Peroxiredoxin 1 aggravates acute kidney injury by promoting inflammation through Mincle/Syk/NF-κB signaling.

Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1-neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/- mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-κB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways.

Increased Expression of SERPINB10 Associated with Postoperative Recurrence in Chronic Rhinosinusitis with Nasal Polyps.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper airway inflammatory disorder with a high rate of postoperative recurrence. SERPINB10 is a proinflammatory cytokine expressed on epithelial cells, but its role in CRSwNP has not been described. This study is aimed at exploring the SERPINB10 expression in CRSwNP and its relationship with postoperative recidivation. Methods: We recruited 140 individuals, consisting of 60 patients with CRSwNP, 40 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 40 healthy controls (HCs). Tissue specimens were collected during the surgery, and SERPINB10 expression was determined by reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence. We determined the tissue SERPINB10 expression levels in CRSwNP and examined its clinical value in predicting postoperative recurrence. Results: We determined that tissue SERPINB10 mRNA and protein levels were increased in the CRSwNP group, especially in the recurrent CRSwNP group, compared with the CRSsNP and HC groups (p < 0.05), and SERPINB10 mRNA levels were correlated with peripheral and tissue eosinophil counts and percentages (p < 0.05). Binary logistic regression analysis and receiver operating characteristic (ROC) curves suggested that the expressions of tissue SERPINB10 mRNA were significantly linked to postoperative recurrence in CRSwNP patients (AUC = 0.741, p < 0.001). Conclusion: Elevated local SERPINB10 levels in patients with CRSwNP were related to tissue eosinophilic inflammation and disease recurrence. These data suggested that SERPINB10 might contribute to the eosinophilic inflammation in CRSwNP and appeared to be a potential biomarker for the prediction of relapse after surgery.

A Potential Role of B7-H4 Expression in Predicting the Recurrence of Chronic Rhinosinusitis with Nasal Polyps.

Background: Chronic rhinosinusitis with polyps (CRSwNP) is a common chronic inflammatory disease of the nasal cavity and sinuses with a high rate of postoperative recurrence. In this study, we aim to investigate the expression of B7-H4 in CRSwNP and its association with postoperative recurrence. Methods: A total of 80 CRSwNP patients, including 40 primary CRSwNP (pCRSwNP) patients and 40 recurrent CRSwNP (rCRSwNP) patients, 27 chronic rhinosinusitis without polyps (CRSsNP) and 32 healthy controls (HC) were enrolled in this study, and the serum, nasal polyps and middle turbinate tissue samples were collected. Peripheral and tissue B7-H4 expressions were detected by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence, and their clinical values in predicting postoperative recurrence of CRSwNP were evaluated. Results: We identified significantly higher tissue B7-H4 mRNA levels in the CRSwNP group than in the HC group, and elevated B7-H4 levels were associated with tissue eosinophil count and percentage (r = 0.469, P < 0.001; r = 0.521, P < 0.001). B7-H4 mRNA and protein levels were significantly higher in the rCRSwNP group than the pCRSwP group. Multivariate analysis and receiver operating characteristic (ROC) curves showed that tissue B7-H4 levels were associated with postoperative recurrence in patients with CRSwNP (P < 0.05). In addition, serum B7-H4 levels were significantly increased in the CRSwNP group than the CRS and HC groups, especially in the rCRSwNP group (P < 0.05), and the ROC curve presented a predictive ability of serum B7-H4 in predicting postoperative recurrence. Conclusion: Our results indicated that B7-H4 level was clearly enhanced in CRSwNP patients and associated with postoperative recurrence. Serum B7-H4 might serve as a simple and convenient biomarker for early predicting postoperative recurrence in CRwNP patients.

Macrophage-derived exosomes mediate silica-induced pulmonary fibrosis by activating fibroblast in an endoplasmic reticulum stress-dependent manner.

Macrophages play a key role in silicosis, and exosomes are potent mediators of intercellular communication. This suggests that macrophage-derived exosomes have a potential contribution to the pathogenesis of silicosis. To investigate whether macrophage-derived exosomes promote or inhibit lung fibrosis, in vitro, silica-exposed macrophage-derived exosomes (SiO2 -Exos) were collected and cocultured with fibroblasts. The expression of collagen I and α-SMA was evaluated. Furthermore, the endoplasmic reticulum (ER) stress markers BIP, XBP1s and P-eIF2α were assessed after treatment with or without the ER stress inhibitor 4-PBA. In vivo, mice were pre-treated with the exosome secretion inhibitor GW4869 prior to silica exposure. After sacrifice, lung tissues were histologically examined, and the expression of proinflammatory cytokines (TNF-α, IL-1ß and IL-6) in bronchoalveolar lavage fluid (BALF) was measured. The results showed that the expression of collagen I and α-SMA was up-regulated after treatment with SiO2 -Exos, accompanied by increased expression of BIP, XBP1s and P-eIF2α. Pre-treatment with 4-PBA reversed this effect. More importantly, an in vivo study demonstrated that pre-treatment with GW4869 decreased lung fibrosis and the expression of TNF-α, IL-1ß and IL-6 in BALF. These results suggested that SiO2 -Exos are profibrogenic and that the facilitating effect is dependent on ER stress.

Increased HSF1 Promotes Infiltration and Metastasis in Cervical Cancer via Enhancing MTDH-VEGF-C Expression.

PURPOSE: To explore the molecular mechanism of promoting cervical cancer by HSF1 in vivo and in vitro. METHODS: The expression of HSF1 in 110 paraffin-embedded cervical cancer sections of different grades was examined via immunohistochemistry analyses. Expression of HSF1 downstream targets Metadherin (MTDH), VEGF-C and CD31 were studied using immunohistochemistry analyses. HSF1 transcriptional activity in the MTDH promoter region was detected by EMSA, CHIP and luciferase. Cell proliferation and clonality were detected by MTT and clonal formation assay. Cell migration and invasion ability were investigated by scratch analysis and transwell assay. HSF1-mediated tumorigenesis in vivo was examined in xenograft models. RESULTS: HSF1 expression of cervical cancer cell line was increased compared to normal human cervical tissues. HSF1 enhanced the expression of MTDH, VEGF-C and CD31. HSF1 can combine with MTDH promoter to promote the expression of MTDH. HSF1 enhanced HeLa cell proliferation and clone formation. Furthermore, HSF1 increased HeLa cells migration and invasion in vitro. In the transplanted tumor model, HSF1 inhibited tumor growth in vivo after interference, and reduced the expression of MTDH, VEGF-C and CD31. DISCUSSION: HSF1 can promote the proliferation, metastasis and invasion of cervical cancer.

HOXC10 promotes tumour metastasis by regulating the EMT-related gene Slug in ovarian cancer.

The mortality rate of ovarian cancer is the highest among gynaecological cancers, primarily due to metastatic symptoms. Recent studies have shown that HOX genes are crucial in tumour progression, but the underlying mechanisms remain unclear. Here, HOXC10 expression was examined in ovarian cancer tissues. The function of HOXC10 in ovarian cancer metastasis was investigated in vitroand via intraperitoneal injection in vivo. A total of 158 ovarian cancer patients with adequate records were enrolled for analysis. HOXC10 was associated with metastasis and poor prognosis in ovarian cancer. In vitro, HOXC10 overexpression promoted ovarian cancer cell migration. Moreover, HOXC10 positively regulated Slug expression, altering the migration ability of cancer cells. Furthermore, our study showed that miR-222-3p was a suppressor of HOXC10. In vivo, a decrease in hepatic metastasis was seen in xenograft mice harbouring tumours with stable HOXC10 overexpression after miR-222-3p agomir (an overexpression reagent) injection. This study provides the first evidence that HOXC10 promotes ovarian cancer metastasis by regulating the transcription of the EMT-related gene Slug. Moreover, we found that HOXC10 is regulated by miR-222-3p. These data highlight the crucial role of HOXC10 in enhancing ovarian cancer metastasis and may provide a therapeutic target for ovarian cancer.

miR-135a Alleviates Silica-Induced Pulmonary Fibrosis by Targeting NF-κB/Inflammatory Signaling Pathway.

Silica exposure triggers inflammatory response and pulmonary fibrosis that is a severe occupational or environmental lung disease with no effective therapies. The complicated biological and molecular mechanisms underlying silica-induced lung damages have not yet been fully understood. miR-135a inhibits inflammation, apoptosis, and cancer cell proliferation. But the roles of miRNA135a involved in the silica-induced lung damages remain largely unexplored. We investigated the roles and mechanisms of miR-135a underlying silica-induced pulmonary fibrosis. The present study showed silica exposure caused the decrease in miR-135a level but the increase in inflammatory mediators. Transduction of lentivirus expressing miR-135a reduced the level of inflammatory mediators in lung tissues from silica-treated mice and improved pulmonary fibrosis which was consistent with the downregulated α-SMA but enhanced E-cadherin. Moreover, miR-135a overexpression inhibited p-p65 level in lung tissues. Overexpression of miR-135a inhibitor strengthened TLR4 protein level and NF-κB activation in BEAS-2B cells. Injection of PDTC, an inhibitor of NF-κB, further reinforced miR-135a-mediated amelioration of inflammation and pulmonary fibrosis induced by silica. The collective data indicate miR-135a restrains NF-κB activation probably through targeting TLR4 to alleviate silica-induced inflammatory response and pulmonary fibrosis.

Efficacy of steroid and immunosuppressant combined therapy in Chinese patients with Henoch-Schönlein purpura nephritis: A retrospective study.

Suitable and efficient treatments for Henoch-Schönlein purpura nephritis (HSPN) with proteinuria remains unclear. Whether steroids combined with immunosuppressive agents improves prognosis compared to steroid therapy alone also remains controversial. This study explored whether combined therapy reduces proteinuria in HSPN patients with different pathological features. Chinese patients (n = 84) diagnosed with HSPN with proteinuria by renal biopsy between 2010 and 2019 were retrospectively studied. Patients were grouped into the steroid group (control) or the combined steroid and immunosuppressant group. Estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2/y) and proteinuria were measured. The primary outcome progression was analyzed using Kaplan-Meier survival curves. The effect of the combined therapy on renal outcome was analyzed by multivariable Cox regression. Propensity score matching and sensitivity analysis were used to explore whether pathological features impacted prognosis. Patients who received combined steroid and immunosuppressant therapy were more likely to recover from HSPN and had proteinuria <3 g/24 h (P = 0.02) or 1 g/24 h (P = 0.03). Multiple Cox regression analysis confirmed that this decrease was independent of renin-angiotensin system blockers. Further sensitivity analysis showed that combined therapy was effective in patients with crescents (P = 0.02). However, combined steroid and immunosuppressant therapy was not more effective in patients with endocapillary hypercellularity (E), tubular atrophy/interstitial fibrosis (T), or segmental sclerosis (S). Combined steroid and immunosuppressant therapy was significantly associated with HSPN remission, and more effectively decreased proteinuria during the initial disease phase.

microRNA-30a attenuates TGF-ß1-induced activation of pulmonary fibroblast cell by targeting FAP-α.

Idiopathic interstitial pulmonary fibrosis is a common diffuse interstitial lung disease and has poor prognosis. And one of the pathological features of it is persistent fibroblast activation. It was reported that microRNA-30a was down-regulated in bronchoalveolar lavage fluid from idiopathic pulmonary fibrosis patients. But whether miR-30a is involved in fibroblast activation and its specific mechanism is unclear. In this study, we aimed to investigate the role of miR-30a in fibroblast activation induced by TGF-ß1. We found miR-30a could targetedly suppress FAP-α expression. In MRC5 cells, miR-30a was not only involved in regulating the expression of FAP-α, col1a and α-SMA induced by TGF-ß1 but also had a role in cell proliferation with or without TGF-ß1 treatment via regulating FAP-α expression. Thus, the results indicated that miR-30a alleviated fibroblast activation by regulating the expression of FAP-α.

Patterns of Immune Infiltration in HNC and Their Clinical Implications: A Gene Expression-Based Study.

Background: Immune infiltration of head and neck cancer (HNC) highly correlated with the patient's prognosis. However, previous studies failed to explain the diversity of different cell types that make up the function of the immune response system. The aim of the study was to uncover the differences in immune phenotypes of the tumor microenvironment (TME) between HNC adjacent tumor tissues and tumor tissues using CIBERSORT method and explore their therapeutic implications. Method: In current work, we employed the CIBERSORT method to evaluate the relative proportions of immune cell profiling in 11 paired HNC and adjacent samples, and analyzed the correlation between immune cell infiltration and clinical information. The tumor-infiltrating immune cells of TCGA HNC cohort was analyzed for the first time. The fractions of LM22 immune cells were imputed to determine the correlation between each immune cell subpopulation and survival and response to chemotherapy. Three types of molecular classification were identified via "CancerSubtypes" R-package. The functional enrichment was analyzed in each subtype. Results: The profiles of immune infiltration in TCGA HNC cohort significantly vary between paired cancer and para-cancerous tissue and the variation could reflect the individual difference. Total Macrophage, Macrophages M0 and NK cells resting were elevated in HNC tissues, while total T cells, total B cells, T cells CD8, B cell navie, T cell follicular helper, NK cells activated, Monocyte and Mast cells resting were decreased when compared to paracancerous tissues. Among each cell immune subtype, T cells regulatory Tregs, B cells naïve, T cells follicular helper, and T cells CD4 memory activated was significantly associated with HNC survival. Three clusters were observed via Cancer Subtypes R-package. Each cancer subtype has a specific molecular classification and subtype-specific immune cell characterization. Conclusions: Our data suggest a difference in immune response may be an important driver of HNC progression and response to treatment. The deconvolution algorithm of gene expression microarray data by CIBERSOFT provides useful information about the immune cell composition of HNC patients.

Chromatin remodeling factor lymphoid-specific helicase links with Epstein-Barr virus associated the follicular germinal center B cell lymphomas.

BACKGROUND: We assessed the frequency of epigenetic lesions, including lymphoid-specific helicase (LSH), 5-hydroxymethylcytosine (5-hmC) and E2F1, and the possible correlations among molecular findings, phenotype, clinical features, and outcome. METHODS: We investigated 181 paraffin-embedded B-cell lymphoma samples using immunohistochemistry and in situ hybridization. RESULTS: The levels of Ki67, LSH, 5-hmC, and E2F1 were all increased in germinal center B-cell lymphomas when compared with those in normal lymph nodes, and LSH was highly expressed in diffuse large B-cell lymphomas (DLBCLs) and Burkitt lymphomas (BLs) that were positive for Epstein-Barr virus (EBV) infection, indicating that LSH is linked to EBV infection in DLBCL and BL. Interestingly, LSH was mainly localized in the germinal centers of lymph nodes whereas 5-hmC staining localized to areas surrounding the germinal centers. CONCLUSIONS: These findings indicate a critical role for LSH as a biomarker and therapeutic target in follicular germinal center B-cell lymphoma.

Circulating Peroxiredoxin-1 is a novel damage-associated molecular pattern and aggravates acute liver injury via promoting inflammation.

Sterile inflammation is initiated by damage-associated molecular patterns (DAMPs) and a key contributor to acute liver injury (ALI). However, the current knowledge on those DAMPs that activate hepatic inflammation under ALI remains incomplete. We report here that circulating peroxiredoxin-1 (Prdx1) is a novel DAMP for ALI. Intraperitoneal injection of acetaminophen (APAP) elicited a progressive course of ALI in mice, which was developed from 12 to 24 h post injection along with liver inflammation evident by macrophage infiltration and upregulations of cytokines (IL-1ß, IL-6 and TNF-α); these alterations were concurrently occurred with a robust and progressive production of serum Prdx1. Similar observations were also obtained in carbon tetrachloride (CCl4)-induced ALI in mice. Removal of the source of serum Prdx1 protected mice deficient in Prdx1 from APAP and CCl4-induced liver injury, and decreased macrophage infiltration, IL-1ß, IL-6 and TNF-α production. As a result, Prdx1-/- mice were strongly protected from APAP-induced death that was likely progressed from ALI. Additionally, intravenous re-introduction of recombinant Prdx1 (rPrdx1) in Prdx1-/- mice reversed or reduced all the above events, demonstrating an important contribution of circulating Prdx1 to ALI. rPrdx1 potently induced in primary macrophages the expression of pro-IL-1ß, IL-6, TNF-α, and IL-1ß through the NF-κB signaling as well as the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, evident by caspase-1 activation. Furthermore, a significant elevation of serum Prdx1 was demonstrated in patients (n = 15) with ALI; the elevation is associated with ALI severity. Collectively, we provide the first demonstration for serum Prdx1 contributing to ALI.

Post-transcriptional regulation DPC4 gene by miR-190 in colorectal cancer cells.

OBJECTIVE: The objective of this study is to elucidate the regulation of the DPC4 gene by miR-190 in colorectal cancer (CRC) cells. The present study was undertaken to determine whether the DPC4 gene is a target gene of miRNA-190, identify target motifs and to elucidate the mechanism of regulation of DPC4 by miRNA-190. MATERIALS AND METHODS: MiR-190 and DPC4 expression were measured in five different CRC cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The regulation of DPC4 by miR-190 was evaluated by qRT-PCR, Western blotting, and luciferase reporter assays in the human CRC cell line HT-29 after treatment with miR-190 mimics and inhibitors. RESULTS: The DPC4 mRNA, miR-, and DPC4 protein expression levels were highest in LS174T cells while lowest in SW480 and SW620 cells. The DPC4/miR-190 ratio in the HT-29 cancer cell line was the largest. MiR-190 expression increased dramatically after treatment with miR-190 mimics and decreased significantly after treatment with miR-190 inhibitors. DPC4 protein expression decreased in the miR-190 mimics transfection group when compared to the negative control (N.C.) group and increased in the miR-190 inhibitor groups when compared to the inhibitor plus N.C. group. MiR-190 inhibits the relative luciferase activity of psiCHECK-2™ vector-3'UTR compared to the N.C. group, while miR-190 had no obvious effect on the relative luciferase activity of the psiCHECK-2™ vector-3'UTRmut and psiCHECK-2™ vector transfected cells. CONCLUSIONS: The DPC4 gene might be the target gene of miR-190, which may negatively regulate the DPC4 gene in human CRC cells by translational suppression rather than mRNA degradation.

Fluorofenidone Inhibits the Proliferation of Lung Adenocarcinoma Cells.

Background: Lung carcinoma is the leading cause of malignant tumor related mortality in China in recent decades, and the development of new and effective therapies for patients with advanced lung carcinoma is needed. We recently found that fluorofenidone (FD), a newly developed pyridine compound, reduced the activation of Stat3 (Signal transducer and activator of transcription 3) in fibroblasts. Stat3 plays a crucial role in the development of lung cancer and may represent a new therapeutic target. In this study, we examined the effect of FD on human lung adenocarcinoma cells in vivo and in vitro. Methods: The effect of FD on the growth of lung cancer cells was measured with a CCK-8 assay, colony formation assay and xenograft tumor model. A flow cytometry analysis was performed to study cell cycle arrest and apoptosis. Western blotting and immunohistochemistry were used to observe the expression of Stat3. Changes in the expression of RNA induced by FD were assessed using gene chip and real-time RT-PCR assays. Results: In vitro, FD inhibited the growth of lung adenocarcinoma A549 and SPC-A1 cells in a dose-dependent manner. After treatment with FD, the A549 and SPC-A1 cells were arrested in the G1 phase, and apoptosis was induced. In vivo, this compound significantly inhibited the growth of tumors that were subcutaneously implanted in mice. Moreover, FD decreased Stat3 activity in lung cancer cells and xenograft tumor tissue, and microarray chip results showed that FD altered the gene expression profile of lung cancer cells. Specifically, NUPR1, which plays a significant role in cancer development, was down-regulated by FD in lung cancer cells. Conclusion: Our study supports the clinical evaluation of FD as a potential lung adenocarcinoma therapy.

ZNF667 Serves as a Putative Oncogene in Human Hepatocellular Carcinoma.

BACKGROUND/AIMS: Zinc finger protein 667 (ZNF667) is a member of C2H2 zinc finger protein family. For the first time, we aim to analyze the expression pattern of ZNF667 in hepatocellular carcinoma (HCC) tissues; to explore its role in HCC tumorigenesis. METHODS: Immuno-histochemistry was carried out to characterize the ZNF667 expression in paraffin-embedded HCC samples. The relationship between ZNF667 expression and the clinical, pathological data of the patients were analyzed. Human normal hepatocyte cells LO2 over expressing ZNF667 (LO2-ZNF667 cells), ZNF667 depleted hepatocellular carcinoma HepG2 cells (HepG2-shZNF667 cells) were set up, their proliferation, migration and invasion abilities were analyzed. Xenograft nude mice were used to analyze the malignancy of HepG2-shZNF667 cells in vivo. Western blot was performed to analyze the expression of Bcl-2 and BAX in LO2-ZNF667 and HepG2-shZNF667 cells. RESULTS: Increased ZNF667 was found via immuno-histochemistry in HCC. Enhanced ZNF667 expression was associated with tumor size, clinical stage and tumor differentiation. LO2-ZNF667 cells displayed increased and HepG2-shZNF667 cells decreased cell proliferation, migration and invasion. Xenograft experiments proved reduced malignancy of HepG2-shZNF667 cells in vivo. LO2-ZNF667 cells displayed increased Bcl-2 and decreased BAX protein expression. HepG2-shZNF667 cells displayed enhanced BAX and inhibited BCL-2 expression. CONCLUSIONS: ZNF667 is shown to be a new oncogene in HCC and it may serve as a new therapeutic target for HCC via enhancing BCL-2 and decreasing BAX expression.

Association of rituximab with graphene oxide confers direct cytotoxicity for CD20-positive lymphoma cells.

Non-Hodgkin lymphoma (NHL) is one of the most common hematologic malignancies among adults for which the chimeric monoclonal anti-CD20 antibody (Ab) rituximab (RTX) is used as first-line therapy. As RTX itself is not directly cytotoxic but relies on host immune effector mechanisms or chemotherapeutic agents to attack target cells, its therapeutic capacity may become limited when host effector mechanisms are compromised. Currently, refractory disease and relapse with NHL are still common, highlighting the need for novel anti-CD20 antibody strategies with superior therapeutic efficacy over current protocols. We hypothesized that making RTX directly cytotoxic might improve the therapeutic efficacy. Graphene oxide (GO) has recently emerged as a highly attractive nanomaterial for biomedical applications; and several studies have reported cytotoxic effect of GO on benign and malignant cells in vitro. Herein, we report that RTX can be stably associated with GO, and that GO-associated RTX (RTX/GO) demonstrates remarkably high avidity for CD20. Binding of GO-associated RTX to CD20-positive lymphoma cells induces CD20 capping and target cell death through an actin dependent mechanism. In vivo, GO-associated RTX, but not free RTX, quickly eliminates high-grade lymphomas in the absence of host effector mechanisms in a xenograft lymphoma mouse model. Our findings represent the first demonstration of using GO-associated antibody as effective cytotoxic therapy for human B cell malignancies in the absence of chemotherapy, and these findings could have important clinical implications.

Peroxiredoxin 1 inhibits the oxidative stress induced apoptosis in renal tubulointerstitial fibrosis.

AIM: Apoptosis is one of the most important mechanisms underlying renal tubulointerstitial fibrosis. We identified a role of protein Peroxiredoxin 1 (Prx1) in protecting apoptosis occurred in tubular epithelial cells of the rat and human kidney. METHODS: Immunohistochemistry (IHC) staining was used to detect Prx1 expression in kidney derived from unilateral-ureteral obstruction (UUO) rats or patients with obstructive nephropathy. Modulation of Prx1 expression by transfecting siRNA and overexpression plasmid approach were carried out in NRK-52E (rat kidney tubular epithelial cell line) cells. UUO-induced apoptosis was determined using TUNEL assay. RESULTS: Immunohistochemistry staining showed that Prx1 expressed in the cytoplasm of renal tubular epithelial cells, in the kidneys of UUO rats. The reduction was confirmed by both IHC and real-time polymerase chain reaction following a course of renal tubulointerstitial fibrosis in UUO rats and a decrease of Prx1 occurred concomitantly with an elevation of TUNEL-positive cells. Fluorofenidone (AKF-PD), a new anti-tubulointerstitial fibrotic agent, attenuated Prx1 reduction in UUO rats. Furthermore, hydrogen peroxide (H2 O2 )-derived oxidative stress activated p38 MAPK, and induced apoptosis in NRK-52E cells; knockdown of Prx1 sensitized both events in NRK-52E cells, and overexpression of Prx1 diminished the apoptosis and the phosphorylation of p38 CONCLUSION: Downregulation of Prx1 occurred in renal tubular epithelial cells of UUO rats and patients with obstructive nephropathy. Prx1 may alleviate the pathogenesis by inhibiting H2 O2 -induced apoptosis via inhibiting the p38 MAPK pathway. Prx1 may represent a useful target for a protective therapy towards renal tubulointerstitial fibrosis.

Upregulation of autophagy-related gene-5 (ATG-5) is associated with chemoresistance in human gastric cancer.

Autophagy-related gene-5 (ATG-5) is one of the key regulators of autophagic cell death. It has been widely regarded as a protective molecular mechanism for tumor cells during the course of chemotherapy. In the present study, we investigated the expression pattern of ATG-5 and multidrug resistance-associated protein-1 (MRP-1) in 135 gastric cancers (GC) patients who were treated with epirubicin, cisplatin and 5-FU adjuvant chemotherapy (ECF) following surgical resection and explored their potential clinical significance. We found that both ATG-5 (77.78%) and MRP-1 (79.26%) were highly expressed in GC patients. ATG-5 expression was significantly associated with depth of wall invasion, TNM stages and distant metastasis of GC (P<0.05), whereas MRP-1 expression was significantly linked with tumor size, depth of wall invasion, lymph node metastasis, TNM stages and differentiation status (P<0.05). ATG-5 expression was positively correlated with MRP-1 (rp = 0.616, P<0.01). Increased expression of ATG-5 and MPR-1 was significantly correlated with poor overall survival (OS; P<0.01) and disease free survival (DFS; P<0.01) of our GC cohort. Furthermore, we demonstrated that ATG-5 was involved in drug resistant of GC cells, which was mainly through regulating autophagy. Our data suggest that upregulated expression of ATG-5, an important molecular feature of protective autophagy, is associated with chemoresistance in GC. Expression of ATG-5 and MRP-1 may be independent prognostic markers for GC treatment.

Is insulin-like growth factor binding protein 2 associated with metastasis in lung cancer?

Insulin-like growth factor binding protein 2 (IGFBP2) is involved in the progression of many epithelial cancers. However, its role in non-small cell lung cancer (NSCLC), another type of epithelial cancer, remains unclear. We detected IGFBP2 expression using immunohistochemistry in surgically resected tumors from 110 NSCLC patients, 37 of which had metastases. The positive rate of IGFBP2 expression was compared between the metastatic and the non-metastatic group, and correlations of IGFBP2 expression with metastasis and overall survival were analyzed. We also investigated the expression of IGFBP2 in microvesicles (MVs) collected from primary lung cancer cell cultures, and in different locations of newly resected NSCLC tumors, using immunoblotting. The overall positive rate of IGFBP2 expression in lung cancer was 51.8 % and it was significantly higher in the metastatic group than in the non-metastatic group (70.3 and 42.5 % respectively, p < 0.01). And the higher the lymph node stage, the higher the positive rate. Cytoplasmic expression was predominant in the majority of the tumors. Based on multivariate regression analysis, IGFBP2 was correlated with metastasis and poor overall survival (Hazard ratio: 3.56 and 3.23 respectively). IGFBP2 was detectable in the MVs collected from IGFBP2 positive cell lines, and its expression was most abundant in the marginal region of the newly resected tumors. IGFBP2 is associated with metastasis and poor survival of lung cancer. Its presence in MVs and high abundance in the marginal region of tumors suggest that its association with metastasis may be related to tumor microenviroment remodeling in NSCLC.