Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.

Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury.

Macrophage migration inhibitory factor (MIF) is a multifaced protein that plays important roles in multiple inflammatory conditions. However, the role of MIF in endothelial cell (EC) death under inflammatory condition remains largely unknown. Here we show that MIF actively promotes receptor-interacting protein kinase 1 (RIPK1)-mediated cell death under oxygen-glucose deprivation condition. MIF expression is induced by surgical trauma in peripheral myeloid cells both in perioperative humans and mice. We demonstrate that MIF-loaded myeloid cells induced by peripheral surgery adhere to the brain ECs after distal middle cerebral artery occlusion (dMCAO) and exacerbate the blood-brain barrier (BBB) disruption. Genetic depletion of myeloid-derived MIF in perioperative ischemic stroke (PIS) mice with MCAO following a surgical insult leads to significant reduction in ECs apoptosis and necroptosis and the associated BBB disruption. The adoptive transfer of peripheral blood mononuclear cells (PBMC) from surgical MIFΔLyz2 mice to wild-type (WT) MCAO mice also shows reduced ECs apoptosis and necroptosis compared to the transfer of PBMC from surgical MIFf  l/f  l mice to MCAO recipients. The genetic inhibition of RIPK1 also attenuates BBB disruption and ECs death compared to that of WT mice in PIS. The administration of MIF inhibitor (ISO-1) and RIPK1 inhibitor (Nec-1s) can both reduce the brain EC death and neurological deficits following PIS. We conclude that myeloid-derived MIF promotes ECs apoptosis and necroptosis through RIPK1 kinase-dependent pathway. The above findings may provide insights into the mechanism as how peripheral inflammation promotes the pathology in central nervous system.

Associations between long-term exposure to ambient air pollution and renal function in Southwest China: The China Multi-Ethnic Cohort (CMEC) study.

BACKGROUND: Limited studies have examined associations between air pollutants exposure and renal function, especially in China, with the most extensive chronic kidney disease (CKD) disease burden worldwide. OBJECTIVES: This study examines associations between long-term exposure to ambient PM2.5, NO2, CO, O3, SO2 and renal function. METHODS: We included 80,225 participants aged 30-79 years from the baseline data of the China Multi-Ethnic Cohort (CMEC) study. Three-year average concentrations of PM2.5, NO2, CO, O3, and SO2 were estimated using satellite-based spatiotemporal models. Renal function is determined by the estimated glomerular filtration rate (eGFR) using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. After adjusting for covariates, generalized propensity scores (GPS) weighting regression was used to estimate associations between ambient air pollutants and renal function. RESULTS: An increase of 0.1 mg/m3 CO (OR [odds ratio] =1.20 95% CI [confidence interval], 1.05-1.37) was positively associated with CKD. An increase of 1 µg/m3 in SO2 (1.07, 1.00-1.14) concentration was positively associated with CKD. An increase of 10 µg/m3 in PM2.5 (1.17, 0.99-1.38), NO2 (1.12, 0.83-1.51) and O3 (1.10, 0.81-1.50) concentration was not associated with CKD. These effects are stronger in those younger than 65, smoking and with low BMI. CONCLUSIONS: In this study, we found that long-term exposure to ambient CO and SO2 were positively associated with CKD. Gaseous pollutants should also arouse the concern of relevant departments.

PCAT19 Regulates the Proliferation and Apoptosis of Lung Cancer Cells by Inhibiting miR-25-3p via Targeting the MAP2K4 Signal Axis.

Both PCAT19 and miR-25-3p have been reported in lung cancer studies, but whether there is a correlation between the two and whether they jointly regulate the progress of lung cancer have not been reported yet. Therefore, this study carried out a further in-depth research. The expression of PCAT19 was detected in lung cancer (LC) tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of PCAT19 on tumor growth was detected in a tumor-bearing model of nude mice. PCAT19-transfected cells were treated with Honokiol and anisomycin. The effects of PCAT19 on proliferation, apoptosis, and cycle of LC cells were investigated by biomolecule experiments. The effects of PCAT19 on the expressions of mitogen-activated protein kinase- (MAPK-) related proteins were evaluated by western blotting. The expression of PCAT19 was decreased in LC tissues and related to patient survival, tumor size, and pathology. In addition, upregulation of PCAT19 hindered LC cell proliferation, miR-25-3p expression, and the activation of extracellular regulated protein kinases (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK), while facilitating LC cell apoptosis. Furthermore, upregulation of PCAT19 reversed the effects of Honokiol and anisomycin on promoting cell proliferation and inhibiting cell apoptosis. Collectively, our findings show that upregulated PCAT19 suppresses proliferation yet promotes the apoptosis of LC cells through modulating the miR-25-3p/MAP2K4 signaling axis.

miR-489-3p promotes malignant progression of non-small cell lung cancer through the inactivation of Wnt/ß-catenin signaling pathway via regulating USP48.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer globally, with average age of cancer patients becoming younger gradually. It is of significance to gain a comprehensive understanding of molecular mechanism underlying NSCLC. METHODS: Quantitative polymerase chain reaction (qPCR) and western blot were applied to measure RNA and protein levels separately. Functional assays and western blot were performed to determine the effects of miR-489-3p and USP48 on cell growth, migration and epithelial-mesenchymal transition (EMT) in NSCLC. TOP/FOP flash luciferase reporter assay was carried out to detect the activity of Wnt pathway. Besides, qPCR, RNA pulldown and luciferase reporter assays were conducted to probe into the target gene of miR-489-3p. Immunoprecipitation-western blot (IP-western blot) analysis was implemented to assess the effect of USP48 on the ubiquitination of ß-catenin. RESULTS: miR-489-3p hampers NSCLC cell proliferation, migration and EMT in vitro and NSCLC tumorigenesis and metastasis in vivo. Additionally, miR-489-3p inactivates Wnt/ß-catenin signaling pathway and regulates USP48 to inhibit the ubiquitination of ß-catenin. Moreover, USP48 propels the development of NSCLC cells. CONCLUSIONS: The current study demonstrated that miR-489-3p promotes the malignant progression of NSCLC cells via targeting USP48, which might offer a new perspective into NSCLC treatment.

Gene expression in the smut fungus Ustilago esculenta governs swollen gall metamorphosis in Zizania latifolia.

Ustilago esculenta, a smut fungus, can induce the formation of culm galls in Zizania latifolia, a vegetable consumed in many Asian countries. Specifically, the mycelia-teliospore (M-T) strain of U. esculenta induces the Jiaobai (JB) type of gall, while the teliospore (T) strain induces the Huijiao (HJ) type. The underlying molecular mechanism responsible for the formation of the two distinct types of gall remains unclear. Our results showed that most differentially expressed genes relevant to effector proteins were up-regulated in the T strain compared to those in the M-T strain during gall formation, and the expression of teliospore formation-related genes was higher in the T strain than the M-T strain. Melanin biosynthesis was also clearly induced in the T strain. The T strain exhibited stronger pathogenicity and greater teliospore production than the M-T strain. We evaluated the implications of the gene regulatory networks in the development of these two type of culm gall in Z. latifolia infected with U. esculenta and suggested potential targets for genetic manipulation to modify the gall type for this crop.

RNA-seq analysis provides insight into reprogramming of culm development in Zizania latifolia induced by Ustilago esculenta.

KEY MESSAGE: We report a transcriptome assembly and expression profiles from RNA-Seq data and identify genes responsible for culm gall formation in Zizania latifolia induced by Ustilago esculenta. The smut fungus Ustilago esculenta can induce culm gall in Zizania latifolia, which is used as a vegetable in Asian countries. However, the underlying molecular mechanism of culm gall formation is still unclear. To characterize the processes underlying this host-fungus association, we performed transcriptomic and expression profiling analyses of culms from Z. latifolia infected by the fungus U. esculenta. Transcriptomic analysis detected U. esculenta induced differential expression of 19,033 and 17,669 genes in Jiaobai (JB) and Huijiao (HJ) type of gall, respectively. Additionally, to detect the potential gall inducing genes, expression profiles of infected culms collected at -7, 1 and 10 DAS of culm gall development were  analyzed. Compared to control, we detected 8089 genes (4389 up-regulated, 3700 down-regulated) and 5251 genes (3121 up-regulated, 2130 down-regulated) were differentially expressed in JB and HJ, respectively. And we identified 376 host and 187 fungal candidate genes that showed stage-specific expression pattern, which are  possibly responsible for gall formation at the initial and later phases, respectively. Our results indicated that cytokinins play more prominent roles in regulating gall formation than do auxins. Together, our work provides general implications for the understanding of gene regulatory networks for culm gall development in Z. latifolia, and potential targets for genetic manipulation to improve the future yield   of  this crop.

Protective effect of crocetin on hemorrhagic shock-induced acute renal failure in rats.

Multiple organ failure is a common outcome of hemorrhagic shock followed by resuscitation, and the kidney is one of the prime target organs involved. The main objective of the study was to evaluate whether crocetin, a natural product from Gardenia jasminoides Ellis, has beneficial effects on renal dysfunction caused by hemorrhagic shock and resuscitation in rats. Anesthetized rats were bled to reduce mean arterial blood pressure to 35 (SD, 5) mmHg for 60 min and then were resuscitated with their withdrawn shed blood and normal saline. Crocetin was administered via the duodenum at a dose of 50 mg/kg 40 min after hemorrhage. The increase in creatinine and blood urea nitrogen was significantly reduced at 2 h after hemorrhage and resuscitation in crocetin-treated rats. The increases in renal nitric oxide, tumor necrosis factor α, and interleukin 6 were also attenuated by crocetin. Hemorrhagic shock resulted in a significant elevation in malondialdehyde production and was accompanied by a reduction in total superoxide dismutase activity, activation of nuclear factor κB, and overexpression of inducible nitric oxide synthase. These changes were significantly attenuated by crocetin at 2 h after resuscitation. These results suggested that crocetin blocks inflammatory cascades by inhibiting production of reactive oxygen species and restoring superoxide dismutase activity to ameliorate renal dysfunction caused by hemorrhage shock and resuscitation.

Hospital costs and length of hospital stay for hepatectomy in patients with hepatocellular carcinoma:results of a prospective case series.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) has become an important health concern. However, data on its economic burden are limited. This study was undertaken to estimate the hospital costs and length of hospital stay (LOHS) for hepatectomy in patients with HCC, and identify the contributing factors to them. METHODOLOGY: A prospective case series observation was performed from January 2009 to December 2009 at two general hospitals in China. The information, such as demographic and clinical data, of HCC patients undergoing hepatectomy was recorded. Hospital costs and LOHS were analyzed to estimate the distribution of healthcare utilization. The multiple linear regression analysis was utilized to determine the impact of different demographic and clinical factors on costs and LOHS. RESULTS: A total of 220 patients were enrolled. The median hospital costs were $3453.7. The median LOHS was 13 days. The major fraction of the total costs was medication costs, accounting for 40.2%. LOHS was the key determinant of hospital costs. Blood transfusion, postoperative complication and Child-Pugh score were also independent but less contributory determinants. Additionally, predictors for prolonged LOHS included postoperative complication and surgical procedure. CONCLUSIONS: Hospital costs and LOHS for hepatectomy have their particular contributing factors. The results may be useful in resource allocation and cost-effectiveness analysis of intervention for HCC treatment.

Epidemiology and cost analysis for patients with oral cancer in a university hospital in China.

BACKGROUND: Although several studies have reported the direct cost of oral cancer (OC), little research has invested the factors that could influence the costs of OC patient. This study analyzes the epidemiological characteristics and the direct cost of OC. More specifically, the study examines the relationship between patients' medical costs and influencing factors of epidemiology. METHODS: All patients encountered from January 2007 to December 2007 at the School of Stomatology of the Fourth Military Medical University (FMMU) in China with diagnosis of oral cancer have been selected. Medical hospitalization days (MHD) and cost per patient (CPP) of the samples have been calculated for different patient groups, and the results have been compared using statistical methods. RESULTS: A total of 456 oral cancer patients have been selected in this study. The epidemical characteristics are as follows: female/male 176/280; squamous cell carcinoma (SCC)/adenocarcinoma/sarcoma/lymphoma/other types 246/127/40/27/16; stage I/II/III/IV 90/148/103/115; smoker/non-smoker 136/320; rural/urban patients 82/374. Of all the patients, 82.24% were over 40 years of age. Rural patients were significantly younger than urban patients. SCC was the majority histology in older patients, while sarcoma was more common in younger patients. 372 of the patients received treatment and 84 gave up any treatment after diagnosis. Treatment cost accounted for majority of the payment. The CPP and MHD of patients in late clinical stage were higher than that of patient in early stage. CONCLUSION: Gender, smoking habit and age older than 40 years are the epidemiological risk factors for oral cancer. Lack of medicare, smoking habit, late clinical stage and SCC are the high economic factors for patient medical cost.

[Treatment of humerus shaft fractures using minimally invasive percutaneous plate osteosynthesis through anterior approach].

OBJECTIVE: To discuss the method and effects of treatment of minimally invasive percutaneous plate osteosynthesis (MIPO) through anterior approach for the treatment of humerus shaft fractures. METHODS: 2006.1 to 2007.10,15 patients with humerus shaft fractures were treated with MIPO through anterior approach. There were 11 males and 4 females, ranging in age from 16 to 59 years, with an average of 35 years old. The duration of the disease was 7.5 days on average (5 to 10 days). Six patients had Type A fractures, 8 Type B, and 1 Type C according to AO classification. The AO LC-DCP with diameter of 4.5 mm was chosen in the operation. The patients were physically examined preoperatively and postoperatively, the range of motion of shoulder and elbow joint was observed, and the joint function was included. RESULTS: All the patients were followed up for a period ranging from 5 to 18 months,averaged 10 months. In terms of Gill ipsilateral total shoulder and elbow arthroplasties, 12 patients got an excellent result (> or = 80 scores), 3 good (between the scores of 66 and 79). The Gill score increased from preoperative (59.33 +/- 8.21) to postoperative (84.67 +/- 5.81). Fractures were healed after 2 to 3 months after operation, and patients resumed daily life without the complications of nervous lesion, incision infection, internal fixation failure and nonunion of fracture etc. CONCLUSION: It is feasible for the treatment of humerus shaft fracture using MIPO through anterior approach,to avoid radial nerve injury and to prompt fracture union.