S-nitrosylation of EMMPRIN influences the migration of HSCs and MMP activity in liver fibrosis.

The mechanism of extracellular matrix metalloproteinase inducer (EMMPRIN) in the regulation of liver fibrosis has not been clarified. This study aims to investigate the role of EMMPRIN S-nitrosylation (SNO) in the regulation of hepatic stellate cell (HSC) migration and matrix metalloproteinase (MMP) activities in liver fibrosis. The results from the tissue microarrays and rat/mouse liver tissues suggest that EMMPRIN mRNA and protein levels in the fibrotic livers are lower than those in the corresponding normal control livers, but higher SNO level of EMMPRIN in fibrotic liver area was shown by immunohistochemistry, immunofluorescence staining, and biotin-switch assay conversely in vivo. Primary EMMPRIN comes from hepatocytes and liver sinus epithelial cells (LSECs) rather than quiescent HSCs. To mimic the uptake of extrinsic EMMPRIN, supernatants from mouse primary hepatocytes/293 cells transfected with EMMPRIN wild-type plasmids (WT) and EMMPRIN SNO site (cysteine 87) mutation plasmids (MUT) were collected and added to JS-1/LX2 cell medium. The MUT EMMPRIN diminishes SNO successfully, enhances the activities of MMP2 and MMP9, and subsequently increases HSC migration. In conclusion, SNO of EMMPRIN influences HSC migration and MMP activities in liver fibrosis. This finding may shed light on the possible regulatory mechanism of MMPs in ECM accumulation in liver fibrosis.

Trimethylamine-N-oxide is an independent risk factor for hospitalization events in patients receiving maintenance hemodialysis.

Background: Hospitalization is a significant outcome measurement for maintenance hemodialysis pantients. Trimethylamine-N-oxide (TMAO), created by gut microflora from dietary l-carnitine and choline, cleared by the kidney, has been implicated in the causation of cardiovascular diseases in patients with chronic kidney disease. However, whether it associates with hospitalization risk for these patients is unclear.Methods: In this study, 69 patients undergoing outpatient dialysis were enrolled. Enzyme-linked immunosorbent assay was used to quantitate the baseline plasma TMAO levels in patients. The patients were divided into a high TMAO level group (TMAO ≥ 15 µmol/L) and a low TMAO level group (TMAO < 15 µmol/L). During the 1-year follow-up, 1-year dialysis-related data and all-cause hospitalization events were recorded.Results: The incidence of hospitalization events was significantly higher in the high TMAO level group than in the low TMAO level group (91 per 100 patient-year vs. 32 per 100 patient-year). The Kaplain-Meier survaial analysis showed that the incidence of hospitalization events in the high TMAO level group was significantly higher than that in the low TMAO level group (log-rank p = 0.0004). After adjustment age, sex, CK-MB and albumin, the results of multivariate Cox proportional hazard analysis showed that high TMAO level was an independent risk factor for hospitalization in maintenance hemodialysis patients.Conclusion: TMAO is an independent risk factor for hospitalization events in patients receiving maintenance hemodialysis. It may be a new therapeutic target for improving the outcomes of these patients.

Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury.

Pulmonary infection is the most common risk factor for acute lung injury (ALI). Innate immune responses induced by Microbe-Associated Molecular Pattern (MAMP) molecules are essential for lung defense but can lead to tissue injury. Little is known about how MAMP molecules are degraded in the lung or how MAMP degradation/inactivation helps prevent or ameliorate the harmful inflammation that produces ALI. Acyloxyacyl hydrolase (AOAH) is a host lipase that inactivates Gram-negative bacterial endotoxin (lipopolysaccharide, or LPS). We report here that alveolar macrophages increase AOAH expression upon exposure to LPS and that Aoah+/+ mice recover more rapidly than do Aoah-/- mice from ALI induced by nasally instilled LPS or Klebsiella pneumoniae. Aoah-/- mouse lungs had more prolonged leukocyte infiltration, greater pro- and anti-inflammatory cytokine expression, and longer-lasting alveolar barrier damage. We also describe evidence that the persistently bioactive LPS in Aoah-/- alveoli can stimulate alveolar macrophages directly and epithelial cells indirectly to produce chemoattractants that recruit neutrophils to the lung and may prevent their clearance. Distinct from the prolonged tolerance observed in LPS-exposed Aoah-/- peritoneal macrophages, alveolar macrophages that lacked AOAH maintained or increased their responses to bioactive LPS and sustained inflammation. Inactivation of LPS by AOAH is a previously unappreciated mechanism for promoting resolution of pulmonary inflammation/injury induced by Gram-negative bacterial infection.

Analysis of a Screening System for Diabetic Cardiovascular Autonomic Neuropathy in China.

BACKGROUND The aim of this study was to create a screening system for diabetic cardiovascular autonomic neuropathy (DCAN) in diabetic patients. MATERIAL AND METHODS A Chinese cohort of 455 diabetic participants was recruited between 2011 and 2013. Short-term heart rate variability testing was used to evaluate cardiovascular autonomic function. A simple model was developed using multiple variable regression to include only significant risk factors that were simple and easily assessed. A DCAN score was determined based on the coefficients of the multiple variable model. This score was tested on the entire cohort of 455 diabetic patients and another independent, external cohort of 115 diabetic patients. RESULTS The screening system consisted of age, body mass index, duration of diabetes mellitus, and resting heart rate, and these factors were significantly (P<0.05) associated with DCAN. Receiver operating characteristic (ROC) curve analysis was done. The areas under the ROC curve were 0.798, 0.756, and 0.729 for the total sample, validation cohort, and external set, respectively. A cutoff DCAN score of 12 out of 25 produced optimal results for sensitivity (80.36%), specificity (58.27%), and percentage of patients that needed subsequent testing (43.55%) for the validation set. CONCLUSIONS The study concludes that a simple and practical DCAN screening can be applied for early intervention to delay or prevent the disease in the Chinese population.

Association and interaction analysis of diabetes mellitus and SCN10A for cardiovascular autonomic neuropathy in a Chinese population.

BACKGROUND: This study assessed the extent to which diabetes mellitus (DM) and SCN10A (rs7375036) and their interaction impact on cardiovascular autonomic neuropathy (CAN) susceptibility in a Chinese Han sample. METHOD: We performed a study in a cross-sectional dataset that included 419 patients with DM and 1557 controls who were genotyped for the presence of the SCN10A rs7375036 polymorphisms. Genotyping was performed by iPLEX technology. The associations of rs7375036 and DM with CAN was assessed by using univariate and multivariate logistic regression controlling for confounders. The interaction between rs7375036 and DM for CAN susceptibility on an additive scale was calculated by using the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S). RESULTS: The univariate logistic analyses failed to show an association between the SCN10A rs7375036 polymorphisms and CAN. Interestingly, a novel interaction effect of SCN10A rs7375036 and DM on CAN was assessed (p=0.055; RERI=3.515, 95% CI 1.829 to 5.805; AP=0.632, 95% CI -0.368 to 1.632; S=4.361, 95% CI 2.071 to 9.184). CONCLUSIONS: Our findings suggest that there are interaction effects of DM and SCN10A (rs7375036) that influence the development of CAN. TRIAL REGISTRATION NUMBER: NCT02461342.

A community-based cross-sectional study for relationship of frequency of vegetables intake and osteoporosis in a Chinese postmenopausal women sample.

BACKGROUND: The main purpose of this study was to explore the associations between frequency of vegetables intake and osteoporosis (OP) in Chinese postmenopausal women. METHODS: We conducted a large-scale, community-based, cross-sectional study to investigate the associations by using self-report questionnaire to access frequency of vegetables intake. The total of 1903 participants was available to data analysis in this study. Multiple regression models to include frequency of vegetables variable were performed to investigate the relationships for OP, after controlling for confounding factors. RESULTS: Multiple regression analysis indicated that the frequency of vegetables intake was independently and significantly associated with OP (P < 0.1 for model 1 and model 2). The postmenopausal women with high frequency of vegetables intake had a higher prevalence of OP. CONCLUSION: The findings indicated that frequency of vegetables intake was independently and significantly associated with OP. The prevalence of OP was more frequent in Chinese postmenopausal women preferring vegetables food habits. TRIAL REGISTRATION: (ClinicalTrials.gov Identifier: NCT02451397 ; date of registration: 2015-05-28).

An association analysis of lipid profile and diabetic cardiovascular autonomic neuropathy in a Chinese sample.

BACKGROUND: Recent studies have shown that triglyceride (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) are related to the prevalence of cardiovascular autonomic neuropathy (CAN). However, little is known about the association of lipid profile with diabetic cardiovascular autonomic neuropathy (DCAN), or its severity in the Chinese population. The purpose of this study is to explore the extent of this phenomenon using a Chinese sample. METHODS: A subgroup analysis on 455 diabetic patients with undiagnosed DCAN was performed to evaluate the relationships of lipids profile and DCAN. DCAN was diagnosed if there were at least two abnormal cardiovascular autonomic reflex test results, based on short-term heart rate variability tests. Multivariable logistic regression (MLR)was carried out to control potential confounders for determining the independent association of variables with DCAN in different models. RESULTS: MLR analysis indicated that TG was significantly and independently associated with DCAN when controlling for confounding factors (P < 0.1 for two models). Additionally, TG combined with TC (LRS-1) and LDL (LRS-2) was associated with this outcome (P < 0.1 for LRS-1 and LRS-2). CONCLUSION: Our findings indicate that TG and the severity of lipids profile is significantly and independently associated with DCAN, respectively. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02461472 , retrospectively registered 2 Jun, 2015.

Analysis of the Synergistic Effects of Fasting Plasma Glucose and Hypertension on Cardiovascular Autonomic Neuropathy.

BACKGROUND: The purpose of this study was to evaluate the associations of fasting plasma glucose (FPG) and hypertension (HTN) with cardiovascular autonomic neuropathy (CAN) and to estimate the extent to which the synergistic effects of FPG and HTN affect outcomes in a Chinese population. METHOD: We conducted a large-scale, population-based study to analyze the association and interaction of the two factors with CAN in a sample of 2,092 Chinese people. Univariate and multiple linear regression (MLR) analyses were employed to detect these relationships. Interaction on an additive scale can be calculated by using the relative excess risk due to interaction, the proportion attributable to interaction (AP), and the synergy index (S). RESULT: After adjusting for confounding factors, MLR showed that FPG and HTN were independently associated with CAN (p < 0.001 for both). A significant synergistic effect of FPG and HTN on CAN was detected (p = 0.046, RETI = 0.733, 95% CI 0.059-1.450; AP = 0.167, 95% CI -0.033 to 0.367; S = 1.275, 95% CI 0.140-2.410). CONCLUSION: Our findings suggest that FPG and HTN are independently associated with CAN, and they offer evidence to support the hypothesis that FPG and HTN have synergistic effects that influence the progression of CAN.

A cross-sectional study for estimation of associations between education level and osteoporosis in a Chinese men sample.

BACKGROUND: The main aim of this study was to evaluate the association between education level and osteoporosis (OP) in general Chinese Men. METHODS: We conducted a large-scale, community-based, cross-sectional study to investigate the association by using self-report questionnaire to assess education levels. The data of 1092 men were available for analysis in this study. Multiple regression models controlling for confounding factors to include education level were performed to explore the relationship between education level and OP. RESULTS: Positive correlations between education level and T-score of quantitative bone ultrasound (QUS-T score) were reported (ß = 0.108, P value < 0.001). Multiple regression analysis indicated that the education level was independently and significantly associated with OP (P < 0.1 for all models). The men with lower education level had a higher prevalence of OP. CONCLUSION: The education level was independently and significantly associated with OP. The prevalence of OP was more frequent in Chinese men with lower education level. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02451397 ; date of registration: 05/28/2015).

Human genetics of diabetic nephropathy.

Diabetic vascular complications (DVCs) affecting several important organ systems of human body such as cardiovascular system contribute a major public health problem. Genetic factors contribute to the risk of diabetic nephropathy (DN). Genetics variants, structural variants (copy number variation) and epigenetic changes play important roles in the development of DN. Apart from nucleus genome, mitochondrial DNA (mtDNA) plays critical roles in regulation of development of DN. Epigenetic studies have indicated epigenetic changes in chromatin affecting gene transcription in response to environmental stimuli, which provided a large body of evidence of regulating development of diabetes mellitus. This review focused on the current knowledge of the genetic and epigenetic basis of DN. Ultimately, identification of genes or genetic loci, structural variants and epigenetic changes contributed to risk or protection of DN will benefit uncovering the complex mechanism underlying DN, with crucial implications for the development of personalized medicine to diabetes mellitus and its complications.

Association and interaction analysis of excess weight and chronic kidney disease for cardiovascular autonomic neuropathy in the general Chinese population.

BACKGROUND: The purpose of this study was to evaluate the associations of excess weight (EW) and/or chronic kidney disease (CKD) with cardiovascular autonomic neuropathy (CAN), and to detect the extent to which interaction of EW and CKD has on the outcome in a Chinese sample. METHOD: We conducted a large-scale, population-based study to analyze the association and interaction of the two factors on CAN in a sample of 2092 Chinese people. Multiple linear regression analysis to include the two main factors and its interaction were employed to detect these relationships. Relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP) and the synergy index (S) were used to estimate the effect of interaction on an additive scale can. RESULT: Multivariable logistic regression (MLR) indicated that body mass index (BMI) was independently associated with CAN (p = 0.006). In addition, a significant positive interaction between BMI and CKD on CAN was estimated (p = 0.042, RETI = 0.473, 95% CI: 0.0615-0.884, AP = 0.203, 95% CI: -0.055 to 0.461 and S = 1.550, 95% CI: 0.667-2.589). CONCLUSION: Our findings suggest that BMI is independently associated with CAN and offer evidence to support the hypothesis that excess weight and CKD have significant positive interactions on CAN.

Method for refractive index measurement of nanoparticles.

A new method of measuring the refractive indices of nanoparticles has been proposed based on refractive index matching between nanoparticles and surrounding organic solvents. By finding the most transparent point of the transmittance spectrum, the refractive index of the nanoparticles is equal to that of the solvents at the corresponding wavelength. Utilizing a Rayleigh scattering model, the effects of refractive index mismatching (Δn) on the transmittance are investigated under different conditions. Some criteria for getting highly transparent nanoparticle dispersion and accurate refractive index measurements are suggested, which can support practical applications for nanomaterials in optical and optoelectronic applications.

Association and predictive value analysis for metabolic syndrome on systolic and diastolic heart failure in high-risk patients.

BACKGROUND: The purpose of this study was, in high-risk patients, to simultaneously estimate the effect of metabolic syndrome (MetS) on diastolic or systolic heart failure (DHF or SHF), to evaluate MetS predictive value for both outcomes. METHOD: We retrospective enrolled 347 high-risk patients who were scheduled to undergo coronary angiography. They were categorized into DHF cases, SHF cases and reference group. The association of MetS with DHF or SHF was assessed by multinomial logistic regression model. The shared contributor to both outcomes was estimated by bivariate association analysis. The predictive performance of MetS severity score was evaluated using the area under the receiver-operating characteristic curve (AUC). RESULT: Hypertension (HT) and triglycerides (TG) were detected to independently associate with DHF (P = 0.044 and 0.049, respectively), while HT and fasting plasma glucose (FPG) independently associate with SHF (P = 0.036 and 0.016, respectively). Bivariate association analysis showed that HT as a shared predictor to both outcomes (P = 0.028). MetS severity score significantly associated with DHF or SHF independently (P = 0.004 and 0.043, respectively), and was a shared predictor to both outcomes (P = 0.049), and showed a high value in predicting DHF and SHF (AUC = 0.701 and 0.722, respectively). CONCLUSION: Our findings signify that MetS is an independently shared predictor of DHF and SHF, and HT is also independently associated with both outcomes in high-risk patients. Prevalence of DHF or SHF trends to increase with increasing MetS severity showing high predictive value for both outcomes.

A Bionic Localization Memristive Circuit Based on Spatial Cognitive Mechanisms of Hippocampus and Entorhinal Cortex.

In this article, a bionic localization memristive circuit is proposed, which mainly consists of head direction cell module, grid cell module, place cell module and decoding module. This work modifies the two-dimensional Continuous Attractor Network (CAN) model of grid cells into two one-dimensional models in X and Y directions. The head direction cell module utilizes memristors to integrate angular velocity and represents the real orientation of an agent. The grid cell module uses memristors to sense linear velocity and orientation signals, which are both self-motion cues, and encodes the position in space by firing in a periodic mode. The place cell module receives the grid cell module's output and fires in a specific position. The decoding module decodes the angle or place information and transfers the neuron state to a 'one-hot' code. This proposed circuit completes the localizing task in space and realizes in-memory computing due to the use of memristors, which can shorten the execution time. The functions mentioned above are implemented in LTSPICE. The simulation results show that the proposed circuit can realize path integration and localization. Moreover, it is shown that the proposed circuit has good robustness and low area overhead. This work provides a possible application idea in a prospective robot platform to help the robot localize and build maps.

Clinical Study of a Four-Step Program for the Treatment of Plantar Fasciitis with Bone Spurs.

OBJECTIVE: The most common causes of plantar and heel pain are plantar fasciitis and calcaneal spurs, and they often co-exist. Surgery is a recognized treatment for refractory plantar fasciitis. However, few studies have proposed treatment options for patients with metatarsophalangeal fasciitis with bone spurs. Accordingly, this study's purpose was to propose a four-step surgical regimen, and to improve the surgical outcome of plantar fasciitis with osteophytes and to establish a procedure for surgical treatment. METHODS: Retrospective analysis of 45 patients suffering from plantar fasciitis with bone spurs from 2020 to 2023. All patients underwent a four-step procedure, including plantar fascia release, calcaneal spur grinding, inflammatory tissue removal, and calcaneal burr decompression. The imaging parameters and functional scores were recorded before and after the operation. The objective evaluation included the measurement of calcaneal spur length on radiographs. Clinical evaluation included the American Orthopaedic Foot and Ankle Society (AOFAS), the Visual Analog Scale (VAS), and the Foot and Ankle Outcome Scale (FAOS). Measurement data that conformed to normal distribution were expressed as (x2 ± s), and pre-and postoperative AOFAS, FAOS, and VAS scores were compared using repeated-measures ANOVA, and preoperative and postoperative spur lengths were compared using paired t-tests. RESULTS: The 45 patients were followed up for 3 to 30 months, (17.72 ± 8.53) months, at final follow-up, the patient's AOFAS score improved from preoperative (74.93 ± 5.56) to (94.78 ± 3.98), FAOS score increased from preoperative (76.42 ± 3.37) to (96.16 ± 2.74), the VAS score decreased from (3.18 ± 0.54) to (1.07 ± 1.20) (p < 0.05), the length of spur decreased from (0.72 ± 1.81) cm to (0.23 ± 1.19) cm, and there were significant differences before and after operation (p < 0.05). CONCLUSION: The four-step surgical regimen is an appropriate and effective surgical procedure to treat plantar fasciitis with bone spurs.

Artificial neural network models for prediction of cardiovascular autonomic dysfunction in general Chinese population.

BACKGROUND: The present study aimed to develop an artificial neural network (ANN) based prediction model for cardiovascular autonomic (CA) dysfunction in the general population. METHODS: We analyzed a previous dataset based on a population sample consisted of 2,092 individuals aged 30-80 years. The prediction models were derived from an exploratory set using ANN analysis. Performances of these prediction models were evaluated in the validation set. RESULTS: Univariate analysis indicated that 14 risk factors showed statistically significant association with CA dysfunction (P < 0.05). The mean area under the receiver-operating curve was 0.762 (95% CI 0.732-0.793) for prediction model developed using ANN analysis. The mean sensitivity, specificity, positive and negative predictive values were similar in the prediction models was 0.751, 0.665, 0.330 and 0.924, respectively. All HL statistics were less than 15.0. CONCLUSION: ANN is an effective tool for developing prediction models with high value for predicting CA dysfunction among the general population.

Y-box binding protein 1 promotes chromatin accessibility to aggravate liver fibrosis.

Y-box binding protein 1 (YBX1) has been reported to be involved in the transcriptional regulation of various pathophysiological processes, such as inflammation, oxidative stress, and epithelial-mesenchymal transformation. However, its precise role and mechanism in regulating hepatic fibrosis remain unclear. In this study, we aimed to investigate the effects of YBX1 on liver fibrosis and its potential mechanism. The expression of YBX1 in human liver microarray, mice tissues and primary mouse hepatic stellate cells (HSCs) was validated to be upregulated in several hepatic fibrosis models (CCl4 injection, TAA injection, and BDL). Hepatic-specific Ybx1 overexpression exacerbated the liver fibrosis phenotypes in vivo and in vitro. Moreover, the knockdown of YBX1 significantly improved TGF-ß-induced fibrosis in the LX2 cell (a hepatic stellate cell line). Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq) of hepatic-specific Ybx1 overexpression (Ybx1-OE) mice with CCl4 injection showed increasing chromatin accessibility than CCl4 only group. Functional enrichments of open regions in the Ybx1-OE group indicated that extracellular matrix (ECM) accumulation, lipid purine metabolism, and oxytocin-related pathways were more accessible in the Ybx1-OE group. Accessible regions of the Ybx1-OE group in the promoter also suggested significant activation of genes related to liver fibrogenesis, such as response to oxidative stress and ROS, lipid localization, angiogenesis and vascular development, and inflammatory regulation. Moreover, we screened and validated the expression of candidate genes (Fyn, Axl, Acsl1, Plin2, Angptl3, Pdgfb, Ccl24, and Arg2), which might be potential targets of Ybx1 in the pathogenesis of liver fibrosis.

Risk prediction model based on blood biomarkers for predicting moderate to severe endoscopic activity in patients with ulcerative colitis.

Object: We explored developing an internal validation model to predict the moderate to severe endoscopic activity of ulcerative colitis (UC) patients based on non-invasive or minimally-invasive parameters. Methods: Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and Mayo endoscopic subscore were performed for UC patients who met the criteria from January 2017 to August 2021 through the electronic database of our center. Logistic regression and a least absolute shrinkage and selection operator (Lasso) regression model were performed to screen the risk factors of moderate to severe UC activity. The nomogram was established subsequently. Discrimination of the model was evaluated using the concordance index (c-index), and the calibration plot and 1,000 Bootstrap were used to evaluate the model's performance and conduct internal validation. Results: Sixty-five UC patients were included in this study. According to UCEIS criteria,45 patients were moderate to severe endoscopic activity. 26 potential predictors of UC were analyzed by logistic and Lasso regression showed that vitamin D (Vit D), albumin (ALB), prealbumin (PAB), and fibrinogen (Fbg) were the best predictors of moderate to severe endoscopic activity of UC. We used these 4 variables to develop a dynamic nomogram prediction model. The c-index was 0.860, which means good discrimination. The calibration plot and Bootstrap analysis showed that the prediction model accurately distinguished the moderate to severe endoscopic activity in UC patients. The prediction model was verified using a cohort of UC patients with moderate to severe activity defined by the Mayo endoscopic subscore, and it was found that the model still had good discrimination and calibration (c-index = 0.891). Conclusion: The model containing Vit D, ALB, PAB, and Fbg was a good tool for evaluating UC activity. The model is simple, accessible, and user-friendly, which has broad application prospects in clinical practice.

Mesoporous polydopamine based biominetic nanodrug ameliorates liver fibrosis via antioxidation and TGF-ß/SMADS pathway.

Early intervention of liver fibrosis can prevent its further irreversible progression. Both excess reactive oxygen species (ROS) and transforming growth factor beta(TGF-ß)/drosophila mothers against decapentaplegic protein (SMADS) pathway balance disorder promote the progression of hepatic stellate cell (HSC) activation, but existing therapeutic strategies failed to focus on those two problems. A new biomimetic mesoporous polydopamine nandrug (MPO) was constructed for liver fibrosis therapy with multiple targets and reliable biosafety. The MPO was formed by mesoporous polydopamine (mPDA) which has the effect of ROS elimination and encapsulated with anti-fibrotic drug -oxymatrine (OMT) which can intervene liver fibrosis targeting TGF-ß/SMADSpathway. Particularly, the nanodrug was completed by macrophage-derived exosome covering. The MPO was confirmed to possess a desired size distribution with negative zeta potential and exhibite strong ROS scavenger ability. Besides, in vitro studies, MPO showed efficient endocytosis and superior intracellular ROS scavenging without cytotoxicity; in vivo studies, MPO effectively cleared the excessive ROS in liver tissue and balanced the TGF-ß/SMADS pathways, which in turn inhibited HSC activation and showed superior anti-liver fibrosis therapeutic efficiency with good biological safety. Taken together, this work showed highlights the great potential of the MPO for ameliorating liver fibrosis via ROS elimination and TGF-ß/SMADS balancing.

Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups.

To identify and validate genes associated with bone mineral density (BMD), which is a prominent osteoporosis risk factor, we tested 379,319 SNPs in 1000 unrelated white U.S. subjects for associations with BMD. For replication, we genotyped the most significant SNPs in 593 white U.S. families (1972 subjects), a Chinese hip fracture (HF) sample (350 cases, 350 controls), a Chinese BMD sample (2955 subjects), and a Tobago cohort of African ancestry (908 males). Publicly available Framingham genome-wide association study (GWAS) data (2953 whites) were also used for in silico replication. The GWAS detected two BMD candidate genes, ADAMTS18 (ADAM metallopeptidase with thrombospondin type 1 motif, 18) and TGFBR3 (transforming growth factor, beta receptor III). Replication studies verified the significant findings by GWAS. We also detected significant associations with hip fracture for ADAMTS18 SNPs in the Chinese HF sample. Meta-analyses supported the significant associations of ADAMTS18 and TGFBR3 with BMD (p values: 2.56 x 10(-5) to 2.13 x 10(-8); total sample size: n = 5925 to 9828). Electrophoretic mobility shift assay suggested that the minor allele of one significant ADAMTS18 SNP might promote binding of the TEL2 factor, which may repress ADAMTS18 expression. The data from NCBI GEO expression profiles also showed that ADAMTS18 and TGFBR3 genes were differentially expressed in subjects with normal skeletal fracture versus subjects with nonunion skeletal fracture. Overall, the evidence supports that ADAMTS18 and TGFBR3 might underlie BMD determination in the major human ethnic groups.