Osteosarcopenia in the Spine Beyond Bone Mineral Density: Association Between Paraspinal Muscle Impairment and Advanced Glycation Endproducts.

STUDY DESIGN: Prospective cross-sectional study. OBJECTIVE: To determine if an accumulation of advanced glycation endproducts (AGEs) is associated with impaired paraspinal muscle composition. BACKGROUND: Impaired bone integrity and muscle function are described as osteosarcopenia. Osteosarcopenia is associated with falls, fragility fractures, and reduced quality of life. Bone integrity is influenced by bone quantity (bone mineral density) and quality (microarchitecture and collagen). The accumulation of AGEs stiffens collagen fibers and increases bone fragility. The relationship between paraspinal muscle composition and bone collagen properties has not been evaluated. METHODS: Intraoperative bone biopsies from the posterior superior iliac spine were obtained and evaluated with multiphoton microscopy for fluorescent AGE cross-link density (fAGEs). Preoperative magnetic resonance imaging measurements at level L4 included the musculus (m.) psoas and combined m. multifidus and m. erector spinae (posterior paraspinal musculature, PPM). Muscle segmentation on axial images (cross-sectional area, CSA) and calculation of a pixel intensity threshold method to differentiate muscle (functional cross-sectional area, fCSA) and intramuscular fat (FAT). Quantitative computed tomography was performed at the lumbar spine. Univariate and multivariable regression models were used to investigate associations between fAGEs and paraspinal musculature. RESULTS: One hundred seven prospectively enrolled patients (50.5% female, age 60.7 y, BMI 28.9 kg/m 2 ) were analyzed. In all, 41.1% and 15.0% of the patients demonstrated osteopenia and osteoporosis, respectively. Univariate linear regression analysis demonstrated a significant association between cortical fAGEs and CSA in the psoas (ρ=0.220, P =0.039) but not in the PPM. Trabecular fAGEs revealed no significant associations to PPM or psoas musculature. In the multivariable analysis, higher cortical fAGEs were associated with increased FAT (ß=1.556; P =0.002) and CSA (ß=1.305; P =0.005) in the PPM after adjusting for covariates. CONCLUSION: This is the first investigation demonstrating that an accumulation of nonenzymatic collagen cross-linking product fAGEs in cortical bone is associated with increased intramuscular fat in the lumbar paraspinal musculature.

Bone collagen quality in lumbar fusion patients: the association between volumetric bone mineral density and advanced glycation endproducts.

PURPOSE: The sole determination of volumetric bone mineral density (vBMD) is insufficient to evaluate overall bone integrity. The accumulation of advanced glycation endproducts (AGEs) stiffens and embrittles collagen fibers. Despite the important role of AGEs in bone aging, the relationship between AGEs and vBMD is poorly understood. We hypothesized that an accumulation of AGEs, a marker of impaired bone quality, is related to decreased vBMD. METHODS: Prospectively collected data of 127 patients undergoing lumbar fusion were analyzed. Quantitative computed tomography (QCT) measurements were performed at the lumbar spine. Intraoperative bone biopsies were obtained and analyzed with confocal fluorescence microscopy for fluorescent AGEs, both trabecular and cortical. Spearman's correlation coefficients were calculated to examine relationships between vBMD and fAGEs, stratified by sex. Multivariable linear regression analysis with adjustments for age, sex, body mass index (BMI), race, diabetes mellitus and HbA1c was used to investigate associations between vBMD and fAGEs. RESULTS: One-hundred and twenty-seven patients (51.2% female, 61.2 years, BMI of 28.7 kg/m2) with 107 bone biopsies were included in the final analysis, excluding patients on anti-osteoporotic drug therapy. In the univariate analysis, cortical fAGEs increased with decreasing vBMD at (r = -0.301; p = 0.030), but only in men. In the multivariable analysis, trabecular fAGEs increased with decreasing vBMD after adjusting for age, sex, BMI, race, diabetes mellitus and HbA1c (ß = 0.99;95%CI=(0.994,1.000); p = 0.04). CONCLUSION: QCT-derived vBMD measurements were found to be inversely associated with trabecular fAGEs. Our results enhance the understanding of bone integrity by suggesting that spine surgery patients with decreased bone quantity may also have poorer bone quality.

Dermal ultrasound measurements for bone quality assessment : An investigation of advanced glycation endproducts derived from confocal fluorescence microscopy.

Bone quality is increasingly being recognized in the assessment of fracture risk. Nonenzymatic collagen cross-linking with the accumulation of advanced glycation end products stiffens and embrittles collagen fibers thus increasing bone fragility. Echogenicity is an ultrasound (US) parameter that provides information regarding the skin collagen structure. We hypothesized that both skin and bone collagen degrade in parallel fashion. Prospectively collected data of 110 patients undergoing posterior lumbar fusion was analyzed. Preoperative skin US measurements were performed in the lumbar region to assess dermal thickness and echogenicity. Intraoperative bone biopsies from the posterior superior iliac spine were obtained and analyzed with confocal fluorescence microscopy for fluorescent advanced glycation endproducts (fAGEs). Pearson's correlation was calculated to examine relationships between  (1) US and fAGEs, and (2) age and fAGEs stratified by sex. Multivariable linear regression analysis with adjustments for age, sex, body mass index (BMI), diabetes mellitus, and hemoglobin A1c (HbA1c) was used to investigate associations between US and fAGEs. One hundred and ten patients (51.9% female, 61.6 years, BMI 29.8 kg/m2 ) were included in the analysis. In the univariate analysis cortical and trabecular fAGEs decreased with age, but only in women (cortical: r = -0.32, p = 0.031; trabecular: r = -0.32; p = 0.031). After adjusting for age, sex, BMI, diabetes mellitus, and HbA1c, lower dermal (ß = 1.01; p = 0.012) and subcutaneous (ß = 1.01; p = 0.021) echogenicity increased with increasing cortical fAGEs and lower dermal echogenicity increased with increasing trabecular fAGEs (ß = 1.01; p = 0.021). This is the first study demonstrating significant associations between skin US measurements and in vivo bone quality parameters in lumbar fusion patients. As a noninvasive assessment tool, skin US measurements might be incorporated into future practice to investigate bone quality in spine surgery patients.

Asymmetric Total Synthesis of (-)-Spirochensilide A, Part 1: Diastereoselective Synthesis of the ABCD Ring and Stereoselective Total Synthesis of 13(R)-Demethyl Spirochensilide A.

A concise and diastereoselective construction of the ABCD ring system of spirochensilide A is described. The key steps of this synthesis are a semipinacol rearrangement reaction to stereoselectively construct the AB ring system bearing two vicinal quaternary chiral centers and a Co-mediated Pauson-Khand reaction to form the spiro-based bicyclic CD ring system. This chemistry leads to the stereoselective synthesis of 13(R)-demethyl spirochensilide A, paving the way for the first asymmetric total synthesis of (-)-spirochensilide A.

Asymmetric Total Synthesis of Pre-schisanartanin C.

Pre-schisanartanin C belongs to the family of Schisandra nortriterpenoids with potent antihepatitis, antitumor, and anti-HIV activities. This paper presents the enantioselective total synthesis of pre-schisanartanin C (1). An important step in the total synthesis of 1 is gold-catalyzed intramolecular cyclopropanation of a 1,8-enyne substrate bearing a secondary ester group at the propargylic position to prepare a bicyclo[6.1.0]nonane core. Additional highlights include (i) an asymmetric Diels-Alder reaction to install the initial C5 stereogenic center of 1 and (ii) a sequential Pd-catalyzed Stille coupling, regio- and stereoselective Sharpless asymmetric dihydroxylation, and a subsequent intramolecular lactonization to construct the side chain of 1. The developed chemistry paves the way for the total syntheses of other family members bearing highly rigid bicyclo[6.1.0]nonane cores.

Canscora lucidissima, a Chinese folk medicine, exerts anti-inflammatory activities by inhibiting the phosphorylation of ERK1/2 in LPS-activated macrophages.

BACKGROUND: Canscora lucidissima (Levl. & Vaniot) Hand.-Mazz. (C. lucidissima), mainly distributed in southern China, has been shown to be effective in the treatment of inflammatory diseases. However, the underlying mechanism of its anti-inflammatory effect is not fully understood. METHODS: In this study, we investigated the anti-inflammatory mechanism of ethanol extract of C. lucidissima (Cl-EE) in lipopolysaccharide (LPS)-induced inflammatory models. ELISA, real-time PCR, Western blot and luciferase reporter assay were used for the experiments in vitro, and ICR mouse endotoxemia model was used for in vivo test. RESULTS: Our data showed that Cl-EE reduced the production of NO by down-regulating the mRNA and protein expression of inducible nitric oxide synthase (iNOS) in LPS-activated RAW 264.7 cells. Meanwhile, it potently decreased other proinflammatory mediators, such as TNF-α, IL-6, MCP-1 and IL-1ß at the transcriptional and translational levels. Further study indicated that Cl-EE did not affect NF-κB signaling pathway but significantly suppressed the phosphorylation of ERK1/2, rather than JNK or p38. In a LPS-induced endotoxemia mouse model, a single intraperitoneal injection of Cl-EE (75-300 mg/kg) could lower circulatory TNF-α, IL-6 and MCP-1 levels. CONCLUSIONS: Collectively, our results indicated that Cl-EE suppressed the phosphorylation level of ERK1/2 thus reducing the transcription and translation of inflammatory genes, thereby exerted anti-inflammatory activity. This study reveals the anti-inflammatory mechanism of C. lucidissima and may provide an effective treatment option for a variety of inflammatory diseases.

[Inhibition and Remediation of Methylmercury Contaminated Soil by Use of Modified Montmorillonite].

Montmorillonite was modified by 3-mercaptopyl trimethoxysilane and chitosan. The modified montmorillonite was characterized by XRD technology. The effects of thiol montmorillonite and chitosan montmorillonite on the inhibition and remediation of methylmercury contaminated soil under different water conditions were studied using laboratory simulation. XRD results showed that both thiol and chitosan were successfully loaded on the montmorillonite. The results of simulation tests showed that the addition of the remediation material to soil contaminated with methylmercury produced a better remediation effect. Compared with the blank control, the content of methylmercury in the soil was reduced by 82.10% (thiol montmorillonite) and 45.20% (chitosan montmorillonite), respectively, in the flooded condition. Under dry/wet alternation, the content of methyl mercury in soil decreased by 66.70% (thiol montmorillonite) and 49.79% (chitosan montmorillonite), respectively. Under drought conditions, the content of methylmercury in soil decreased by 44.66% (thiol montmorillonite), and the concentration of methylmercury in soil decreased by 54.37% after adding chitosan montmorillonite for 4 weeks. Compared with single modified montmorillonite, the repair effect of combined modified montmorillonite and lime treatment was not improved significantly.

Asymmetric Total Synthesis of Lancifodilactone G Acetate. 2. Final Phase and Completion of the Total Synthesis.

The asymmetric total synthesis of lancifodilactone G acetate was accomplished in 28 steps. The key steps in this synthesis include (i) an asymmetric Diels-Alder reaction for formation of the scaffold of the BC ring; (ii) an intramolecular ring-closing metathesis reaction for the formation of the trisubstituted cyclooctene using a Hoveyda-Grubbs II catalyst; (iii) an intramolecular Pauson-Khand reaction for construction of the sterically congested F ring; (iv) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment of lancifodilactone G; and (v) a Dieckmann-type condensation reaction for installation of the A ring. The strategy and chemistry developed for the total synthesis will be useful in the synthesis of other natural products and complex molecules.

Biomimetically inspired asymmetric total synthesis of (+)-19-dehydroxyl arisandilactone A.

Complex natural products are a proven and rich source of disease-modulating drugs and of efficient tools for the study of chemical biology and drug discovery. The architectures of complex natural products are generally considered to represent significant barriers to efficient chemical synthesis. Here we describe a concise and efficient asymmetric synthesis of 19-dehydroxyl arisandilactone A-which belongs to a family of architecturally unique, highly oxygenated nortriterpenoids isolated from the medicinal plant Schisandra arisanensis. This synthesis takes place by means of a homo-Michael reaction, a tandem retro-Michael/Michael reaction, and Cu-catalysed intramolecular cyclopropanation as key steps. The proposed mechanisms for the homo-Michael and tandem retro-Michael/Michael reactions are supported by density functional theory (DFT) calculation. The developed chemistry may find application for the synthesis of its other family members of Schisandraceae nortriterpenoids.