Proteome-wide profiling reveals dysregulated molecular features and accelerated aging in osteoporosis: A 9.8-year prospective study.

The role of circulatory proteomics in osteoporosis is unclear. Proteome-wide profiling holds the potential to offer mechanistic insights into osteoporosis. Serum proteome with 413 proteins was profiled by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline, and the 2nd, and 3rd follow-ups (7704 person-tests) in the prospective Chinese cohorts with 9.8 follow-up years: discovery cohort (n = 1785) and internal validation cohort (n = 1630). Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA) at follow-ups 1 through 3 at lumbar spine (LS) and femoral neck (FN). We used the Light Gradient Boosting Machine (LightGBM) to identify the osteoporosis (OP)-related proteomic features. The relationships between serum proteins and BMD in the two cohorts were estimated by linear mixed-effects model (LMM). Meta-analysis was then performed to explore the combined associations. We identified 53 proteins associated with osteoporosis using LightGBM, and a meta-analysis showed that 22 of these proteins illuminated a significant correlation with BMD (p < 0.05). The most common proteins among them were PHLD, SAMP, PEDF, HPTR, APOA1, SHBG, CO6, A2MG, CBPN, RAIN APOD, and THBG. The identified proteins were used to generate the biological age (BA) of bone. Each 1 SD-year increase in KDM-Proage was associated with higher risk of LS-OP (hazard ratio [HR], 1.25; 95% CI, 1.14-1.36, p = 4.96 × 10-06 ), and FN-OP (HR, 1.13; 95% CI, 1.02-1.23, p = 9.71 × 10-03 ). The findings uncovered that the apolipoproteins, zymoproteins, complements, and binding proteins presented new mechanistic insights into osteoporosis. Serum proteomics could be a crucial indicator for evaluating bone aging.

The associations of erythrocyte membrane polyunsaturated fatty acids with skeletal muscle loss: A prospective cohort study.

BACKGROUND & AIMS: Polyunsaturated fatty acids (PUFAs) may play a vital role in maintaining skeletal muscle mass in the aged population. This study investigated the longitudinal relationship between the concentrations of erythrocyte membrane PUFAs and age-related changes in skeletal muscle mass over an average 6.5 years of follow-up in a Chinese middle-aged and older adult population. METHODS: A total of 1494 participants aged 57.4 ± 4.7 years were included in this study. Skeletal muscle mass was determined using dual-energy X-ray absorptiometry. Per year percent changes in the skeletal muscle index (Δ% SMI), appendicular skeletal muscle index (Δ% ASMI), and total body lean mass index (Δ% TBLMI) from baseline were calculated. Concentrations of total and individual cis-n-3 and cis-n-6 PUFAs of the erythrocyte membrane were determined using gas-liquid chromatography. RESULTS: Fully adjusted linear regression models showed that per unit increases in the concentrations of C18:2 n-6, C20:4 n-6, C22:4 n-6, and total n-6 PUFAs resulted in increases of 0.022%-0.155 % in the Δ% SMI (P for linearity: <0.001-0.006). Restricted cubic spline analysis revealed an inverted U-shaped relationship between the concentrations of C20:2 n-6, C22:5 n-3, C22:6 n-3, and total n-3 PUFAs and the Δ% SMI (P for non-linearity: <0.001-0.036). In addition, an inverted U-shaped curve was also detected for the relationships of the linoleic acid/α-linolenic acid ratio (P for non-linearity = 0.010) and n-6/n-3 PUFA ratio (P for non-linearity = 0.013) with the Δ% SMI, with the Δ% SMI peaking at respective ratios of 124.96 and 3.69. Similar associations were revealed by the Bayesian kernel machine regression model. No interaction effect was detected between the individual PUFAs for the Δ% SMI in the bivariate exposure-response analysis. Overall, similar results were observed for the Δ% ASMI and Δ% TBLMI. CONCLUSIONS: The associations between different individual PUFAs and age-related muscle loss in middle-aged and older adults may be different. Our results suggest that high concentrations of erythrocyte membrane n-6 PUFAs may be correlated with less skeletal muscle mass loss, whereas extremely high concentrations of n-3 PUFAs may be correlated with more muscle loss.

Association of Serum Pepsinogens With Esophageal Squamous Cell Carcinoma Risk: A Systematic Review and Meta-Analysis.

Background: Serum pepsinogens are serological biomarkers of gastric atrophy, and the latter is a risk factor for esophageal squamous cell carcinoma (ESCC). However, the association of serum pepsinogens with ESCC risk remains unclear. This systematic review and meta-analysis aimed to assess the relationship between serum pepsinogen I (PGI) and pepsinogen I: pepsinogen II ratio (PGR) and ESCC risk. Methods: PubMed, Embase, and Web of Science were searched for articles on the effect of serum PGI and PGR on ESCC risk, published up to the end of February 2022. Meta-analysis with a random-effect model was used to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Results: Five case-control studies and three prospective studies were included. In comparison with the high categories, the low categories of serum PGI (OR: 1.92, 95% CI: 1.45-2.56) and PGR (OR: 1.70, 95% CI: 1.01-2.85) were associated with an increased risk of ESCC, although a substantial heterogeneity was observed in serum PGR (I 2 = 60.2%, P = 0.028) rather than in serum PGI (I 2 = 46.4%, P = 0.070). In stratified analysis by study quality, the significant risk effect on ESCC was remained for PGI (OR: 2.05, 95% CI: 1.48-2.84) and PGR (OR: 2.07, 95% CI: 1.17-3.75) when only the studies with high quality were pooled. Conclusions: Based on the available studies, although limited in number, this systematic review along with meta-analysis suggests that low serum PGI and low PGR may be related to an increased risk of ESCC. This present study provides evidence for using serum pepsinogen biomarkers in predicting ESCC. More delicate well-designed cohort studies with high study quality are needed, and dose-response analysis should be performed.

Association Between Eating Habits and Risk of Obstructive Sleep Apnea: A Population-Based Study.

OBJECTIVE: The effect of dietary factors on OSA remains unclear. This study was to investigate the association of obstructive sleep apnea (OSA) with individual and overall effects of eating habits among adult Chinese. METHODS: A total of 9733 participants were selected from the baseline survey of the Guangzhou Heart Study. OSA was ascertained by Berlin Questionnaire. Food consumption was collected using a food frequency questionnaire, and eating patterns were extracted by principal component analysis. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated by the logistic regression model. RESULTS: After adjustment for confounders, fried food intake with ≥1/week was associated with an increased risk of OSA (OR: 1.77, 95% CI: 1.37-2.27), while fruit consumption of ≥1/day was associated with a 26% reduced risk of OSA (OR: 0.74, 95% CI: 0.62-0.88). Three eating patterns were defined and labeled as pattern I, II, and III. Eating pattern III which had higher factor loadings of animal innards, fried food, salted food, carbonate, and non-carbonated beverages was associated with an increased risk of OSA (OR: 1.30, 95% CI: 1.09-1.55) when comparing the highest with the lowest tertile of pattern score, after adjusting for confounders; every 1-unit increment of pattern III score was associated with an increased risk of OSA (OR: 1.09, 95% CI: 1.04-1.14). Neither pattern I nor pattern II was observed to be associated with OSA risk. CONCLUSION: A higher frequency intake of fruits was associated with a reduced OSA risk and a diet with higher levels of consumption of animal innards, fried food, salted food, carbonated beverages, and non-carbonated beverages may increase the risk of OSA.

The N-end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin.

Anthrax lethal toxin (LT) is known to induce NLRP1B inflammasome activation and pyroptotic cell death in macrophages from certain mouse strains in its metalloprotease activity-dependent manner, but the underlying mechanism is unknown. Here, we establish a simple but robust cell system bearing dual-fluorescence reporters for LT-induced ASC specks formation and pyroptotic lysis. A genome-wide siRNA screen and a CRISPR-Cas9 knockout screen were applied to this system for identifying genes involved in LT-induced inflammasome activation. UBR2, an E3 ubiquitin ligase of the N-end rule degradation pathway, was found to be required for LT-induced NLRP1B inflammasome activation. LT is known to cleave NLRP1B after Lys44. The cleaved NLRP1B, bearing an N-terminal leucine, was targeted by UBR2-mediated ubiquitination and degradation. UBR2 partnered with an E2 ubiquitin-conjugating enzyme UBE2O in this process. NLRP1B underwent constitutive autocleavage before the C-terminal CARD domain. UBR2-mediated degradation of LT-cleaved NLRP1B thus triggered release of the noncovalent-bound CARD domain for subsequent caspase-1 activation. Our study illustrates a unique mode of inflammasome activation in cytosolic defense against bacterial insults.

Chemical probing reveals insights into the signaling mechanism of inflammasome activation.

Caspase-1-mediated IL-1ß production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF-κB-dependent pro-IL-1ß transcription; NOD-like receptors (NLRs) assemble caspase-1-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specific and potent inhibitor of the caspase-1 pathway. Bromoxone is effective over diverse inflammatory stimuli including TLR ligands plus ATP/nigericin, cytosolic DNA, flagellin and Bacillus anthracis lethal toxin. Bromoxone also efficiently suppresses caspase-1 activation triggered by several types of bacterial infection. Bromoxone acts upstream or at the level of the inflammasome in a transcription-independent manner. Bromoxone also inhibits pro-IL-1ß expression by targeting components upstream of IKK in the TLR-NF-κB pathway. The unique dual activities of bromoxone are shared by the known TAK1 inhibitor that specifically blocks Nalp3 inflammasome activation. Hinted from the mechanistic and pharmacological properties of bromoxone, we further discover that several known NF-κB inhibitors that act upstream of IKK, but not those targeting IKK or IKK downstream, are potent blockers of different NLRs-mediated caspase-1 activation. Our study uncovers a possible non-transcriptional molecular link between the NLR (Nalp3)-mediated inflammasome pathway and TLR-NF-κB signaling, and suggests a potential strategy to develop new anti-inflammatory drugs.

Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement.

Cul3, a Cullin family scaffold protein, is thought to mediate the assembly of a large number of SCF (Skp1-Cullin1-F-box protein)-like ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors. Cul3 controls early embryonic development in several genetic models through mechanisms not understood. Very few functional substrate/adaptor pairs for Cul3 ubiquitin ligases have been identified. Here, we show that Cul3 knockdown in human cells results in abnormal actin stress fibers and distorted cell morphology, owing to impaired ubiquitination and degradation of small GTPase RhoA. We identify a family of RhoA-binding BTB domain adaptors conserved from insects to mammals, designated BACURDs. BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Dysfunction of the Cul3/BACURD complex decreases cell migration potential and impairs RhoA-mediated convergent extension movements during Xenopus gastrulation. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.