit from ICIs treatment, a large proportion of patients show primary or acquired resistance. Previously intensive studies indicated that the efficacy of ICIs was determined by a series of factors including tumor mutation burden, programmed death ligand-1 (PD-L1) expression, and TILs status. Recently, it was reported that transforming growth factor-beta (TGF-ß) signaling pathway participated in cancer immune escape and ICI resistance. Concurrent TGF-ß blockade might be a feasible strategy to enhance the efficacy of immunotherapy and relieve ICI resistance. In this mini-review, we summarized the latest understanding of TGF-ß signaling pathway and cancer immunity. Besides, we highlighted the synergistic effect of TGF-ß blockade and ICIs.

[Correlation of behavioral performance with expressions of substance P and neurokinin-1 receptor in the L5－S2 spinal cord of chronic prostatitis rats].

OBJECTIVE: To investigate the correlation between the behavioral performance and the expressions of substance P (SP) and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5－S2 spinal cord in rats with chronic prostatitis (CP). METHODS: A CP model was made in 30 adult male SD rats by intraperitoneal injection of 0.5 ml dyphtheria pertussis tetanus (DPT) vaccine and mixed solution of 1 ml prostatein extract and complete adjuvant in a 1∶1 ratio, and another 10 rats were injected with the same volume of normal saline as controls. At 45 (n = 10), 60 (n = 10) and 90 days (n = 10) after modeling, the behavioral changes of the rats were observed by open-field and sucrose consumption tests, the prostatic indexes and levels of serum TNF-α, IL-1ß, IL-2 and IL-10 were obtained, and the expressions of SP and NK1-R in the L5－S2 spinal cord were determined by immunohistochemistry. RESULTS: Compared with the controls, the CP model rats showed obviously decreased horizontal and vertical movement scores and sucrose consumption, particularly in the 90 d group (P < 0.05), significantly reduced prostatic indexes in the 45 d, 60 d and 90 d groups (all P < 0.05), even lower in the 90 d than in the 45 d and 60 d groups (P < 0.05). Edema and lymphocytes were increased in the prostatic tissue with the prolonged time of modeling. The levels of serum TNF-α, IL-1ß, IL-2 and IL-10 were markedly elevated in all the CP rats as compared with those in the controls (P < 0.05), and so were the expressions of SP and NK-1R in the L5－S2 spinal cord (P < 0.05), even more significantly in the 90 d than in the 45 d and 60 d groups (P < 0.05). CONCLUSIONS: Rats with chronic prostatitis are characterized by behavioral manifestation of depression, increased levels of serum TNF-α, IL-1ß, IL-2 and IL-10, and a time-dependent upregulation of the expressions of SP and NK-1R in the posterior horn of the L5-S2 spinal cord, which suggests a correlation between the behavioral performance and the expressions of SP and NK-1R in the L5－S2 spinal cord of the rats.

Progression and prognostic value of ECT2 in non-small-cell lung cancer and its correlation with PCNA.

PURPOSE: Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor, which is involved in cell division regulation and cell cycle modulation. Recent evidence indicates that ECT2 is overexpressed in many human cancers. However, the exact prognostic value of ECT2 in lung cancer has not been elucidated. PATIENTS AND METHODS: In the current study, we performed correlation and prognosis analyses using public databases and conducted immunohistochemical staining in tissue microarrays, using samples from 204 lung cancer patients with survival data. RESULTS: We found that the expression of ECT2 was markedly increased in lung cancer tissues compared with normal tissues. Moreover, we demonstrated that the expression of ECT2 was related to tumor cell differentiation degree, TNM stage, lymph node metastasis, and prognosis in non-small-cell lung cancer (NSCLC). A correlation analysis indicated that ECT2 levels were significantly correlated with proliferating cell nuclear antigen (PCNA) levels in NSCLC. Furthermore, Kaplan-Meier analyses revealed that high ECT2 expression was associated with unfavorable overall survival (OS) and progression-free survival (PFS) in NSCLC patients. CONCLUSION: Taken together, these results indicate that the overexpression of ECT2 contributes to tumor invasion and progression, suggesting that ECT2 is a potential prognostic marker for NSCLC patients.

Molecular cloning and characterization of two genes encoding peroxiredoxins from freshwater bivalve Anodonta woodiana: Antioxidative effect and immune defense.

Members of Prx family function as an important players in host defense against oxidative stress, and modulate immune responses. In the current study, two complete Prx sequences were isolated from bivalve Anodonta woodiana and respectively named AwPrx4a and AwPrx4b. Regulative characterizations of AwPrx4a and AwPrx4b derived from perfluorooctanesulfonate (PFOS), perfluoroocanoic acid (PFOA), lipopolysaccharide (LPS) and polyinosinic:polycytidylic (Poly I:C) challenge in hepatopancreas, gill and hemocytes were measured by quantitative real-time PCR, respectively. The full-length cDNA of AwPrx4a had an open reading frame ORF of 588 bp encoding 196 amino acids. Two highly conserved Prxs signature motifs were observed in deduced amino acid sequence, one was FYPLDFTFACPTEI, and the other was GEVCPA. Complete cDNA sequence of AwPrx4b was comprised of a 5' untranslated region (UTR) of 120 nucleotides, a 426 bp ORF which was encoded 142 amino acids, and a long 3'-UTR of 412 nucleotides. Expressions of AwPrx4a and AwPrx4b showed a significant up-regulation pattern in groups at lower concentration treatment of PFOS and PFOA, a biphasic profile in groups with a higher concentration treatment. Compared with that of control group, expressions of AwPrx4a and AwPrx4b were significantly induced by LPS and Poly I:C treatment in the hepatopancreas, gill and hemocytes. These results indicate up-regulations of AwPrx4a and AwPrx4b expression are associated with eliminating oxidative stress derived from PFOS and PFOA administration as well as enhancing immune defense against LPS and Poly I:C challenge.

MAT1 correlates with molecular subtypes and predicts poor survival in breast cancer.

OBJECTIVE: Menage a trois 1 (MAT1) is a targeting subunit of cyclin-dependent kinase-activating kinase and general transcription factor IIH kinase, which modulates cell cycle, transcription and DNA repair. Its dysregulation is responsible for diseases including cancers. To further explore the role of MAT1 in breast cancer, we investigated the pathways in which MAT1 might be involved, the association between MAT1 and molecular subtypes, and the role of MAT1 in clinical outcomes of breast cancer patients. METHODS: We conducted immunohistochemistry staining on tissue microarray and immunofluorescence staining on sections of MAT1 stable breast cancer cells. Also, we performed Kyoto Encyclopedia of Genes and Genomes pathway analysis, correlation analysis and prognosis analysis on public databases. RESULTS: MAT1 was involved in multiple pathways including normal physiology signaling and disease-related signaling. Furthermore, MAT1 positively correlated with the protein status of estrogen receptor and progesterone receptor, and was enriched in luminal-type and human epidermal growth factor receptor 2-enriched breast cancer in comparison with basal-like subtype at both mRNA and protein levels. Correlation analysis revealed significant association between MAT1 mRNA amount and epithelial markers, mesenchymal markers, cancer stem cell markers, apoptosis markers, transcription markers and oncogenes. Consistently, the results of immunofluorescence stain indicated that MAT1 overexpression enhanced the protein abundance of epidermal growth factor receptor, vimentin, sex determining region Y-box 2 and sine oculis homeobox homolog 1. Importantly, Kaplan-Meier Plotter analysis reflected that MAT1 could serve as a prognostic biomarker predicting worse relapse-free survival and metastasis-free survival. CONCLUSIONS: MAT1 is correlated with molecular subtypes and is associated with unfavorable prognosis for breast cancer patients.

The clinical significance of CXCL5 in non-small cell lung cancer.

As a CXC-type chemokine, ENA78/CXCL5 is an important attractant for granulocytes by binding to its receptor CXCR2. Recent studies proved that CXCL5/CXCR2 axis plays an oncogenic role in many human cancers. However, the exact clinical significance of CXCL5 in lung cancer has not been well defined. Here, we found that the serum protein expression of CXCL5 was significantly increased in non-small cell lung cancer (NSCLC) compared with that in healthy volunteers. Immunohistochemistry staining revealed that CXCL5 protein was higher in various lung cancer tissues compared with normal tissues. Moreover, CXCL5 expression correlated with histological grade, tumor size, and TNM stage in NSCLC. Elevated CXCL5 protein abundance predicted poor overall survival in adenocarcinoma patients. Further meta-analysis demonstrated that CXCL5 mRNA expression was also positively associated with tumor stage, lymph node metastasis, and worse survival. Kaplan-Meier plot analyses indicated high CXCL5 was associated with short overall survival and progression-free survival. Together, these results indicated that CXCL5 may be a potential biomarker for NSCLC.

[Expressions of SP and NK-1R increase in the posterior horn of the L5－S2 spinal cord in rats with chronic nonbacterial prostatitis].

OBJECTIVE: To investigate the expressions of substance P (SP) and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5－S2 spinal cord in the rat model of chronic nonbacterial prostatitis (CNP) at different time points of modeling. METHODS: Forty adult male SD rats were randomly divided into four groups of equal number, control, 45 d model, 60 d model, and 90 d model, and proteins were obtained from the prostatic tissue of another 30 rats. The CNP model was made by intraperitoneal injection of 0.5 ml DPT vaccineand intradermal injection of mixed solution of 1 ml prostatein extract and complete adjuvant at a 1∶1 ratio, while the control rats were injected with the same volume of normal saline. At 45, 60, and 90 days after modeling, we measured the paw withdrawal threshold (PWT) of the rats, determined the levels of TNF-α, IL-1ß, IL-2, and IL-10 in the prostate tissue by ELISA, observed the histomorphological changes in the prostate by transmission electron and light microscopy, and detected the expressions of SP and NK1-R in the L5－S2 spinal cord by immunohistochemistry. RESULTS: The model rats showed significantly increased sensitivity to pain, with remarkably lowered PWT at 45, 60, and 90 days after modeling. The levels of TNF-α, IL-1ß, IL-2, and IL-10 in the prostate tissue were markedly elevated in the CNP models as compared with those in the controls (all P<0.05), most significantly at 90 days (all P<0.05). Immunohistochemistry showed that the expressions of SP and NK-1R were remarkably higher in the CNP model groups than in the control (all P<0.05), the highest at 90 days. Light microscopy revealed no inflammatory cell infiltration in the prostate tissue of the control rats, and obvious edema and increased lymphocytes were observed with the prolonged time of modeling.Transmission electron microscopy showed inflammatory changes in the prostate tissue of the model rats and that peritubular interstitial edema was most obvious at 90 days, with widened intervals between peritubular cells and the epithelial base and increased numbers of fibroblasts and collagen fibrils. CONCLUSIONS: The synthesis of SP and the level of NK-1R were increased in the posterior horn of the L5－S2 spinal cord in the rat model of CNP.

Methodologic research on TIMP-1, TIMP-2 detection as a new diagnostic index for hepatic fibrosis and its significance.

AIM: To set up a new method to detect tissue inhibitors of metalloproteinase-1 and -2(TIMP-1 and TIMP-2) in sera of patients with hepatic cirrhosis, and to investigate the expression and location of TIMP-1 and TIMP-2 in liver tissue of patients with hepatic cirrhosis, and the correlation between TIMPs in liver and those in sera so as to discuss whether TIMPs can be used as a diagnosis index of hepatic fibrosis. METHODS: The monoclonal antibodies (McAbs) of TIMP-1 and TIMP-2 were used to sensitize erythrocytes, and solid-phase absorption to sensitized erythrocytes (SPASE) was used to detect TIMP-1 and TIMP-2 in the sera of patients with hepatic cirrhosis. Meanwhile, with the method of in situ hybridization and immunohistochemistry, we studied the mRNA expression and antigen location of TIMP-1 and TIMP-2 in the livers of 40 hepatic cirrhosis patients with pathologic diagnosis. RESULTS: With SPASE, they were 16.4% higher in the acute hepatitis group, 33.3% higher in the chronic hepatitis group, and the positive rates were 73.6% and 61.2% respectively in sera of hepatic cirrhosis patients, which were remarkably higher than those in chronic hepatitis and acute hepatitis group (P<0.001). In 40 samples of hepatic cirrhosis tissues, all of them showed positive expression of TIMP-1 and TIMP-2 mRNA detected with immunohistochemistry or in situ hybridization (positive rate was 100%). Expression of TIMPs in different degrees could be found in liver tissue with cirrhosis. TIMPs were located in cytoplasm of liver cells of patients with hepatic cirrhosis. There was a significant correlation between serum TIMPs level and liver TIMPs level. CONCLUSION: SPASE is a useful method to detect the TIMP-1 and TIMP-2 in sera of patients with hepatic cirrhosis, and TIMP-1 and TIMP-2 can be considered as a useful diagnostic index of hepatic fibrosis, especially TIMP-1.