Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: A real-world multicenter study.

Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current knowledge regarding MN after allo-HSCT is limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT centers. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (P = 0.0102) and peripheral blood as the graft source (P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared to those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (P = 0.0002). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment.

Long Non-Coding RNA NEAT1 Regulates Pyroptosis in Diabetic Nephropathy via Mediating the miR-34c/NLRP3 Axis.

INTRODUCTION: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and is considered to be a sterile inflammatory disease. Increasing evidence suggest that pyroptosis and subsequent inflammatory response play a key role in the pathogenesis of DN. However, the underlying cellular and molecular mechanisms responsible for pyroptosis in DN are largely unknown. METHODS: The rat models of DN were successfully established by single 65 mg/kg streptozotocin treatment. Glomerular mesangial cells were exposed to 30 mmol/L high glucose media for 48 h to mimic the DN environment in vitro. Gene and protein expressions were determined by quantitative real-time PCR and Western blot. Cell viability and pyroptosis were measured by MTT assay and flow cytometry analysis, respectively. The relationship between lncRNA NEAT1, miR-34c, and Nod-like receptor protein-3 (NLRP3) was confirmed by luciferase reporter assay. RESULTS: We found that upregulation of NEAT1 was associated with the increase of pyroptosis in DN models. miR-34c, as a target gene of NEAT1, mediated the effect of NEAT1 on pyroptosis in DN by regulating the expression of NLRP3 as well as the expressions of caspase-1 and interleukin-1ß. Either miR-34c inhibition or NLRP3 overexpression could reverse the accentuation of pyroptosis and inflammation by sh-NEAT1 transfection in the in vitro model of DN. CONCLUSIONS: Our findings suggested NEAT1 and its target gene miR-34c regulated cell pyroptosis via mediating NLRP3 in DN, providing new insights into understanding the molecular mechanisms of pyroptosis in the pathogenesis of DN.

Specific expression network analysis of diabetic nephropathy kidney tissue revealed key methylated sites.

Diabetic nephropathy (DN) is one of the most common and serious complication in diabetes patients. However, the evidences of gene regulation mechanism and epigenetic modification with DN remain unclear. Therefore, it is necessary to search regulating genes for early diagnosis on DN. We identified tissue specific genes through mining the gene expression omnibus (GEO) public database, enriched function by gene ontology (GO), and kyoto encyclopedia of genes and genomes (KEGG) analysis, and further compared tissue-specific network. Meanwhile, combining with differentially methylated sites, we explored the association epigenetic modification with the pathogenesis of DN. Glomeruli (Glom) may be the main tissue of signal recognition and tubulointerstitium (Tub) is mainly associated with energy metabolism in the occurrence of DN. By comparing tissue-specific networks between Glom and Tub, we screened 319 genes, which played an important role in multiple tissue on kidney. Among them, ANXA2, UBE2L6, MME, IQGAP, SLC7A7, and PLG played a key role in regulating the incidence of DN. Besides, we also identified 1 up-regulated gene (PIK3C2B) and 39 down-regulated genes (POLR2G, DDB1, and ZNF230, etc.) in the methylated data of Glom specific genes. In the Tub specific expressed genes, we identified two hypo-methylated genes (PPARA and GLS). Tub mainly caused abnormal energy metabolism, and Glom caused the changes in cell connections and histone modification. By analyzing differentially methylated sites and tissue-specific expressed genes, we found the change of methylated status about the core regulating genes may be a potential factor in the pathogenesis of DN.

Exendin-4 alleviates high glucose-induced rat mesangial cell dysfunction through the AMPK pathway.

BACKGROUND/AIMS: Glucagon-like peptide-1 (GLP-1), which counteracts insulin resistance in humans with type 2 diabetes, has been shown to ameliorate diabetic nephropathy in experimental models. However, the mechanisms through which GLP-1 modulates renal function remained illdefined. The present study investigated the putative mechanisms underlying effects of exendin-4, a GLP-1 analog, on mesangial cell proliferation and fibronectin. METHODS: Rat mesangial cells (MCs) were treated with exendin-4 under high glucose conditions. AMP-activated protein kinase (AMPK) inhibitors (compound C) and agonists (AICAR) were used to analyze the role of this kinase. Cell proliferation was measured using a MTT assay. Fibronectin expression and AMPK-signaling pathway activity were assessed using ELISA and Western blotting, respectively. The production of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinases (TIMP)-2 was evaluated using quantitative real-time RT-PCR. RESULTS: Exendin-4 inhibited cell proliferation and fibronectin secretion in high glucose-induced MCs. It also caused phosphorylation of AMPK and subsequently increased the ratio of MMP-2 to TIMP-2, which resulted in the degradation of fibronectin. Exendin-4 reversed extracellular signal-regulated kinase (ERK) phosphorylation and enhanced expression of mammalian target of rapamycin (mTOR) in MCs. Moreover, the activation of the AMPK pathway by exendin-4 was induced by AICAR, which was inhibited by compound C. CONCLUSION: Exendin-4 exerts an inhibitory effect on cell proliferation and fibronectin secretion in rat MCs, partly through AMPK activation. These results may explain some of the beneficial effects of exendin-4 on the kidney.

[Study of WIF-1 promoter methylation with expressions of ß-catenin in acute leukemia].

OBJECTIVE: To explore the significance of WIF-1 gene promoter methylation and the expression of ß-catenin in acute leukemia (AL) patients. METHODS: The method of methylation specific polymerase chain reaction was employed to detect the status of WIF-1 gene methylation in 55 acute leukemia patients and normal controls from January 2009 to June 2010 in our hospital. The expression of ß-catenin was measured by flow cytometry. RESULTS: The methylation of WIF-1 gene promoter was found in 32.7% (18/55) AL patients. And the percentage was significantly higher than that of the controls (0). The patients with the methylation of WIF-1 gene had a lower complete remission rate (38.9%, 7/18) for the first chemotherapy than those without (81.1%, 30/37) (P < 0.05). The expressions of ß-catenin in methylation AL patients and those with non-methylation were 17.5% ± 3.3% and 15.4% ± 3.6% respectively. And they were significantly higher than the controls (10.5% ± 1.5%, P < 0.05). The expression of ß-catenin was higher in positive methylation patients than those negative ones (P < 0.05). CONCLUSION: The methylation of WIF-1 gene promoter and ß-catenin may be involved in the abnormal activation of Wnt/ß-catenin signal in acute leukemia.

[Retracted] In vitro and in vivo anticancer effects of marmesin in U937 human leukemia cells are mediated via mitochondrial­mediated apoptosis, cell cycle arrest, and inhibition of cancer cell migration.

Following the publication of the above paper, a concerned reader drew to the Editor's attention that a pair of tumors in Fig. 10 appeared to have been duplicated, although one of the tumors appeared at a larger size in the figure relative to the first one. Furthermore, the flow cytometric plots shown in Fig. 2B in the above paper appeared to be remarkably similar to data presented in a paper published in Phytomedicine [Sui C­G, Meng F­D and Jiang Y­H: Antiproliferative activity of rosamultic acid is associated with induction of apoptosis, cell cycle arrest, inhibition of cell migration and caspase activation in human gastric cancer (SGC­7901) cells. Phyomedicine 22: 796­806, 2015]. After having conducted an independent investigation in the Editorial Office, the Editor of Oncology Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence concerning the originality and the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal. [the original article was published in Oncology Reports 39: 597­602, 2018; DOI: 10.3892/or.2017.6147].

Red blood cell distribution width is associated with mortality risk in patients with acute respiratory distress syndrome based on the Berlin definition: A propensity score matched cohort study.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder of the lungs and is associated with oxidative damage. However, red blood cell distribution width (RDW), as an indicator of body response to inflammation and oxidative stress, has not been studied for its relationship with ARDS as diagnosed by the Berlin definition. OBJECTIVES: To examine the value of RDW in predicting the prognosis of in patients with ARDS. METHODS: This is a retrospective study based on the Medical Information Mart for Intensive Care III (MIMIC-III) database. Berlin-defined ARDS patients using mechanical ventilation for more than 48 hours were selected using structured query language. The primary statistical methods were propensity score matching and sensitivity analysis, including an inverse probability weighting model to ensure the robustness of our findings. RESULTS: A total of 529 intensive care unit (ICU) patients with ARDS according to the Berlin definition were enrolled in the study. The adjusted OR showed an adverse effect between the higher RDW group and 30-day mortality [OR 2.33, 95% CI (1.15-4.75), P=0.019]. However, we found that length of ICU stay was not related to RDW (P=0.167), and in the anaemia group, RDW was poorly predictive of 30-day mortality (P=0.307). CONCLUSION: In unselected ARDS patients, higher RDW was associated with higher 30-day mortality rate. Further investigation is required to validate this relationship with prospectively collected data.

In vitro and in vivo anticancer effects of marmesin in U937 human leukemia cells are mediated via mitochondrial-mediated apoptosis, cell cycle arrest, and inhibition of cancer cell migration.

Leukemia is one of the highly lethal cancers among all pediatric cancers. With limited drug options and the severe side effects associated with the current chemotherapy, there is pressing need to look for new and novel anticancer agents. Against this backdrop, in the present study we evaluated the anticancer activity of a natural coumarin, marmesin against human leukemia cell line U937 and normal human monocytes It was observed that marmesin exhibited an IC50 value of 40 µM and exerted its cytotoxic effects in a dose-dependent manner. However, the cytotoxic effects of marmesin were comparatively lower for the normal human monocytes as evident from the IC50 of 125 µM. Our results indicated that marmesin inhibits colony formation and induces apoptosis dose-dependently. We also investigated the effect of marmesin on the expression of Bax and Bcl-2 proteins. It was observed that marmesin treatment triggered upregulation of Bax and downregulation of Bcl-2 causing significant increase in the Bax/Bcl-2 ratio, marmesin could also induce ROS mediated alterations in mitochondrial membrane potential. Additionally, marmesin induced G2/M cell cycle arrest and significantly inhibited cell migration potential of leukemia cells at the IC50. Remarkably, marmesin prevent tumor growth significantly in vivo at the dosage of 30 mg/kg in vivo. These results strongly indicate that marmesin may prove to be a novel anticancer lead for the management of leukemia.

[Study on early fibrinolytic therapy to avoid acute myocardial infarction].

OBJECTIVE: To investigate the frequency of aborted AMI and clinical characteristics of the patients received prompt fibrinolytic therapy. METHODS: 1120 patients with AMI were divided into two groups, true AMI group and aborted AMI group. Aborted AMI was defined as maximal creatine kinase-MB < or = 2 x upper limit of normal coupled with the presence of resolution of chest pain and 50% of ST-segment deviation within 2 hours after onset of therapy. We compared some characteristic of two groups such as the fibrinolytic time after symptom onset and the frequency of aborted AMI. RESULTS: The reopening ratio of infarct was 80.5%. 7.1% of the patients escaped myocardial necrosis. Aborted AMI was highest frequency within the first hour (22.0%) than other time groups (P < 0.01); There were no significant differences in the frequency of Aborted AMI in UK group, SK group and rt-PA group (7.0%, 6.7%, 7.1%, P > 0.05); The rate of Killip III/IV, major arrhythmias, angina pectoris and mortality at 30 day in aborted AMI patients compared with those who had true AMI was 3.9% versus 17.1%, 18.0% versus 30.0%, 1.3% versus 8.0%, 0 versus 6.0%, respectively (P < 0.01). CONCLUSION: Prompt fibrinolytic therapy improved the likelihood of aborted AMI and clinical outcomes. The frequency of aborted AMI has no relationship with fibrinolytic drug, but closely related to the starting time of treatment from symptom onset.

Inhibition of lipoprotein-associated phospholipase A2 ameliorates inflammation and decreases atherosclerotic plaque formation in ApoE-deficient mice.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: ApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-α in the darapladib group. CONCLUSIONS/SIGNIFICANCE: Inhibition of lp-PLA2 by darapladib leads to attenuation of in vivo inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis.

[A preliminary study on the implication of Apaf-1 promoter methylation and the expression of apoptosis inhibitor protein Apollon in adult acute leukemia].

OBJECTIVE: To investigate the role of Apaf-1 gene promoter methylation and apoptosis inhibitor protein Apollon in pathogenesis of acute leukemia (AL) and their clinical significance. METHODS: Methylation specific PCR (MSP) was used to detect the methylation status of Apaf-1 gene promoter in 53 AL patients (28 AML, 10 ALL and 15 relapsed) and 10 healthy or nonmalignant blood diseases patients as control. RT-PCR was used to detect the expression levels of Apaf-1 mRNA and immunocytochemistry to detect the expression levels of Apollon protein. RESULTS: The abnromal methylation of Apaf-1 gene promotor in AL was 18/53(33.9%). No Apaf-1 mRNA was detected in methylation positive patients. Only one case in healthy and nonmalignant individuals was deletion of Apaf-1 mRNA expression without abnormal methylation. The positive methylation rate in AL bone marrow mononuclear cells was significantly higher than that in controls (P < 0.05). The expressin levels of Apollon protein in AL patients was higher than that in control (P < 0.05). The positive methylation ratio and Apollon protein level were higher in white blood cell count > 10 × 10(9)/L than in ≤ 10 × 10(9)/L (P < 0.05). There is a positive correlaiton between positive methylation ratio and Apollon protein expression in AL patients. CONCLUSION: Abnormal methylation of Apaf-1 gene promotor and high expression of Apollon might involved in leukemogenesis.