5-Demethoxy-10'-ethoxyexotimarin F, a New Coumarin with MAO-B Inhibitory Potential from Murraya exotica L.

Rutaceae plants are known for being a rich source of coumarins. Preliminary molecular docking showed that there was no significant difference for coumarins in Clausena and Murraya, both of which had high scoring values and showed good potential inhibitory activity to the MAO-B enzyme. Overall, 32 coumarins were isolated from Murraya exotica L., including a new coumarin 5-demethoxy-10'-ethoxyexotimarin F (1). Their structures were elucidated on the basis of a comprehensive analysis of 1D and 2D NMR and HRMS spectroscopic data, and the absolute configurations were assigned via a comparison of the specific rotations and the ECD exciton coupling method. The potential of new coumarin (1) as a selective inhibitor of MAO-B was initially evaluated through molecular docking and pharmacophore studies. Compound (1) showed selectivity for the MAO-B isoenzyme and inhibitory activity in the sub-micromolar range with an IC50 value of 153.25 ± 1.58 nM (MAO-B selectivity index > 172).

Screening of osteoarthritis diagnostic markers based on immune-related genes and immune infiltration.

Osteoarthritis (OA) is a chronic degenerative disease of the bone and joints. Immune-related genes and immune cell infiltration are important in OA development. We analyzed immune-related genes and immune infiltrates to identify OA diagnostic markers. The datasets GSE51588, GSE55235, GSE55457, GSE82107, and GSE114007 were downloaded from the Gene Expression Omnibus database. First, R software was used to identify differentially expressed genes (DEGs) and differentially expressed immune-related genes (DEIRGs), and functional correlation analysis was conducted. Second, CIBERSORT was used to evaluate infiltration of immune cells in OA tissue. Finally, the least absolute shrinkage and selection operator logistic regression algorithm and support vector machine-recurrent feature elimination algorithm were used to screen and verify diagnostic markers of OA. A total of 711 DEGs and 270 DEIRGs were identified in this study. Functional enrichment analysis showed that the DEGs and DEIRGs are closely related to cellular calcium ion homeostasis, ion channel complexes, chemokine signaling pathways, and JAK-STAT signaling pathways. Differential analysis of immune cell infiltration showed that M1 macrophage infiltration was increased but that mast cell and neutrophil infiltration were decreased in OA samples. The machine learning algorithm cross-identified 15 biomarkers (BTC, PSMD8, TLR3, IL7, APOD, CIITA, IFIH1, CDC42, FGF9, TNFAIP3, CX3CR1, ERAP2, SEMA3D, MPO, and plasma cells). According to pass validation, all 15 biomarkers had high diagnostic efficacy (AUC > 0.7), and the diagnostic efficiency was higher when the 15 biomarkers were fitted into one variable (AUC = 0.758). We developed 15 biomarkers for OA diagnosis. The findings provide a new understanding of the molecular mechanism of OA from the perspective of immunology.

Decreased plasma n6 : n3 polyunsaturated fatty acids ratio interacting with high C-peptide promotes non-alcoholic fatty liver disease in type 2 diabetes patients.

AIMS/INTRODUCTION: To explore relationships between polyunsaturated fatty acids (PUFA) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes, and whether insulin action has an interactive effect with PUFA on NAFLD progression. MATERIALS AND METHODS: We extracted clinical and omics data of 482 type 2 diabetes patients from a tertiary hospital consecutively from April 2018 to April 2019. NAFLD was estimated by ultrasound at admission. Plasma fasting n3 and n6 fatty acids were quantified by liquid chromatography-tandem mass spectrometry analysis. Restricted cubic spline nested in binary logistic regression was used to select the cut-off point, and estimate odds ratios and 95% confidence intervals. Additive interactions of the n6 : n3 ratio with insulin action for NAFLD were estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Relative excess risk due to interaction >0, attributable proportion due to interaction >0 or synergy index >1 indicates biological interaction. Spearman correlation analysis was used to obtain partial correlation coefficients between PUFA and hallmarks of NAFLD. RESULTS: Of 482 patients, 313 were with and 169 were without NAFLD. N3 ≥800 and n6 PUFA ≥8,100 µmol/L were independently associated with increased NAFLD risk; n6 : n3 ratio ≤10 was associated with NAFLD (odds ratio 1.80, 95% confidence interval 1.20-2.71), and the effect size was amplified by high C-peptide (odds ratio 8.89, 95% confidence interval 4.48-17.7) with significant interaction. The additive interaction of the n6 : n3 ratio and fasting insulin was not significant. CONCLUSION: Decreased n6 : n3 ratio was associated with increased NAFLD risk in type 2 diabetes patients, and the effect was only significant and amplified when there was the co-presence of high C-peptide.

Interactive effects of asparagine and aspartate homeostasis with sex and age for the risk of type 2 diabetes risk.

BACKGROUND: Asparagine and aspartate homeostasis are linked with type 2 diabetes (T2D). This study aimed to explore whether asparagine and aspartate metabolism interacted with sex and age to increase the risk of T2D. METHODS: From 27 May 2015 to 3 August 2016, we consecutively retrieved 1032 T2D patients and 1522 subjects without T2D from a tertiary care hospital in Liaoning, China. Restricted cubic spline nested in the logistic regression was used to draw odds ratio curves of plasma asparagine to aspartate ratio for T2D by sex and age. Cut-off point was selected where curves went apart, indicating possible interaction. Addictive interactions of asparagine to aspartate ratio with sex or age and secondary interaction with copresence of unfavorable sex and age were further estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RESULTS: Ratio of asparagine to aspartate > 1.5 was associated with elevated risk of T2D (OR 7.99, 95%CI 5.50 to 11.6), which was enhanced by female gender to 13.6, (95%CI 8.10-22.9) and by > 50 years of age to 28.7 (14.6-56.3), with significant additive interactions. There was a significant secondary-interaction of copresence of female sex and > 50 years of age with high asparagine to aspartate ratio for increased T2D risk with the OR being further increased to 34.4 (20.5-57.5). CONCLUSIONS: High asparagine to aspartate ratio was associated with markedly increased risk of T2D, which was further amplified by either female gender or > 50 years of age, and especially both.

Plasma phenylalanine and tyrosine and their interactions with diabetic nephropathy for risk of diabetic retinopathy in type 2 diabetes.

OBJECTIVE: Tight control of hyperglycemia reduces risk of diabetic retinopathy (DR), but the residual risk remains high. This study aimed to explore relationships between plasma phenylalanine and tyrosine with DR in type 2 diabetes (T2D) and interactions between the two amino acids, and their secondary interaction with renal dysfunction. RESEARCH DESIGN AND METHODS: We extracted data of 1032 patients with T2D from tertiary hospital consecutively from May 2015 to August 2016. Binary logistic regression models with restricted cubic spline were used to check potential non-linear associations and to obtain ORs and 95% CIs of variables under study. Addictive interaction was estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Area under the receiver operating characteristic curve was used to check increased predictive values. RESULTS: Of 1032 patients, 162 suffered from DR. Copresence of low phenylalanine and low tyrosine increased DR risk (OR 6.01, 95% CI 1.35 to 26.8), while either of them alone did not have a significant effect with significant additive interaction. Presence of diabetic nephropathy further increased the OR of copresence of low phenylalanine and low tyrosine for DR to 25.9 (95% CI 8.71 to 76.9) with a significant additive interaction. Inclusion of phenylalanine and tyrosine in a traditional risk factor model significantly increased area under the curve from 0.81 to 0.83 (95% CI 0.80 to 0.86). CONCLUSION: Plasma low phenylalanine and low tyrosine worked independently and synergistically to increase the risk of DR in T2D. Presence of renal dysfunction further amplified the effect of copresence of low phenylalanine and low tyrosine on DR risk.

Lumbar disc rehydration in the bridged segment using the BioFlex dynamic stabilization system: A case report and literature review.

BACKGROUND: In recent years, the mechanical concept of intervertebral disc regeneration has become more and more popular due to the increasing awareness of the importance of preservation of spine movement. Interestingly, there is increasing evidence, however, that dynamic stabilization systems may compensate non-physiological loads, limit pathological movement, normalize disc height and intradiscal pressure, and provide an adaptive environment for disc regeneration. CASE SUMMARY: The patient was a 54-year-old man, who presented with a 10-year history of mechanical back pain, which had become progressively serious and radiated into the left lower limb with numbness 3 mo prior. He had decreased muscle strength (class IV) of the left dorsal extensor and plantar flexor. Magnetic resonance imaging scans showed L3-S1 disc degeneration and L4-L5 disc herniation. Because the patient did not respond to various conservative treatments, he underwent a posterior L4-5 discectomy with fixation of the BioFlex dynamic stabilization system (Bio-Spine, Seoul, Korea). Preoperative symptoms were relieved and lumbar function was markedly improved after the operation. L4-L5 disc rehydration of instrumented segment was noted on magnetic resonance imaging at the 2-year follow-up. CONCLUSION: Rehydration of the degenerated disc in our patient indicates that the BioFlex dynamic stabilization system may promote disc regeneration. Further research is needed to provide more evidence to support lumbar disc rehydration in the bridged segment using this system.

The Association Between Acylcarnitine Metabolites and Cardiovascular Disease in Chinese Patients With Type 2 Diabetes Mellitus.

Objective: The association between acylcarnitine metabolites and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) remains uncertain. This study aimed to investigate associations between acylcarnitines and CVD in Chinese patients with T2DM. Methods: A cross-sectional study was conducted from May 2015 to August 2016. Medical records of 741 patients with T2DM were retrieved from the main electronic database of Liaoning Medical University First Affiliated Hospital. CVD was defined as having either coronary artery disease (CAD) or heart failure (HF) or stroke. Mass Spectrometry was utilized to measure levels of 25 acylcarnitine metabolites in fasting plasma. Factor analysis was used to reduce the dimensions and extracted factors of the 25 acylcarnitine metabolites. Multivariable binary logistic regression was used to obtain odds ratios (OR) of the factors extracted from the 25 acylcarnitine metabolites and their 95% confidence intervals (CI) for CVD. Results: Of the 741 patients with T2DM, 288 had CVD. Five factors were extracted from the 25 acylcarnitines and they accounted for 65.9% of the total variance. Factor 1 consisted of acetylcarnitine, butyrylcarnitine, hydroxylbutyrylcarnitine, glutarylcarnitine, hexanoylcarnitine, octanoylcarnitine, and tetradecanoyldiacylcarnitine. Factor 2 consisted of decanoylcarnitine, lauroylcarnitine, myristoylcarnitine, 3-hydroxyl-tetradecanoylcarnitine, tetradecenoylcarnitine, and 3-hydroxypalmitoylcarnitine. After adjusting for potential confounders, increased factor 1 and 2 were associated with increased risks of CVD in T2DM (OR of factor 1: 1.45, 95% CI: 1.03-2.03; OR of factor 2: 1.23, 95% CI: 1.02-1.50). Conclusions: Elevated plasma levels of some acylcarnitine metabolites, i.e., those extracted into factor 1 and 2, were associated with CVD risk in T2DM.

Plasma Free Amino Acids and Risk of Cardiovascular Disease in Chinese Patients With Type 2 Diabetes.

Objectives: This study aimed to explore associations between plasma free amino acids (PFAA) and risk of cardiovascular disease (CVD) in Chinese with Type 2 diabetes (T2D). Methods: We retrieved 741 inpatients with T2D consecutively from tertiary hospital. Twenty-three PFAA were measured. CVD was defined as having coronary heart disease (CHD) or stroke. Principal component analysis was used to extract factors of PFAA. Factors and their components were introduced into binary logistic regressions as continuous and tertiles to obtain OR (odds ratio) and 95% confidence interval (CI) for CVD (or its components) risk. Results: Of 741 inpatients, 282 (38.1%) had CVD (CHD alone: 122, stroke alone: 109, both: 51). Five factors were extracted, accounting for 65% of the total variance. Factor 3 composed of glutamate and tryptophan was associated with increased CVD risk (ORs, 95%CI of top vs. bottom tertiles: 1.60, 1.02-2.50 for CVD; 2.19, 1.17-4.07 for stroke, 1.51, 0.83-2.73 for CHD); the ORs (top vs. bottom tertiles) of glutamate were 2.62 (95%CI, 1.18-5.84) for stroke and 1.44 (0.80-2.61) for CHD; the ORs (top vs. bottom tertiles) of tryptophan were 1.50 (0.81-2.75) for stroke and 1.07 (0.58-1.97) for CHD. Comparable results were observed according to important confounders (all P for interaction >0.05). Conclusions: Elevated factor 3 composed of glutamate and tryptophan was associated with increased CVD, especially stroke in T2D in China.

Exploring the Pathological Mechanism of Bladder Cancer Based on Tumor Mutational Burden Analysis.

Although immunotherapy has progressed in the treatment of bladder cancer, some patients still have poor prognosis. New therapeutic targets are eager to be discovered to improve the outcomes of bladder cancer. With the development of high-throughput sequencing and tumor profiling, potential tumor biomarkers were identified. Through the interpretation of related data from the Cancer Genome Atlas database (TCGA), some key genes have been discovered to drive the development and prognosis of urinary bladder neoplasm. On account of the success of immunotherapy in many cancer types, we established the relationship between tumor mutation burden and immune microenvironment of bladder cancer and found the changes of several immune cells in this disease. Based on the understanding of the bladder tumor genome and immune environment, this study is supposed to provide new therapies for the treatment of bladder neoplasm.

Plasma Levels of Amino Acids Related to Urea Cycle and Risk of Type 2 Diabetes Mellitus in Chinese Adults.

Objective: This study aimed to test associations between type 2 diabetes mellitus (T2DM) and metabolites in urea cycle including arginine, citrulline and ornithine. Methods:This study used a hospital-based cross-sectional study design. We retrieved medical notes of 401 in-patients with onset of T2DM within 2 years and 1,522 healthy subjects who attended annual physical examination. All cases were admitted to a tertiary care center in Jinzhou, China from May 2015 to August 2016. Binary logistic regression analyses were performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Results:Patients with T2DM had higher arginine, and lower ornithine than control subjects. Levels of citrulline were similar in two groups. Arginine was positively associated with T2DM (ORs: 1.20, 1.17-1.23) while ornithine was negatively associated with T2DM (OR: 0.89, 0.88-0.91). After adjustment for other amino acids and traditional risk factors, these associations were still significant and persistent for arginine and ornithine. The association between citrulline and T2DM was not significant. Their ratios of pairs of two amino acids were associated with increased risk of T2DM. After adjustment for other ratios of amino acids, effect size for T2DM remained significant. Further adjustment for traditional risk factors did not lead to large changes (ORs: 1.78, 1.20-2.65 for the ratio of arginine to ornithine; ORs: 1.59, 1.37-1.86 for the ratio of citrulline to ornithine, respectively) except the ratio of arginine to citrulline. Conclusions: Plasma levels of amino acids related to urea cycle and their ratios of these amino-acids were associated with T2DM in Chinese adults.