Bone-derived sclerostin and Wnt/ß-catenin signaling regulate PDGFRα+ adipoprogenitor cell differentiation.

The Wnt signaling antagonist, sclerostin, is a potent suppressor of bone acquisition that also mediates endocrine communication between bone and adipose. As a result, Sost-/- mice exhibit dramatic increases in bone formation but marked decreases in visceral and subcutaneous adipose that are secondary to alterations in lipid synthesis and utilization. While interrogating the mechanism by which sclerostin influences adipocyte metabolism, we observed paradoxical increases in the adipogenic potential and numbers of CD45- :Sca1+ :PDGFRα+ adipoprogenitors in the stromal vascular compartment of fat pads isolated from male Sost-/- mice. Lineage tracing studies indicated that sclerostin deficiency blocks the differentiation of PDGFRα+ adipoprogenitors to mature adipocytes in association with increased Wnt/ß-catenin signaling. Importantly, osteoblast/osteocyte-specific Sost gene deletion mirrors the accumulation of PDGFRα+ adipoprogenitors, reduction in fat mass, and improved glucose metabolism evident in Sost-/- mice. These data indicate that bone-derived sclerostin regulates multiple facets of adipocyte physiology ranging from progenitor cell commitment to anabolic metabolism.

Lrp4 expression by adipocytes and osteoblasts differentially impacts sclerostin's endocrine effects on body composition and glucose metabolism.

Sclerostin exerts profound local control over bone acquisition and also mediates endocrine communication between fat and bone. In bone, sclerostin's anti-osteoanabolic activity is enhanced by low-density lipoprotein receptor-related protein 4 (Lrp4), which facilitates its interaction with the Lrp5 and Lrp6 Wnt co-receptors. To determine whether Lrp4 similarly affects sclerostin's endocrine function, we examined body composition as well as glucose and fatty acid metabolism in mice rendered deficient of Lrp4 in the adipocyte (AdΔLrp4) or the osteoblast (ObΔLrp4). AdΔLrp4 mice exhibit a reduction in adipocyte hypertrophy and improved glucose and lipid homeostasis, marked by increased glucose and insulin tolerance and reduced serum fatty acids, and mirror the effect of sclerostin deficiency on whole-body metabolism. Indeed, epistasis studies place adipocyte-expressed Lrp4 and sclerostin in the same genetic cascade that regulates adipocyte function. Intriguingly, ObΔLrp4 mice, which exhibit dramatic increases in serum sclerostin, accumulate body fat and develop impairments in glucose tolerance and insulin sensitivity despite development of a high bone mass phenotype. These data indicate that expression of Lrp4 by both the adipocyte and osteoblast is required for normal sclerostin endocrine function and that the impact of sclerostin deficiency on adipocyte physiology is distinct from the effect on osteoblast function.

Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes.

Sclerostin has traditionally been thought of as a local inhibitor of bone acquisition that antagonizes the profound osteoanabolic capacity of activated Wnt/ß-catenin signaling, but serum sclerostin levels in humans exhibit a correlation with impairments in several metabolic parameters. These data, together with the increased production of sclerostin in mouse models of type 2 diabetes, suggest an endocrine function. To determine whether sclerostin contributes to the coordination of whole-body metabolism, we examined body composition, glucose homeostasis, and fatty acid metabolism in Sost-/- mice as well as mice that overproduce sclerostin as a result of adeno-associated virus expression from the liver. Here, we show that in addition to dramatic increases in bone volume, Sost-/- mice exhibit a reduction in adipose tissue accumulation in association with increased insulin sensitivity. Sclerostin overproduction results in the opposite metabolic phenotype due to adipocyte hypertrophy. Additionally, Sost-/- mice and those administered a sclerostin-neutralizing antibody are resistant to obesogenic diet-induced disturbances in metabolism. This effect appears to be the result of sclerostin's effects on Wnt signaling and metabolism in white adipose tissue. Since adipocytes do not produce sclerostin, these findings suggest an unexplored endocrine function for sclerostin that facilitates communication between the skeleton and adipose tissue.

[2-Bromoethylamine protects vascular endothelium by inhibiting SSAO activity in diabetic rats].

The purpose of this study was to investigate the change of aortic semicarbazide-sensitive amine oxidase (SSAO) activity in diabetic rats and examine the effect of 2-bromoethylamine (2-BEA) on SSAO activity and vascular endothelium in diabetic rats. SSAO was prepared from rat aorta. For assessment of the inhibitory effect, the enzymes were preincubated in the presence of different concentrations of 2-BEA before the addition of benzylamine in vitro. Type 1 diabetic rat model was induced by a single intraperitoneal injection of streptozotocin (STZ). Sprague Dawley (SD) rats were randomly divided into normal control group (NC), diabetic model group (DM), 2-BEA 5 mg/kg group, 2-BEA 20 mg/kg group (n = 10 in each group). 2-BEA was administered daily via intraperitoneal injection for 8 weeks. At the end of 8 weeks, blood sample was collected from the abdominal aorta. Plasma nitric oxide (NO) was determined by nitrate reductase method. Plasma endothelin-1 (ET-1) was determined by radioimmunoassay. Aorta SSAO was determined by high performance liquid chromatography. The aorta was prepared to observe morphological changes and ultramicroscopic structures. The results were as follows: Compared with NC group, aortic SSAO activity and the plasma ET-1 were significantly increased (P < 0.01), and plasma NO was significantly decreased (P < 0.01) in DM group. 2-BEA decreased plasma ET-1 and elevated plasma NO by inhibiting aortic SSAO activity in diabetic rats (P < 0.01), and 2-BEA 20 mg/kg group was more significant than 2-BEA 5 mg/kg group (P < 0.05). Endothelial injury of 2-BEA group rats was less serious than DM group. These results suggest that 2-BEA protect aortic endothelium by inhibiting aortic SSAO activity.

Serum cystatin C, monocyte/high-density lipoprotein-C ratio, and uric acid for the diagnosis of coronary heart disease and heart failure.

BACKGROUND: Coronary heart disease (CHD) and heart failure (HF) are the major causes of morbidity and mortality worldwide. Early and accurate diagnoses of CHD and HF are essential for optimal management and prognosis. However, conventional diagnostic methods such as electrocardiography, echocardiography, and cardiac biomarkers have certain limitations, such as low sensitivity, specificity, availability, and cost-effectiveness. Therefore, there is a need for simple, noninvasive, and reliable biomarkers to diagnose CHD and HF. AIM: To investigate serum cystatin C (Cys-C), monocyte/high-density lipoprotein cholesterol ratio (MHR), and uric acid (UA) diagnostic values for CHD and HF. METHODS: We enrolled 80 patients with suspected CHD or HF who were admitted to our hospital between July 2022 and July 2023. The patients were divided into CHD (n = 20), HF (n = 20), CHD + HF (n = 20), and control groups (n = 20). The serum levels of Cys-C, MHR, and UA were measured using immunonephelometry and an enzymatic method, respectively, and the diagnostic values for CHD and HF were evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Serum levels of Cys-C, MHR, and UA were significantly higher in the CHD, HF, and CHD + HF groups than those in the control group. The serum levels of Cys-C, MHR, and UA were significantly higher in the CHD + HF group than those in the CHD or HF group. The ROC curve analysis showed that serum Cys-C, MHR, and UA had good diagnostic performance for CHD and HF, with areas under the curve ranging from 0.78 to 0.93. The optimal cutoff values of serum Cys-C, MHR, and UA for diagnosing CHD, HF, and CHD+HF were 1.2 mg/L, 0.9 × 109, and 389 µmol/L; 1.4 mg/L, 1.0 × 109, and 449 µmol/L; and 1.6 mg/L, 1.1 × 109, and 508 µmol/L, respectively. CONCLUSION: Serum Cys-C, MHR, and UA are useful biomarkers for diagnosing CHD and HF, and CHD+HF. These can provide information for decision-making and risk stratification in patients with CHD and HF.

[Association between high-sensitivity C-reactive protein and contrast-induced nephropathy after primary percutaneous coronary intervention].

OBJECTIVE: To explore the association between high-sensitivity C-reactive protein (hs-CRP) and contrast-induced nephropathy (CIN) in patients with ST-segment elevated myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) . METHODS: A total of 220 STEMI patients undergoing primary PCI from Guangdong general hospital were recruited. Patients were divided into four groups according to the quartile of hs-CRP (Q1 group:hs-CRP < 6.26 mg/L,Q2 group:6.26-14.44 mg/L, Q3 group:14.45-33.08 mg/L, Q4 group:hs-CRP > 33.08 mg/L) . Baseline data, CIN incidence and other in-hospital outcomes were compared among groups. CIN was defined as an increase in serum creatinine of more than 5 mg/L from baseline within 48-72 hours after contrast media exposure. Receiver operator characteristics (ROC) curves and multivariate logistic regression were used to assessed the correlation between hs-CRP and CIN. RESULTS: CIN occurred in 21 (9.8%) patients. CIN incidence of hs-CRP quartitles were 1.8%(1/55), 1.8% (1/55), 14.5% (8/55) and 20.0% (11/55) (P-trend < 0.01), respectively. In-hospital death (P-trend > 0.05) , required renal replace therapy (P-trend > 0.05) were similar among groups. ROC analysis revealed that the optimal cutoff value of hs-CRP to predict the onset of CIN was 16.85 mg/L (sensitivity: 81.0%, specificity: 61.8%, AUC: 0.748). Univariate logistic analysis showed that hs-CRP was strongly related with CIN incidence (OR = 6.88,95%CI:2.23-21.21, P < 0.01). Multivariate logistic regression analysis showed that after adjusting other traditional risk factors including female gender, anemia, ACEI/ARB use, IABP support, LVEF < 40%, age > 75 years, baseline eGFR and diabetes, hs-CRP > 16.85 mg/L was still a significant independent predictor of CIN in patients with STEMI undergoing primary PCI. Additionally, age > 75 years (OR = 7.27,95%CI:1.85-28.63, P < 0.01), eGFR (OR = 6.38,95% CI:1.48-27.41, P < 0.05) were also independent risk factors of CIN. CONCLUSIONS: hs-CRP is positively correlated with CIN incidence. STEMI patients with higher hs-CRP level post PCI is at higher risk of developing CIN.

[Increased platelet-leukocyte aggregates in patients with acute coronary syndrome].

OBJECTIVE: To compare the platelet-leukocyte-aggregates (PLAs) level among patients with acute coronary syndrome (ACS) and stable angina pectoris (SAP). METHODS: Hospitalized patients were divided into three groups [ACS group (n=86), SAP group (n=54), the control group with 46 patients without coronary artery disease]. PLAs were measured by flow cytometry at admission before coronary angiography. ACS patients were further divided into low-risk group (0-108 points) and high-risk group (>109 points) according to GRACE scores at admission. PLA, platelet-monocyte aggregations (PMA), platelet-neutrophil aggregations (PNA), platelet-lymphocyte aggregations (PlyA) and hs-CRP values were compared among groups. RESULTS: PLA (4.40%±3.08%), PMA (33.6%±21.5%), PNA (3.76%±5.06%), PLyA (2.03%±1.27%) and hs-CRP [5.75 (3.49, 9.15)] levels in ACS group were significantly higher than those in SAP and control groups (all P<0.05). PLA was also significantly higher in high-risk group than in the low-risk group (44.8%±18.0% vs. 13.0%±6.3%, P<0.01). Spearman correlation analysis showed that hs-CRP was positively correlated with PMA (r=0.547, P<0.01) and GRACE score is positively correlated with PMA, PLA, PNA and PlyA (r=0.746, 0.652, 0.460, respectively, all P<0.01). CONCLUSION: PLAs is increased in ACS patients and higher PMA level is related with the unstable coronary syndrome in ACS patients. Increased PMA, PLA, PNA and PlyA levels is associated with higher GRACE score in ACS patients.

Complete chloroplast genome of Lonicera crassifolia Batalin (Caprifoliaceae) and its phylogenetic implications.

Lonicera crassifolia is a prostrate or creeping, evergreen Lonicera species endemic to southwest China. Here, we reported the complete chloroplast (cp) genome of L. crassifolia (GenBank accession number: OK393707). The cp genome was 154,731 bp long, with a large single-copy region (LSC) of 88,619 bp and a small single-copy region (SSC) of 18,642 bp separated by a pair of inverted repeats (IRs) of 23,735 bp. It encodes 130 genes, including 85 protein-coding genes, 37 tRNA genes, and 8 ribosomal RNA genes. We also reconstructed the phylogeny of Lonicera using the maximum-likelihood (ML) method, including our data and previously reported cp genomes of related taxa. The phylogenetic analysis showed that L. crassifolia is a sister to the remaining Nintooa clade with strong bootstrap support.

Complete chloroplast genome of Prunus fasciculata (Rosaceae), a species native to western North America.

Prunus fasciculata is a wild species of Prunus native to western North America. Here, we reported the complete chloroplast (cp) genome of P. fasciculata (GenBank accession number: MW160273). The cp genome was 157,986 bp long, with a large single-copy (LSC) region of 86,068 bp and a small single-copy (SSC) region of 19,166 bp separated by a pair of inverted repeats (IRs) of 26,376 bp. It encodes 129 genes, including 84 protein-coding genes, 37 tRNA genes, and eight ribosomal RNA genes. We also reconstructed the phylogeny of Prunus sensu lato using maximum-likelihood (ML) method, including our data and previously reported cp genomes of related taxa. The phylogenetic analysis confirmed the sister group relationship between P. fasciculata and the remaining subg. Prunus.

Bioengineered Zinc Oxide Nanoparticle-Loaded Hydrogel for Combinative Treatment of Spinal Cord Transection.

Spinal cord injury (SCI) is one of the most destructive diseases. The neuroinflammation microenvironment needs comprehensive mitigation of damages. Thus, regulation of local, microenvironment drugs could be a potential effective treatment. However, clinical studies on SCI with common treatment have reported it to cause systemic toxicity and side effects. Zinc oxide nanoparticles (ZnONPs) have been widely reported to have satisfying anti-inflammation function. Furthermore, green synthesis procedures can improve the capability and possible utilization of ZnONPs. However, the efficient administration and underlying mechanism of ZnONPs in SCI treatment remain unclear. Herein, an innovative approach was built by utilizing ZnONPs loaded in a skeletal muscle-derived adhesive hydrogel (ZnONPs-Gel). Different from the systemic application of ZnONPs, the local administration of ZnONPs-Gel offered the ZnONPs-loaded extracellular matrix with beneficial biocompatibility to the injured spinal cord, thereby promoting effective function recovery. Mechanistically, the ZnONPs-Gel treatment not only markedly reduced ROS production but also decreased apoptosis in the injured spinal cord. Therefore, the strategy based on local administration of the ZnONPs-Gel in the early stage of SCI may be an effective therapeutic treatment.

Plasma D-dimer as a predictor of intraluminal thrombus burden and progression of abdominal aortic aneurysm.

AIM: Intraluminal thrombus (ILT) is presented in most abdominal aortic aneurysms (AAAs) and is suggested to promote AAA expansion. D-dimer, a breakdown product in the thrombus remodeling, may have prognostic value for AAA. This study investigated the interrelation between plasma D-dimer level, ILT volume, AAA size and progression. MAIN METHODS: This was a retrospective observational study that involved 181 patients with infra-renal AAA. They were divided into small and large AAA groups according to AAA diameter. 24 of them had repeated abdominal computed tomography angiography (CTA) scan and were divided into slow-growing and fast-growing AAA groups according to the median value of AAA growth rate. Baseline and follow-up plasma D-dimer level, maximum diameter of AAA, total infra-renal aortic volume and ILT volume were analyzed. KEY FINDINGS: Plasma D-dimer level was positively correlated with ILT volume (R = 0.382, P < 0.001) and maximum diameter of AAA (R = 0.442, P < 0.001). Increasing value of plasma D-dimer was positively associated with the accelerated growth rate of AAA (R = 0.720, P < 0.01). ILT volume showed positive correlation with maximum diameter (R = 0.859, P < 0.001) and growth rate of AAA (R = 0.490, P < 0.05). After adjusting the baseline ILT volume, the positive correlations remained to be statistically significant between plasma D-dimer level and AAA size (R = 0.200, P < 0.05), as well as increasing value of plasma D-dimer and growth rate of AAA (R = 0.642, P < 0.05). SIGNIFICANCE: Plasma D-dimer level reflected ILT burden in AAAs. Plasma D-dimer level and ILT volume were positively correlated with AAA size. Increasing value of plasma D-dimer and baseline ILT volume could be predictors of AAA progression.

Effects of chemical and low-temperature treatments and adaption on the responses of virulence factor genes and outer membrane proteins in Escherichia coli O157:H7.

BACKGROUND: In the years after the discovery of this pathogen, Escherichia coli O157:H7 has become increasingly prominent, and outbreaks have been reported in many areas. METHODS: In the current study, we determined the expressions of virulent factor genes shiga-like toxin II (stxII) and E. coli attaching and effacing (eaeA), in strains that were isolated from cattle feces and a clinical case in Taiwan. In addition, the effects of chemical and low-temperature stresses and adaptions on the expressions of virulent factor genes were investigated. Furthermore, the outer membrane proteins of acid-adapted E. coli O157:H7 TWC01 (TWC01) was separated using two-dimensional electrophoresis, and proteins were identified using mass spectrometry in order to illustrate the changes in protein expression after adaption. RESULTS: Expressions of stxII and eaeA in the TWC01 isolated from a clinical case were higher than those in two strains isolated from cattle feces, and both organic and inorganic acid stresses and adaptions enhance the expression of genes encoding virulent factors in strains. In addition, the outer membrane proteins of TWC01 were regulated under hydrochloric acid adaption, indicating induction of acid tolerance and enhancement adhesion in TWC01. Lactic acid treatment of TWC01 resulted in downregulation of channel protein and adherence-related protein expressions. CONCLUSION: The results of this study are helpful in understanding the resistance of locally isolated TWC01 to chemical and low-temperature stresses, and improving the control of this pathogen.

Preprocedural N-terminal pro-brain natriuretic peptide (NT-proBNP) is similar to the Mehran contrast-induced nephropathy (CIN) score in predicting CIN following elective coronary angiography.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) has been associated with important risk factors for contrast-induced nephropathy (CIN). However, few studies have investigated the predictive value of NT-proBNP itself. This study investigated whether levels of preprocedural NT-proBNP could predict CIN after elective coronary angiography as effectively as the Mehran CIN score. METHODS AND RESULTS: We retrospectively observed 2248 patients who underwent elective coronary angiography. The predictive value of preprocedural NT-proBNP for CIN was assessed by receiver operating characteristic and multivariable logistic regression analysis. The 50 patients (2.2%) who developed CIN had higher Mehran risk scores (9.5 ± 5.1 versus 4.8 ± 3.8), and higher preprocedural levels of NT-proBNP (5320 ± 7423 versus 1078 ± 2548 pg/mL, P<0.001). Receiver operating characteristic analysis revealed that NT-proBNP was not significantly different from the Mehran CIN score in predicting CIN (C=0.7657 versus C=0.7729, P=0.8431). An NT-proBNP cutoff value of 682 pg/mL predicted CIN with 78% sensitivity and 70% specificity. Multivariable analysis suggested that, after adjustment for other risk factors, NT-proBNP >682 pg/mL was significantly associated with CIN (odds ratio: 4.007, 95% CI: 1.950 to 8.234; P<0.001) and risk of death (hazard ratio: 2.53; 95% CI: 1.49 to 4.30; P=0.0006). CONCLUSIONS: Preprocedural NT-proBNP >682 pg/mL was significantly associated with the risk of CIN and death. NT-proBNP, like the Mehran CIN score, may be another useful and rapid screening tool for CIN and death risk assessment, identifying subjects who need therapeutic measures to prevent CIN.

Safe limits of contrast vary with hydration volume for prevention of contrast-induced nephropathy after coronary angiography among patients with a relatively low risk of contrast-induced nephropathy.

BACKGROUND: Few studies have investigated the safe limits of contrast to prevent contrast-induced nephropathy (CIN) based on hydration data. We aimed to investigate the relative safe maximum contrast volume adjusted for hydration volume in a population with a relatively low risk of CIN. METHODS AND RESULTS: The ratios of contrast volume-to-creatinine clearance (V/CrCl) and hydration volume to body weight (HV/W) were determined in patients undergoing cardiac catheterization. Receiver-operator characteristic curve analysis based on the maximum Youden index was used to identify the optimal cutoff for V/CrCl in all patients and in HV/W subgroups. Eighty-six of 3273 (2.6%) patients with mean CrCl 71.89±27.02 mL/min developed CIN. Receiver-operator characteristic curve analysis indicated that a V/CrCl ratio of 2.44 was a fair discriminator for CIN in all patients (sensitivity, 73.3%; specificity, 70.4%). After adjustment for other confounders, V/CrCl >2.44 continued to be significantly associated with CIN (adjusted odds ratio, 4.12; P<0.001) and the risk of death (adjusted hazard ratio, 2.62; P<0.001). The mean HV/W was 12.18±7.40. We divided the patients into 2 groups (HV/W ≤12 and >12 mL/kg). The best cutoff value for V/CrCl was 1.87 (sensitivity, 67.9%; specificity, 64.4%; adjusted odds ratio, 3.24; P=0.011) in the insufficient hydration subgroup (HV/W, ≤12 mL/kg; CIN, 1.32%) and 2.93 (sensitivity, 69.0%; specificity, 65.0%; adjusted odds ratio, 3.04; P=0.004) in the sufficient hydration subgroup (HV/W, >12 mL/kg; CIN, 5.00%). CONCLUSIONS: The V/CrCl ratio adjusted for HV/W may be a more reliable predictor of CIN and even long-term outcomes after cardiac catheterization. We also found a higher best cutoff value for V/CrCl to predict CIN in patients with a relatively sufficient hydration status, which may be beneficial during decision-making about contrast dose limits in relatively low-risk patients with different hydration statuses.