Gender-Specific Risk Factors for Asymmetric Bone Density in Adult Degenerative Lumbar Scoliosis: A Retrospective Cohort Analysis.

BACKGROUND This study aimed to evaluate the performance of Hounsfield Unit (HU) value on the vertebral bone mineral density associated with adult degenerative lumbar scoliosis (ADLS) and to compare the HU and coronal height changes of the lumbar spine on the concave and convex sides. The secondary aim was to investigate the risk factors for increased asymmetric ratio of HU (ARH) by concave-to-convex. MATERIAL AND METHODS A total of 74 patients aged ≥50 years were retrospectively reviewed. The height and the HU values of the region of interest were measured and compared. Multiple linear regression and gender-stratified analyses were performed to explore risk factors. Restricted cubic spline (RCS) was used to visually assess the dose-effect relationship between the Cobb angle and ARH. RESULTS The heights on the concave sides were significantly lower while HU values were significantly higher than that of the convex side. Cobb angle (95% CI: 0.001 to 0.009, P=0.034) was positively correlated with the increased ARH, while apex orientation to the right (95% CI: -0.152 to -0.013, P=0.022) was negatively associated. Gender-stratified analyses showed age and apex vertebrae location are 2 additional risk factors in male patients but not in female patients. Cobb angle was identified by RCS as a risk factor both in males and females and the inflection points were 15 and 17.5, respectively. CONCLUSIONS HU values on the concave side are significantly higher than on the convex side, showing the asymmetrical bone mass distribution of ADLS patients. Several gender-related risk factors for increased ARH have been identified.

Acetylcholine ameliorates colitis by promoting IL-10 secretion of monocytic myeloid-derived suppressor cells through the nAChR/ERK pathway.

The alteration of the enteric nervous system (ENS) and its role in neuroimmune modulation remain obscure in the pathogenesis of inflammatory bowel diseases (IBDs). Here, by using the xCell tool and the latest immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs technique, we found severe pathological damage of the entire ENS and decreased expression of choline acetyltransferase (ChAT) in IBD patients. As a result, acetylcholine (ACh), a major neurotransmitter of the nervous system synthesized by ChAT, was greatly reduced in colon tissues of both IBD patients and colitis mice. Importantly, administration of ACh via enema remarkably ameliorated colitis, which was proved to be directly dependent on monocytic myeloid-derived suppressor cells (M-MDSCs). Furthermore, ACh was demonstrated to promote interleukin-10 secretion of M-MDSCs and suppress the inflammation through activating the nAChR/ERK pathway. The present data reveal that the cholinergic signaling pathway in the ENS is impaired during colitis and uncover an ACh-MDSCs neuroimmune regulatory pathway, which may offer promising therapeutic strategies for IBDs.

Neutralization of Intracellular pH Homeostasis to Inhibit Osteoclasts Based on a Spatiotemporally Selective Delivery System.

Osteoporosis is a global disease caused by abnormal overactivation of osteoclasts. The acidic environment in sealing zone of osteoclasts with H+ pumped from cytoplasm is critical to the maturation of osteoclasts. Therefore, reducing the intracellular H+ concentration can reduce the H+ secretion of osteoclasts from the source. In our study, we developed a novel nanovesicle which encapsulates Na2HPO4 with a liposome hybridizes with preosteoclast membrane (Na2HPO4@Lipo-pOCm). These nanovesicles release Na2HPO4 into the preosteoclast by targeting preosteoclasts and membrane fusion, reducing the intracellular H+ concentration, and achieve biological cascade regulation of osteoclasts through simple pH regulation. In vitro and in vivo experiments confirmed that these nanovesicles reduce mitochondrial membrane potential by decreasing intracellular H+ concentration, thereby reducing the ROS in osteoclasts as well as the expression of the upstream transcription factor FOXM1 of Acp5. In short, this nanovesicle can significantly inhibit the osteoclasts and ameliorate osteoporosis caused by OVX.

A model based on immune-related lncRNA pairs and its potential prognostic value in immunotherapy for melanoma.

A model based on long non-coding RNA (lncRNA) pairs independent of expression quantification was constructed to evaluate prognosis melanoma and response to immunotherapy in melanoma. RNA sequencing data and clinical information were retrieved and downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. We identified differentially expressed immune-related lncRNAs (DEirlncRNAs), matched them, and used least absolute shrinkage and selection operator and Cox regression to construct predictive models. The optimal cutoff value of the model was determined using a receiver operating characteristic curve and used to categorize melanoma cases into high-risk and low-risk groups. The predictive efficacy of the model with respect to prognosis was compared with that of clinical data and ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data). Then, we analyzed the correlations of risk score with clinical characteristics, immune cell invasion, anti-tumor, and tumor-promoting activities. Differences in survival, degree of immune cell infiltration, and intensity of anti-tumor and tumor-promoting activities were also evaluated in the high- and low-risk groups. A model based on 21 DEirlncRNA pairs was established. Compared with ESTIMATE score and clinical data, this model could better predict outcomes of melanoma patients. Follow-up analysis of the model's effectiveness showed that patients in the high-risk group had poorer prognosis and were less likely to benefit from immunotherapy compared with those in the low-risk group. Moreover, there were differences in tumor-infiltrating immune cells between the high-risk and low-risk groups. By pairing the DEirlncRNA, we constructed a model to evaluate the prognosis of cutaneous melanoma independent of a specific level of lncRNA expression.

Important Roles and Formation of Atmospheric Organosulfates in Marine Organic Aerosols: Influence of Phytoplankton Emissions and Anthropogenic Pollutants.

Organosulfates (OSs) could be potentially important compounds in marine organic aerosols, while their formation in marine atmospheres is far from clear due to a lack of cruise observations. In this work, shipboard atmospheric observations were conducted over the Yellow Sea and Bohai Sea to investigate the abundance and formation of biogenic isoprene/monoterpene-OSs in marine aerosols. The quantified OSs and NOSs accounted for 0.04-6.9% of marine organic aerosols and were 0.07-2.2% of the non-sea-salt (nss) sulfate in terms of sulfur content. Isoprene-related (nitrooxy-)OSs occupied 27-87% of the total quantified OSs, following the abundance order of summer > autumn > spring or winter. This order was driven by the marine phytoplankton biomass and sea surface temperature (SST), which controlled the seawater and atmospheric isoprene concentration levels. Under the severe impacts of anthropogenic pollutants from the East Asia continent in winter, monoterpene nitrooxy-OSs, generated with NOx involved in, increased to 34.4 ± 35.5 ng/m3 and contributed 68% of the quantified (nitrooxy-)OSs. Our results highlight the notable roles of biogenic OSs in marine organic aerosols over regions with high biological activity and high SST. The formation of biogenic OSs and their roles in altering marine aerosol properties calls for elaboration through cruise observations in different marine environments.

Characteristics of MRI­based vertebral bone quality scores in elderly patients with vertebral fragility fractures.

OBJECTIVE: To explore the characteristics of vertebral bone quality (VBQ) scores in patients with vertebral fragility fractures, including VBQ score and single-level VBQ score, and evaluate their effectiveness as predictors. METHODS: The VBQ scores were measured using T1-weighted MRI images. VBQ scores were compared in patients with different times of previous fragility fractures. In addition, patients with fractures were matched for age and sex with patients without fractures, and VBQ scores were compared between the two groups. Finally, the predictive efficiency of VBQ scores for vertebral fragility fractures was analyzed by the receiver-operator curve (ROC). RESULTS: The average VBQ score and single-level VBQ score in patients with fractures were 3.48 ± 0.56 and 3.60 ± 0.60 and no difference among patients with different times of previous fractures. As for the age- and sex-matched patients, fracture patients had higher VBQ scores (VBQ score: 3.48 ± 0.56 vs. 2.88 ± 0.40, p < 0.001; single-level VBQ score: 3.60 ± 0.60 vs. 2.95 ± 0.44, p < 0.001). The AUCs using the VBQ score and single-level VBQ score to predict fragility fractures were 0.815 and 0.817, respectively. The optimal thresholds of the VBQ score and single-level VBQ score for predicting fragility fractures were 3.22 and 3.16, respectively. CONCLUSION: MRI­based VBQ scores are important predictors of vertebral fragility fracture but have no predictive value for the recurrence of fractures in patients with a history of fragility fractures. The VBQ score of 3.22 and single-level VBQ score of 3.16 are optimal thresholds that can be used when using lumbar MRI scans to identify individuals at high risk for fragility fractures.

CPT1C-mediated fatty acid oxidation facilitates colorectal cancer cell proliferation and metastasis.

Fatty acid oxidation (FAO) has been proven to be an accomplice in tumor progression. Carnitine palmitoyltransferase 1C (CPT1C), a rate-limiting enzyme in FAO, mainly functions to catalyze fatty acid carnitinylation and guarantee subsequent entry into the mitochondria for FAO in colorectal cancer (CRC). Gene expression data and clinical information extracted from The Cancer Genome Atlas (TCGA) database show significantly higher expression of CPT1C in patients with metastatic CRC ( P=0.005). Moreover, overexpression of CPT1C is correlated with worse relapse-free survival in CRC (HR 2.1, P=0.0006), while no statistical significance is indicated for CPT1A and CPT1B. Further experiments demonstrate that downregulation of CPT1C expression leads to a decrease in the FAO rate, suppression of cell proliferation, cell cycle arrest and repression of cell migration in CRC, whereas opposite results are obtained when CPT1C is overexpressed. Furthermore, an FAO inhibitor almost completely reverses the enhanced cell proliferation and migration induced by CPT1C overexpression. In addition, analysis of TCGA data illustrates a positive association between CPT1C expression and HIF1α level, suggesting that CPT1C is a transcriptional target of HIF1α. In conclusion, CPT1C overexpression indicates poor relapse-free survival of patients with CRC, and CPT1C is transcriptionally activated by HIF1α, thereby promoting the proliferation and migration of CRC cells.

Combinations of two imaging parameters to improve bone mineral density (BMD) assessment in patients with lumbar degenerative diseases.

PURPOSE: To explore whether combining the Hounsfield unit (HU) values and vertebral bone quality (VBQ) scores can improve the BMD assessment in patients with lumbar degenerative diseases. METHODS: The HU values were measured by CT image, and VBQ scores were calculated by lumbar MRI image. The correlations of the opportunistic imaging parameters to the lowest T-scores were analyzed. Receiver-operating characteristic curve (ROC) analysis was used to evaluate the accuracy in detecting osteoporosis. Finally, the specificity and sensitivity of different combined methods of the HU values and VBQ scores in the diagnosis of osteoporosis were compared. RESULTS: Patients with osteoporosis had the lowest HU values and the highest VBQ scores. The correlation coefficients between the VBQ scores and the T-scores were smaller than HU values (L1 HU value: 0.702; average HU value:0.700; L1 VBQ score: -0.413; VBQ score: -0.386). The areas under the curve (AUCs) of the HU values were greater than those of the VBQ scores, and the AUCs of the L1 VBQ score were similar to the VBQ score (L1 HU value: 0.850; average HU value:0.857; L1 VBQ score: 0.704; VBQ score: 0.673). When combining the two imaging parameters in series, the specificity of the detection of osteoporosis was improved (L1 HU value and L1 VBQ score: 87.3%; Average HU value and VBQ score: 85.9%). When combining the two imaging parameters in parallel, the sensitivity of the detection of osteoporosis was improved (L1 HU value or L1 VBQ score: 88.1%; Average HU value or VBQ score: 91.5%). CONCLUSIONS: Combinations of the HU values and VBQ scores could improve the diagnostic performance of osteoporosis. In addition, considering the same diagnostic performance but easier measurement, parameters at the single-segment level were recommended to assist in the diagnosis of osteoporosis.

Cloning and sequence analysis of a serine protease gene from Rhizoctonia solani Kühn AG5.

The present study aimed to identify the subtilisin-like proteases (SLPs) of Rhizoctonia solani Kühn potentially involved in the virulence of this phytopathogenic fungus, which has 14 anastomosis groups (AGs) responsible for many crop diseases. Through mycelial microscope observation and strain identification of pathogenic fungus MS-3, it was determined to be R. solani AG-5. Both 5' and 3' rapid amplification of cDNA ends were used to clone the serine protease gene RsSLP from R. solani AG-5. The full-length obtained for RsSLP was 1714 bp with an open reading frame of 1587 bp, encoding a protein of 528 amino acids with a molecular mass of 55.8 kDa. This protein contained a predicted signal peptide for secretion but lacked a transmembrane domain or membrane anchor site. Bioinformatics analysis identified this protein as a serine protease with the Peptidase_S8 and Inhibitor_I9 characteristic domains of SLPs. Phylogenetic analysis suggested that frequent gene duplications of the SLPs occurred in R. solani (RsSLP), and RsSLP shares characteristic sequence features with virulence factors of other phytopathogenic fungi. Because the secretory serine protease RsSLP from R. solani AG5 is similar to the virulence factors of other phytopathogenic fungi, its identification will be helpful in studies considering the roles of these proteases in pathogen virulence.

The morphological characteristics of paraspinal muscles in young patients with unilateral neurological symptoms of lumbar disc herniation.

OBJECTIVE: The objective of this study was to explore the morphological characteristics of paraspinal muscles in young patients with unilateral neurological symptoms of lumbar disc herniation. METHODS: This study retrospectively analyzed young patients aged 18-40 years who were hospitalized for lumbar disc herniation in our hospital from June 2017 to June 2020. Data on sex, age, body mass index (BMI), subcutaneous fat tissue thickness (SFTT) at the L1-L2 level, duration of symptoms, degree of lumbar disc herniation, visual analog scale (VAS) for the lower back, Mo-fi-disc score, relative cross-sectional area (RCAS) of the paravertebral muscles (psoas major [PM], multifidus [MF], and erector spinae [ES]), and degree of fat infiltration (DFF) of the paravertebral muscles were collected. The VAS was used to evaluate the intensity of low back pain. Patients with VAS-back >4 points were defined as the low back pain group, and patients with ≤4 points were defined as the control group. The demographic characteristics, as well as the bilateral and ipsilateral paravertebral muscles, of the two groups were compared and analyzed. RESULT: A total of 129 patients were included in this study (52 patients in the LBP group and 77 patients in the control group). There were no significant differences in sex, BMI, or Pfirrmann grade of lumbar disc herniation between the two groups (P > 0.05). The age of the LBP group (33.58 ± 2.98 years) was greater than that of the control group (24.13 ± 2.15 years) (P = 0.002), and the SFTT at the L1-L2 level (13.5 ± 7.14 mm) was higher than that of the control group (7.75 ± 6.31 mm) (P < 0.05). Moreover, the duration of symptoms (9.15 ± 0.31 months) was longer than that of the control group (3.72 ± 0.48 months) (P < 0.05), and the Mo-fi-disc score (8.41 ± 3.16) was higher than that of the control group (5.53 ± 2.85) (P < 0.05). At L3/4 and L5/S1, there was no significant difference in the RCSA and DFF of the bilateral and ipsilateral paraspinal muscles between the LBP group and the control group. At L4/5, there was no significant difference in the RCSA and DFF of the paraspinal muscles on either side in the LBP group (P > 0.05). In the control group, the RCSA of the MF muscle on the diseased side was smaller than that on the normal side (P < 0.05), and the DFF of the MF muscle on the diseased side was larger than that on the normal side (P < 0.05). In addition, there was no significant difference in the ES and PM muscles on both sides (P > 0.05). At L4/5, the RCSA of the MF muscle on the normal side was significantly smaller in the LBP group than in the control group (P < 0.05), and the DFF of the MF muscle on the normal side was significantly larger in the LBP group than in the control group (P < 0.05). There was no significant difference in the ES and PM muscles on the same side between the two groups (P > 0.05). CONCLUSION: In young patients with unilateral neurological symptoms of lumbar disc herniation, symmetrical atrophy of the bilateral MF muscle is more prone to causing low back pain. Older age, higher SFTT at the L1-L2 levels, longer symptom duration, higher Mo-fi-di score, and greater muscle atrophy on the normal side of the MF increased the incidence of low back pain in young patients with unilateral lumbar disc herniation.

Reliable Quantification of pH Variation in Live Cells Using Prussian Blue-Caged Surface-Enhanced Raman Scattering Probes.

Intracellular pH is an important parameter that is highly associated with diverse physiological processes. The reliable measurement of pH values inside cells remains a formidable challenge because of the complexity of cytoplasm. Herein, we report a robust Prussian blue (PB)-caged pH-responsive surface-enhanced Raman scattering (SERS) probe for precisely mapping the dynamic pH values in live cells. The PB shell has a subnanoscale porous structure that allows only very small biospecies such as H+ or OH- to pass freely through the shell and react with the encased pH-responsive SERS probe, while physically resisting the entry of large biomolecules. This probe achieved unmatched detection linearity (R2 > 0.999) for pH measurements in diverse complex biological samples. Moreover, the nitrile (C≡N) in PB shows a sharp band in the cellular Raman-silent region, which serves as a background-free internal standard for accurate profiling of the probe distribution inside the cells. We applied the proposed probe to monitor the dynamic pH changes during cellular autophagy induced by different stimuli and thereby demonstrated that the PB-caged probe can reliably quantify subtle intracellular pH variations, providing an effective tool for revealing the relationship between abnormal intracellular pH and cellular functions.

Fluorescent recognition and selective detection of nitrite ions with carbon quantum dots.

The nitrite ion (NO2-) is a vital inorganic species that occurs both in natural ecological systems and human bodies. The high concentration of NO2- can be harmful for animal and human health. It is important to develop a simple, sensitive, reliable, and economic methodology to precisely monitor NO2- in various environmental and biological fields. Thus, a novel nitrite biosensor based on carbon quantum dots (PA-CDs) has been constructed and prepared via a high-efficiency, one-pot hydrothermal route using primary arylamines (PA) such as m-phenylenediamine. The device exhibits bright green fluorescence and a high quantum yield of 20.1% in water. In addition, the PA-CDs also possess two broad linear ranges: 0.05-1.0 µM and 1.0-50 µM with a low detection limit of 7.1 nM. The classical diazo reaction is firstly integrated into the PA-CD system by primary arylamines, which endows the system with high sensitivity and specific selectivity towards nitrite. Importantly, the nanosensor can detect NO2- in environmental water and serum samples with high fluorescence recoveries, demonstrating its feasibility in practical applications. This work broadens a new method to fabricate novel nanosensors and provides a prospective application for fluorescent carbon quantum dots (CDs). Graphical abstract.

H19/miR-148a/USP4 axis facilitates liver fibrosis by enhancing TGF-ß signaling in both hepatic stellate cells and hepatocytes.

Liver fibrosis is a wound-healing response represented by excessive extracellular matrix deposition. Activation of hepatic stellate cell (HSC) is the critical cellular basis for hepatic fibrogenesis, whereas hepatocyte undergoes epithelial-mesenchymal transition (EMT) which is also involved in chronic liver injury. Long noncoding RNA H19 has been found to be associated with cholestatic liver fibrosis lately. However, the role of H19 in liver fibrosis remains largely to be elucidated. In this study, we found that the expression of H19 was significantly upregulated in the liver tissue of CCl4 -induced mice, a toxicant-induced liver fibrogenesis model. Overexpression of H19 significantly aggravated activation of HSC and EMT of hepatocyte both by stimulating transforming growth factor-ß (TGF-ß) pathway. In terms of mechanism, H19 functioned as a competing endogenous RNA to sponge miR-148a and subsequently sustained the level of ubiquitin-specific protease 4 (USP4), which was an identified target of miR-148a and was able to stabilize TGF-ß receptor I. In conclusion, our findings revealed a novel H19/miR-148a/USP4 axis which promoted liver fibrosis via TGF-ß pathway in both HSC and hepatocyte, indicating that H19 could become a promising target for the treatment of liver fibrosis.

Dysregulation of FTX/miR-545 signaling pathway downregulates Tim-3 and is responsible for the abnormal activation of macrophage in cirrhosis.

BACKGROUND: Accumulating evidence has suggested the involvement of miR-545 and long noncoding RNA (lncRNA) FTX in a wide range of diseases. Therefore, this study aimed to investigate the molecular mechanism underlying the function of miR-545 and lncRNA FTX in hepatitis B virus (HBV)-related cirrhosis. METHOD: The level of Tim-3, TLR-4, and endotoxin was detected in CD14+ , CD14 + CD16 + , and CD14 + CD16 - monocytes isolated from both patients with cirrhosis and healthy controls. ELISA assays were performed to detect the effect of Lipopolysaccharide (LPS) or FTX on the expression of tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), IL-1ß, and Nuclear factor kB (NF-kB). In-silico analysis, luciferase assay, real-time polymerase chain reaction (PCR), and Western blot analysis were utilized to determine the regulatory relationship between miR-545 and Tim-3. RESULTS: The levels of Tim-3, Tim-3 MIF and endotoxin were reduced in the CD14+ monocytes isolated from patients with cirrhosis. In addition, the level of Tim-3 was also decreased in the CD14 + CD16 - monocytes isolated from patients with cirrhosis, whereas the level of Tim-3 in CD14 + CD16 + monocytes showed no evident difference between healthy controls and patients with cirrhosis. Furthermore, TLR-4 was highly expressed in CD14 + CD16 + monocytes isolated from patients with cirrhosis, whereas Tim-3 was negatively regulated by endotoxin and the correlation coefficient was -0.5287. After the LPS stimulation, although the level of TNF-a, IL-6, IL-1ß, and NF-kB was higher in both patients with cirrhosis and healthy controls, the effect of LPS in patients with cirrhosis was much more significant. In addition, the cirrhosis group showed a lower level of FTX and Tim-3, but a higher level of miR-545. Moreover, miR-545 directly bound to the 3'untranslated region (3'UTR) of Tim-3 and inhibited the luciferase activity of cells cotransfected with miR-545 mimics and wild-type 3'UTR of Tim-3. Furthermore, FTX downregulated the expression of miR-545, TNF-a, IL-6, IL-1ß, and NF-kB, but upregulated the expression of Tim-3. CONCLUSION: The results of this study confirmed the effect of FTX, miR-545, and Tim-3 on the expression of inflammatory cytokines, the lymphocyte/monocyte ratio, and the severity and prognosis of HBV-related cirrhosis.

MicroRNA-212 activates hepatic stellate cells and promotes liver fibrosis via targeting SMAD7.

There has been an increasing number of researches about microRNAs (miRNAs) in the progression of liver fibrosis from the point of their comprehensive functions in regulating the activation of hepatic stellate cells (HSCs). Among them, it has been reported that miR-212 is up-regulated in activated rat primary HSCs. However, its mechanism has not been determined yet. Here, we confirmed that the level of miR-212-3p was up-regulated in livers of carbon tetrachloride (CCl4)-treated mice compared with the normal control, which is a classical model of chronically damaged fibrotic liver. In vitro, we demonstrated that TGF-ß, a master fibrogenic cytokine, could induce the level of miR-212. In turn, overexpression of miR-212 could induce the activation marker of HSC including α-smooth muscle actin (α-SMA) and collagens by activating TGF-ß signaling pathway. Furthermore, SMAD7, a dominant suppressor of TGF-ß pathway, was identified as a direct target of miR-212-3p. Our results indicate that miR-212-3p facilitates the activation of HSCs and TGF-ß pathway by targeting SMAD7, highlighting that it can be served as a novel biomarker or therapeutic target for liver fibrosis.

Intakes of magnesium, calcium and risk of fatty liver disease and prediabetes.

OBJECTIVE: Obesity and insulin resistance play important roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Mg intake is linked to a reduced risk of metabolic syndrome and insulin resistance; people with NAFLD or alcoholic liver disease are at high risk of Mg deficiency. The present study aimed to investigate whether Mg and Ca intakes were associated with risk of fatty liver disease and prediabetes by alcohol drinking status. DESIGN: We analysed the association between Ca or Mg intake and fatty liver disease, prediabetes or both prediabetes and fatty liver disease in cross-sectional analyses. SETTING: Third National Health and Nutrition Examination Survey (NHANES III) follow-up cohort of US adults. SUBJECTS: Nationally representative sample of US adults in NHANES (n 13 489). RESULTS: After adjusting for potential confounders, Mg intake was associated with approximately 30 % reduced odds of fatty liver disease and prediabetes, comparing the highest intake quartile v. the lowest. Mg intake may only be related to reduced odds of fatty liver disease and prediabetes in those whose Ca intake is less than 1200 mg/d. Mg intake may also only be associated with reduced odds of fatty liver disease among alcohol drinkers. CONCLUSIONS: The study suggests that high intake of Mg may be associated with reduced risks of fatty liver disease and prediabetes. Further large studies, particularly prospective cohort studies, are warranted to confirm the findings.

Positive feedback loop of YB-1 interacting with Smad2 promotes liver fibrosis.

Y-box binding protein (YB-1), known as a multifunctional cellular protein in various biological processes, was recently reported to be associated with liver fibrosis. The critical role of TGF-ß/Smad signaling pathway in stimulating the transcription of fibrotic genes in fibroblasts have already been identified, however, whether and how YB-1 modulated liver fibrosis via TGF-ß/Smad signaling pathway remains largely unknown. In our previous study, we proved that ectopic TGF-ß was associated with YB-1 expression. Herein, by combining in vitro experiments in LX2 human hepatic stellate cells and in vivo studies by building CCl4 based mice liver fibrosis model, we showed that YB-1 and p-YB-1 were upregulated in liver fibrosis tissue, and YB-1 promoted the deposition of excess extracellular matrix. Mechanistically, Smad2, a key member in TGF-ß signaling pathway, acted as a transcription factor that triggered YB-1 promoter, while on the other hand, p-YB-1 stabilized Smad2 by attenuating its ubiquitination. Knockdown of Smad2 could reduce YB-1 expression, which in turn shorter the half time of Smad2. Furthermore, the serine102 residue of YB-1 both affected its binding and stabilizing activity to Smad2. These finding demonstrated that YB-1 and Smad2 played as a positive feedback loop in promoting liver fibrosis. In conclusion, TGF-ß signaling pathway may influence liver fibrosis by incorporating with YB-1, indicating that YB-1 could be a potential target for therapies against liver fibrosis.

Association of microRNA-933 variant with the susceptibility to gastric cancer.

PURPOSE: Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRs) have been shown to be associated with susceptibility to several types of human cancer. However, the association of miR-933 rs79402775 with gastric cancer (GC) has not been explored. METHODS: The association between rs79402775 in miR- 933 and the risk of GC was explored in Chinese population based on MassARRAY technology. A total 374 GC patients and 999 cancer-free controls were enrolled in this study. RESULTS: Compared with the wild-type GG, GA genotype was associated with a significantly decreased risk of GC (OR=0.542, 95% CI=0.299-0.983, p=0.044) in female subjects. Moreover, the variant was also associated with the expression of alpha fetoprotein (AFP) and carcinoembryonic antigen (CEA). CONCLUSIONS: miR-933(rs79402775) may contribute to decreased susceptibility to GC and this SNP could be developed as a biomarker for GC prognosis.

[Association between microRNA single nucleotide polymorphisms and the risk of hepatocellular carcinoma]. / Asociación entre polimorfismos de un nucleótido en microRNA circulante y riesgo de carcinoma hepatocelular.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high morbidity and mortality. Single nucleotide polymorphisms (SNPs) of microRNA (miRNA) may be associated with the susceptibility to develop certain malignant tumors. AIM: To study the association between SNPs of miRNA and hepatocellular carcinoma in peripheral blood samples. MATERIAL AND METHODS: Three SNPs in miRNA were studied in peripheral blood samples of 498 patients with HCC and 520 controls. RESULTS: A significant association was observed between rs13299349 in miRNA3152 and HCC. AA genotype or A allele were significantly associated with increased risk of HCC. A allele was associated with the size and number of tumor foci. There was also a relationship between rs10061133 in miRNA449b and HCC. The G allele was significantly associated with increased risk of HCC compared with A allele. CONCLUSIONS: This study links rs13299349 in miRNA3152 and rs10061133 in miRNA449b with the risk of developing HCC.

Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo.

BACKGROUND: Silence of the tumor suppressor miR-34c is implicated in the development of colorectal cancer (CRC). For the past few years, Resveratrol (Res) has been introduced to oncotherapies alone or with traditional chemotherapeutic drugs. However, the study of molecular mechanism involved in the anti-CRC effect of Res is still ongoing. METHODS: The anti-CRC effect of Res alone or with Oxaliplatin (Oxa) was determined by cell viability assay, soft agar colony formation assay, flow cytometry and real-time cellular analyzer in HT-29 (p53+) and HCT-116 (p53-) CRC cell lines. Expressions of miR-34c and its targets were detected by qPCR and/or western blot. To evaluate the role of miR-34c in anti-CRC effect by Res alone or with Oxa, miR-34c was up or down-regulated by lentiviral mediation or specific inhibitor, respectively. To investigate how miR-34c was increased by Res, the methylation status of miR-34c promoter was detected by MSP. The tumor bearing mouse model was established by subcutaneous injection of HCT-116 cells to assess anti-CRC effect of Res alone or with Oxa in vivo. IL-6 and TNF-α in xenografts were detected by ELISA. RESULTS: Res inhibited cell viability, proliferation, migration and invasion as well as promoted apoptosis both in HT-29 and HCT-116 CRC cells. The anti-CRC effect of Res was partially but specifically through up-regulating miR-34c which further knocked down its target KITLG; and the effect was enhanced in the presence of p53 probably through inactivating PI3K/Akt pathway. Besides, Res sensitized CRC cells to Oxa in a miR-34c dependent manner. The xenograft experiments showed that exposure to Res or Oxa suppressed tumor growth; and the efficacy was evidently augmented by the co-treatment of Res and Oxa. Likewise, miR-34c level was elevated in xenografts of Res-treated mice while the KITLG was decreased. Finally, Res clearly reduced IL-6 in xenografts. CONCLUSION: Res suppressed CRC by specifically activating miR-34c-KITLG in vitro and in vivo; and the effect was strengthened in the presence of p53. Besides, Res exerted a synergistic effect with Oxa in a miR-34c dependent manner. We also suggested that Res-increased miR-34c could interfere IL-6-triggered CRC progression.