Predicting intercellular communication based on metabolite-related ligand-receptor interactions with MRCLinkdb.

BACKGROUND: Metabolite-associated cell communications play critical roles in maintaining human biological function. However, most existing tools and resources focus only on ligand-receptor interaction pairs where both partners are proteinaceous, neglecting other non-protein molecules. To address this gap, we introduce the MRCLinkdb database and algorithm, which aggregates and organizes data related to non-protein L-R interactions in cell-cell communication, providing a valuable resource for predicting intercellular communication based on metabolite-related ligand-receptor interactions. RESULTS: Here, we manually curated the metabolite-ligand-receptor (ML-R) interactions from the literature and known databases, ultimately collecting over 790 human and 670 mouse ML-R interactions. Additionally, we compiled information on over 1900 enzymes and 260 transporter entries associated with these metabolites. We developed Metabolite-Receptor based Cell Link Database (MRCLinkdb) to store these ML-R interactions data. Meanwhile, the platform also offers extensive information for presenting ML-R interactions, including fundamental metabolite information and the overall expression landscape of metabolite-associated gene sets (such as receptor, enzymes, and transporter proteins) based on single-cell transcriptomics sequencing (covering 35 human and 26 mouse tissues, 52 human and 44 mouse cell types) and bulk RNA-seq/microarray data (encompassing 62 human and 39 mouse tissues). Furthermore, MRCLinkdb introduces a web server dedicated to the analysis of intercellular communication based on ML-R interactions. MRCLinkdb is freely available at https://www.cellknowledge.com.cn/mrclinkdb/ . CONCLUSIONS: In addition to supplementing ligand-receptor databases, MRCLinkdb may provide new perspectives for decoding the intercellular communication and advancing related prediction tools based on ML-R interactions.

Plasma Alkylresorcinol Metabolite, a Biomarker for Whole-Grain Intake, Is Inversely Associated with Risk of Nonalcoholic Fatty Liver Disease in a Case-Control Study of Chinese Adults.

BACKGROUND: Epidemiologic studies consistently find associations between whole-grain intake and reduced risk of obesity and related metabolic diseases, yet data on the potential of whole grains to prevent fatty liver diseases are scarce. OBJECTIVES: To examine whether plasma 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA), a biomarker of whole-grain wheat and rye intake, is associated with nonalcoholic fatty liver disease (NAFLD). METHODS: This case-control study of Chinese adults enrolled 940 NAFLD cases and 940 age- and sex-matched non-NAFLD controls (mean age: 55.2 y; 65% males). NAFLD diagnosis was defined as individuals whose hepatic ultrasound disclosed hepatic steatosis at any stage, after the exclusion of alcohol abuse and other liver diseases. Fasting plasma DHPPA concentration was measured by LC-MS/MS. Multivariate adjusted ORs and 95% CIs were estimated to assess the association between plasma DHPPA and NAFLD using conditional logistic regression. RESULTS: Plasma concentration of DHPPA was significantly lower in patients with NAFLD compared with controls (median: 9.86 nmol/L compared with 10.9 nmol/L, P = 0.002). In multivariable logistic regression models, the ORs (95% CIs) for NAFLD across increasing tertiles of plasma DHPPA were 1 (reference), 0.76 (0.54, 1.05), and 0.65 (0.45, 0.93), respectively (P-trend = 0.026). In addition, the inverse associations persisted in subgroups stratified by sex, age, BMI, abdominal adiposity, smoking status, physical activity, diabetes, hypertension, and hyperlipidemia. CONCLUSIONS: These results indicate that increased plasma DHPPA concentration is associated with lower risk of NAFLD in Chinese adults, independently of well-known risk factors. Our finding provides evidence to support health benefits of whole-grain consumption on NAFLD. This trial was registered at clinicaltrials.gov as NCT03845868.

Plasma Alkylresorcinol Metabolite, a Biomarker for Whole-Grain Intake, Is Inversely Associated with Risk of Nonalcoholic Fatty Liver Disease in a Case-Control Study of Chinese Adults.

BACKGROUND: Epidemiologic studies consistently find associations between whole-grain intake and reduced risk of obesity and related metabolic diseases, yet data on the potential of whole grains to prevent fatty liver diseases are scarce. OBJECTIVES: To examine whether plasma 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA), a biomarker of whole-grain wheat and rye intake, is associated with nonalcoholic fatty liver disease (NAFLD). METHODS: This case-control study of Chinese adults enrolled 940 NAFLD cases and 940 age- and sex-matched non-NAFLD controls (mean age: 55.2 y; 65% males). NAFLD diagnosis was defined as individuals whose hepatic ultrasound disclosed hepatic steatosis at any stage, after the exclusion of alcohol abuse and other liver diseases. Fasting plasma DHPPA concentration was measured by LC-MS/MS. Multivariate adjusted ORs and 95% CIs were estimated to assess the association between plasma DHPPA and NAFLD using conditional logistic regression. RESULTS: Plasma concentration of DHPPA was significantly lower in patients with NAFLD compared with controls (median: 9.86 nmol/L compared with 10.9 nmol/L, P = 0.002). In multivariable logistic regression models, the ORs (95% CIs) for NAFLD across increasing tertiles of plasma DHPPA were 1 (reference), 0.76 (0.54, 1.05), and 0.65 (0.45, 0.93), respectively (P-trend = 0.026). In addition, the inverse associations persisted in subgroups stratified by sex, age, BMI, abdominal adiposity, smoking status, physical activity, diabetes, hypertension, and hyperlipidemia. CONCLUSIONS: These results indicate that increased plasma DHPPA concentration is associated with lower risk of NAFLD in Chinese adults, independently of well-known risk factors. Our finding provides evidence to support health benefits of whole-grain consumption on NAFLD. This trial was registered at clinicaltrials.gov as NCT03845868.

DHPPA, a major plasma alkylresorcinol metabolite reflecting whole-grain wheat and rye intake, and risk of metabolic syndrome: a case-control study.

PURPOSE: Whole-grain intake assessed through self-reported methods has been suggested to be inversely associated with the metabolic syndrome (MetS) risk in epidemiological studies. However, few studies have evaluated the association between whole-grain intake and MetS risk using objective biomarkers of whole-grain intake. The aim of this study was to examine the association between plasma 3-(3,5-Dihydroxyphenyl)-1-propanoic acid (DHPPA), a biomarker of whole-grain wheat and rye intake, and MetS risk in a Chinese population. METHODS: A case-control study of 667 MetS cases and 667 matched controls was conducted based on baseline data of the Tongji-Ezhou Cohort study. Plasma DHPPA concentrations were assessed by high-performance liquid chromatography-tandem mass spectrometry. The MetS was defined based on criteria set by the Joint Interim Statement. RESULTS: Plasma DHPPA was inversely associated with MetS risk. After adjustment for age, sex, body mass index, smoking status, alcohol drinking status, physical activity and education level, the odds ratios (ORs) for MetS across increasing quartiles of plasma DHPPA concentrations were 1 (referent), 0.86 (0.58-1.26), 0.77 (0.52-1.15), and 0.59 (0.39-0.89), respectively. In addition, the cubic spline analysis revealed a potential nonlinear association between plasma DHPPA and MetS, with a steep reduction in the risk at the lower range of plasma DHPPA concentration. CONCLUSION: Our study revealed that individuals with higher DHPPA concentrations in plasma had lower odds of MetS compared to those with lower DHPPA concentrations in plasma. Our findings provided further evidence to support health benefits of whole grain consumption.

Association of plasma ß-amyloid 40 and 42 concentration with type 2 diabetes among Chinese adults.

AIMS/HYPOTHESIS: There is evidence for a bidirectional association between type 2 diabetes and Alzheimer's disease. Plasma ß-amyloid (Aß) is a potential biomarker for Alzheimer's disease. We aimed to investigate the association of plasma Aß40 and Aß42 with risk of type 2 diabetes. METHODS: We performed a case-control study and a nested case-control study within a prospective cohort study. In the case-control study, we included 1063 newly diagnosed individuals with type 2 diabetes and 1063 control participants matched by age (±3 years) and sex. In the nested case-control study, we included 121 individuals with incident type 2 diabetes and 242 matched control individuals. Plasma Aß40 and Aß42 concentrations were simultaneously measured with electrochemiluminescence immunoassay. Conditional logistic regression was used to evaluate the association of plasma Aß40 and Aß42 concentrations with the likelihood of type 2 diabetes. RESULTS: In the case-control study, the multivariable-adjusted ORs for type 2 diabetes, comparing the highest with the lowest quartile of plasma Aß concentrations, were 1.97 (95% CI 1.46, 2.66) for plasma Aß40 and 2.01 (95% CI 1.50, 2.69) for plasma Aß42. Each 30 ng/l increment of plasma Aß40 was associated with 28% (95% CI 15%, 43%) higher odds of type 2 diabetes, and each 5 ng/l increment of plasma Aß42 was associated with 37% (95% CI 21%, 55%) higher odds of type 2 diabetes. Individuals in the highest tertile for both plasma Aß40 and Aß42 concentrations had 2.96-fold greater odds of type 2 diabetes compared with those in the lowest tertile for both plasma Aß40 and Aß42 concentrations. In the nested case-control study, the multivariable-adjusted ORs for type 2 diabetes for the highest vs the lowest quartile were 3.79 (95% CI 1.81, 7.94) for plasma Aß40 and 2.88 (95% CI 1.44, 5.75) for plasma Aß42. The multivariable-adjusted ORs for type 2 diabetes associated with each 30 ng/l increment in plasma Aß40 and each 5 ng/l increment in plasma Aß42 were 1.44 (95% CI 1.18, 1.74) and 1.47 (95% CI 1.15, 1.88), respectively. CONCLUSIONS/INTERPRETATION: Our findings suggest positive associations of plasma Aß40 and Aß42 concentration with risk of type 2 diabetes. Further studies are warranted to elucidate the underlying mechanisms and explore the potential roles of plasma Aß in linking type 2 diabetes and Alzheimer's disease.

Inverse association of plasma vanadium levels with newly diagnosed type 2 diabetes in a Chinese population.

Vanadium compounds have been proposed to have beneficial effects on the pathogenesis and complications of type 2 diabetes. Our objective was to evaluate the association between plasma vanadium levels and type 2 diabetes. We performed a case-control study involving 1,598 Chinese subjects with or without newly diagnosed type 2 diabetes (December 2004-December 2007). Cases and controls were frequency-matched by age and sex. Plasma vanadium concentrations were measured and compared between groups. Analyses showed that plasma vanadium concentrations were significantly lower in cases with newly diagnosed type 2 diabetes than in controls (P = 0.001). Mean plasma vanadium levels in participants with and without diabetes were 1.0 µg/L and 1.2 µg/L, respectively. Participants in the highest quartile of plasma vanadium concentration had a notably lower risk of newly diagnosed type 2 diabetes (odds ratio = 0.26, 95% confidence interval: 0.19, 0.35; P < 0.001), compared with persons in the lowest quartile. The trend remained significant after adjustment for known risk factors and in further stratification analyses. Our results suggested that plasma vanadium concentrations were inversely associated with newly diagnosed type 2 diabetes in this Chinese population.

Association of heme oxygenase-1 with the risk of polycystic ovary syndrome in non-obese women.

STUDY QUESTION: Is circulating heme oxygenase-1 (HO-1) associated with the risk of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Lower circulating HO-1 is associated with a higher risk of PCOS in non-obese women, in a dose-related manner. WHAT IS KNOWN ALREADY: PCOS is one of the most common endocrine disorders in women of reproductive age, with increasing worldwide incidence. HO-1 plays a crucial role in many physiological systems, with potent anti-inflammatory, antioxidant and antimetabolic properties. STUDY DESIGN, SIZE, DURATION: This hospital-based case-control study included 80 women with PCOS and 80 healthy control women seen at the Reproductive Center of Tongji Hospital (Wuhan, China) from November 2011 to May 2012. Cases and controls were frequency-matched on age and BMI and were enrolled into the study once written informed consent had been obtained. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum hormones, glucose, insulin and lipid concentrations were measured using an automated platform. Correlation coefficients and multiple linear regression models were calculated in the combined group (both cases and controls) using serum HO-1 concentration as the independent variable and age and BMI as covariate variables to explore the association between HO-1 and the pathophysiology of PCOS. To examine the independent association of serum HO-1 levels with the likelihood of PCOS, multivariate logistic analysis was used. The strength of the association was tested further by receiver-operating characteristic (ROC) curve models, with or without the addition of HO-1. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with controls, women with PCOS were found to have significantly increased insulin resistance (IR), oxidative stress (OS) and inflammation levels, creating a vicious circle of effects in the pathophysiology of PCOS. However, serum HO-1 was negatively associated with this vicious circle. Women with the highest tertile of HO-1 (≥5.29 ng/ml) had an odds ratio (OR) of PCOS of 0.02 (95% CI 0.0034-0.07) compared with women with the lowest quartile (<3.14 ng/ml) (P < 0.01). This trend remained after adjustment for potential confounders in the multivariable model (all P < 0.01). ROC analysis based on an existing prognostic model yielded significantly discriminative values for PCOS, with or without the addition of HO-1 (areas under the curves were 0.86 (95% CI 0.81-0.92) versus 0.95 (95% CI 0.92-0.98); P for difference = 0.0005). LIMITATIONS, REASONS FOR CAUTION: It is difficult to establish a time-integrated measure of circulating HO-1 during the progression of PCOS and these findings should be confirmed in large-scale studies involving different ethnic groups. Moreover, the study lacks measurements of glycated hemoglobin (HbA1c) to provide an index of blood glucose concentrations over time. WIDER IMPLICATIONS OF THE FINDINGS: Circulating HO-1 that provides protection against IR, OS and chronic inflammation is markedly reduced in non-obese women with PCOS. Low serum HO-1 is suggested as an independent risk factor for PCOS; thus, circulating HO-1 levels may be a novel biomarker for PCOS in young, non-obese women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Natural Science Foundation of China (81202210) and the National Science and Technology Support Program of China (2012BAI02B02). None of the authors has any conflict of interest to declare.

Plasma niacin is inversely associated with hyperlipidemia in participants with diabetes among Chinese adults.

Evidence is limited regarding the association of plasma niacin with the risk of hyperlipidemia in participants with diabetes. We aimed to determine the relationship between plasma niacinamide/nicotinic acid and hyperlipidemia in participants with/without diabetes. Plasma niacinamide/nicotinic acid concentrations were measured using high-performance liquid chromatography-tandem mass spectroscopy. Multivariable logistic regression analyses were performed to evaluate the association between plasma niacin and hyperlipidemia in participants with diabetes and nondiabetes in a cross-sectional study. Compared to the first quartile, plasma nicotinamide, nicotinic acid, and niacin (nicotinamide plus nicotinic acid) were associated with a 54%, 50%, and 52% lower risk of hyperlipidemia in diabetic participants, respectively, but no significant association was observed in nondiabetic participants. These inverse associations persisted across subgroups stratified by sex, age, body mass index, smoking status, alcohol consumption, and physical activity. In addition, the fully adjusted odds ratios (95% confidence intervals) for hypercholesterolemia and hypertriglyceridemia among diabetic participants were 0.54 (0.38, 0.77) and 0.61 (0.44, 0.85), respectively, when comparing to the first quartile of plasma niacin concentrations (all Ptrend < .001). This study of 2647 participants observed that plasma niacin was inversely associated with hyperlipidemia in those with diabetes.

Competing endogenous RNA networks were associated with fat accumulation in skeletal muscle of aged male mice.

Muscle aging contributed to morbidity and mortality in the elderly adults by leading to severe outcomes such as frailty, falls and fractures. Post-transcriptional regulation especially competing endogenous RNA (ceRNA) mechanism may modulate the process of skeletal muscle aging. RNA-seq was performed in quadriceps of 6-month-old (adult) and 22-month-old (aged) male mice to identify differentially expressed ncRNAs and mRNAs and further construct ceRNA networks. Decreased quadriceps-body weight ratio and muscle fiber cross-sectional area as well as histological characteristics of aging were observed in the aged mice. Besides, there were higher expressions of atrogin-1 and MuRF-1 and lower expression of Myog, Myf4 and Myod1 in the quadriceps of aged mice relative to that of adult mice. The expression of 85 lncRNAs, 52 circRNAs, 10 miRNAs and 277 mRNAs were significantly dysregulated in quadriceps between the two groups, among which two ceRNA networks lncRNA 2700081O15Rik/circRNA_0000820-miR-673-3p-Tmem120b were constructed. Level of triglycerides and expression of PPARγ, C/EBPα, FASN and leptin were elevated and the expression of adiponectin was reduced in quadriceps of aged mice compared with that of adult mice. LncRNA 2700081O15Rik/circRNA_0000820-miR-673-3p-Tmem120b were possibly associated with the adipogenesis and fat accumulation in skeletal muscle of age male mice.

RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumour immunity.

Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.

Physical Frailty, Genetic Predisposition, and Incident Parkinson Disease.

Importance: Cross-sectional evidence implicates high prevalent frailty in patients with Parkinson disease (PD), whereas the longitudinal association remains unknown. Objectives: To examine the longitudinal association of the frailty phenotype with the development of PD and to explore the modification role of genetic risk of PD in such an association. Design, Setting, and Participants: This prospective cohort study launched in 2006 to 2010 with a follow-up of 12 years. Data were analyzed from March 2022 to December 2022. The UK Biobank recruited over 500 000 middle-aged and older adults from 22 assessment centers across the United Kingdom. Participants who were younger than 40 years (n = 101), diagnosed with dementia or PD at baseline, and developed dementia, PD, or died within 2 years from baseline were excluded (n = 4050). Participants who had no genetic data or mismatch between genetic sex and reported gender (n = 15 350), were not of self-reported British White descent (n = 27 850), and had no data for frailty assessment (n = 100 450) or any covariates were also excluded (n = 39 706). The final analysis included 314 998 participants. Exposures: The physical frailty was assessed by the Fried criteria's frailty phenotype through 5 domains, ie, weight loss, exhaustion, low physical activity, slow walking speed, and low grip strength. The polygenic risk score (PRS) for PD comprised 44 single-nucleotide variants. Main Outcomes and Measures: New-onset PD was identified through the hospital admission electronic health records and death register. Results: Among 314 998 participants (mean age, 56.1 years; 49.1% male), 1916 new-onset PD cases were documented. Compared with nonfrailty, the hazard ratio (HR) of incident PD in prefrailty and frailty was 1.26 (95% CI, 1.15-1.39) and 1.87 (95% CI, 1.53-2.28), respectively, and the absolute rate difference per 100 000 person-years was 1.6 (95% CI, 1.0-2.3) for prefrailty and 5.1 (95% CI, 2.9-7.3) for frailty. Exhaustion (HR, 1.41; 95% CI, 1.22-1.62), slow gait speed (HR, 1.32; 95% CI, 1.13-1.54), low grip strength (HR, 1.27; 95% CI, 1.13-1.43), and low physical activity (HR, 1.12; 95% CI, 1.00-1.25) were associated with incident PD. A significant interaction between frailty and PRS on PD was found and the highest hazard was observed in participants with frailty and high genetic risk. Conclusions and Relevance: Physical prefrailty and frailty were associated with incident PD independent of sociodemographic factors, lifestyles, multiple morbidities, and genetic background. These findings may have implications for the assessment and management of frailty for PD prevention.

Spheroid on-demand printing and drug screening of endothelialized hepatocellular carcinoma model at different stages.

Hepatocellular carcinoma (HCC) poses a significant threat to human health and medical care. Its dynamic microenvironment and stages of development will influence the treatment strategies in clinics. Reconstructing tumor-microvascular interactions in different stages of the microenvironment is an urgent need forin vitrotumor pathology research and drug screening. However, the absence of tumor aggregates with paracancerous microvascular and staged tumor-endothelium interactions leads to bias in the antitumor drug responses. Herein, a spheroid-on-demand manipulation strategy was developed to construct staged endothelialized HCC models for drug screening. Pre-assembled HepG2 spheroids were directly printed by alternating viscous and inertial force jetting with high cell viability and integrity. A semi-open microfluidic chip was also designed to form a microvascular connections with high density, narrow diameter, and curved morphologies. According to the single or multiple lesions in stages Ⅰ or Ⅰ HCC, endothelialized HCC models from micrometer to millimeter scale with dense tumor cell aggregation and paracancerous endothelial distribution were successively constructed. A migrating stage Ⅰ HCC model was further constructed under TGF-ßtreatment, where the spheroids exhibited a more mesenchymal phenotype with a loose cell connection and spheroid dispersion. Finally, the stage ⅠHCC model showed stronger drug resistance compared to the stage Ⅰ model, while the stage III showed a more rapid response. The corresponding work provides a widely applicable method for the reproduction of tumor-microvascular interactions at different stages and holds great promise for the study of tumor migration, tumor-stromal cell interactions, and the development of anti-tumor therapeutic strategies.

Association of fat-soluble vitamins (A, D, and E) status with humoral immune response to COVID-19 inactivated vaccination.

Background: Fat-soluble vitamins (A, D, and E) are essential for the proper functioning of the immune system and are of central importance for infection risk in humans. Vitamins A, D, and E have been reported to be associated with the immune response following vaccination; however, their effects on the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination remain unknown. Methods: We measured the neutralizing antibody titers against wild type and omicron within 98 days after the third homologous boosting shot of inactivated SARS-CoV-2 vaccine (BBIBP-CorV or CoronaVac) in 141 healthy adults in a prospective, open-label study. High-performance liquid chromatography-tandem mass spectroscopy was used to determine the concentrations of plasma vitamins A, D, and E. Results: We found that the anti-wide-type virus and anti-omicron variant antibody levels significantly increased compared with baseline antibody levels (P < 0.001) after the third vaccination. 25(OH)D3 was significantly negatively associated with the baseline anti-wide-type virus antibody concentrations [beta (95% CI) = -0.331 (-0.659 ~ -0.003)] after adjusting for covariates. A potentially similar association was also observed on day 98 after the third vaccination [beta (95% CI) = -0.317 (-0.641 ~ 0.007)]. After adjusting for covariates, we also found that 25(OH)D3 was significantly negatively associated with the seropositivity of the anti-omicron variant antibody at day 98 after the third vaccination [OR (95% CI) = 0.940 (0.883 ~ 0.996)]. The association between plasma 25(OH)D3 with anti-wild-type virus antibody levels and seropositivity of anti-omicron variant antibodies were persistent in subgroup analyses. We observed no association between retinol/α-tocopherol and anti-wide-type virus antibody levels or anti-omicron variant antibody seropositive in our study. Conclusion: The third inactivated SARS-CoV-2 vaccination significantly improved the ability of anti-SARS-CoV-2 infection in the human body. Higher vitamin D concentrations could significantly decrease the anti-wide-type virus-neutralizing antibody titers and anti-omicron variant antibody seropositive rate after the inactivated SARS-CoV-2 vaccination in people with adequate levels of vitamin D, better immune status, and stronger immune response; further studies comprising large cohorts of patients with different nutritional status are warranted to verify our results.

Association of selenium profile with neutralizing antibody response to inactivated SARS-CoV-2 vaccination.

BACKGROUND: Selenium profile has been related with humoral immune response after vaccination, but evidence with regard to inactivated SARS-CoV-2 vaccine is lacking. OBJECTIVE: The current study aimed to examine the relationship between selenium profile and neutralizing antibody response to inactivated SARS-CoV-2 vaccine. METHODS: Plasma selenium and selenoprotein P concentrations, neutralizing antibody against the wild-type and Omicron variant were measured at baseline and at 14 days, 98 days after the third dose of inactivated SARS-CoV-2 vaccine. RESULTS: Neutralizing antibody against the wild-type and Omicron variant increased significantly after the third vaccination dose. Both higher plasma selenium and selenoprotein P were associated with increased neutralizing antibody against the wild-type strain at baseline. Moreover, higher plasma selenoprotein P was associated with increased neutralizing antibody against Omicron variant at baseline. However, nonsignificant association were observed after the third vaccine dose. CONCLUSION: Higher selenium profile was associated with neutralizing antibody response before the third dose of inactivated SARS-CoV-2 vaccine, but not after the third dose. Further prospective cohort studies are warranted to confirm our findings.

Association of urinary phthalate metabolites with all-cause and cardiovascular disease mortality among adults with diabetes mellitus: National Health and Nutrition Examination Survey 2005-2014.

Background: The study regarding phthalate metabolites and mortality among diabetes mellitus (DM) is limited. We aimed to examine the association of urinary phthalate metabolites with all-cause and cardiovascular disease (CVD) mortality among adults with DM. Methods: This study included 8,931 adults from the National Health and Nutrition Examination Survey (NHANES) from 2005-2006 to 2013-2014. Mortality data were linked to National Death Index public access files through December 31, 2015. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidences (CIs) for mortality. Results: We identified 1,603 adults with DM [mean ± SE age, 47.08 ± 0.30 years; 50.5% (833) were men]. Mono-(carboxynonyl) phthalate (MCNP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), and the sum of Di (2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHP) were positively associated with DM (MCNP: OR = 1.53, 95%CI = 1.16-2.01; MECPP: OR = 1.17, 95% CI = 1.03-1.32; ∑DEHP: OR = 1.14, 95% CI = 1.00-1.29). Among DM patients, mono-(3-carboxypropyl) phthalate (MCPP) was associated with a 34% (HR 1.34, 95% CI 1.12-1.61) increased risk of all-cause mortality while the HRs (95%CI) of CVD mortality were 2.02 (1.13-3.64) for MCPP, 2.17 (1.26-3.75) for mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), 2.47 (1.43-4.28) for mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), 2.65 (1.51-4.63) for MECPP, and 2.56 (1.46-4.46) for ∑DEHP, respectively. Conclusion: This study is an academic exploration of the association between urinary phthalate metabolites and mortality among adults with DM, suggesting that exposure to phthalates might be associated with an increased risk of all-cause and CVD mortality in DM. These findings suggest that patients with DM should carefully use plastics products.

Plasma Transthyretin Levels and Risk of Type 2 Diabetes Mellitus and Impaired Glucose Regulation in a Chinese Population.

Plasma transthyretin may be engaged in glucose regulation. We aimed to investigate the association between plasma transthyretin levels and the risk of newly diagnosed T2DM and impaired glucose regulation (IGR) in a Chinese population. We conducted a case-control study including 1244 newly diagnosed T2DM patients, 837 newly diagnosed IGR patients, and 1244 individuals with normal glucose tolerance (NGT) matched by sex and age. Multivariate logistic regression analysis was utilized to estimate the independent association of plasma transthyretin concentrations with the risk of T2DM and IGR. Plasma transthyretin concentrations were significantly higher in T2DM and IGR patients compared with control subjects (p < 0.005). After multiple adjustment and comparison with the lowest quartile of plasma transthyretin concentrations, the odds ratios (95% confidence intervals) of T2DM and IGR in the highest quartile were 2.22 (1.66, 2.98) and 2.29 (1.72, 3.05), respectively. Plasma transthyretin concentrations also showed a great performance in predicting the risk of T2DM (AUC: 0.76). Moreover, a potential nonlinear trend was observed. Our results demonstrated that higher plasma transthyretin concentrations, especially more than 290 mg/L, were associated with an increased risk of T2DM and IGR. Further studies are warranted to confirm our findings and elucidate the potential mechanisms.

Associations of Plasma Fatty Acid Patterns During Pregnancy With Gestational Diabetes Mellitus.

Background: Limited studies have explored the difference of fatty acid profile between women with and without gestational diabetes mellitus (GDM), and the results were inconsistent. Individual fatty acids tend to be interrelated because of the shared food sources and metabolic pathways. Thus, whether fatty acid patters during pregnancy were related to GDM odds needs further exploration. Objective: To identify plasma fatty acid patters during pregnancy and their associations with odds of GDM. Methods: A hospital-based case-control study including 217 GDM cases and 217 matched controls was carried out in urban Wuhan, China from August 2012 to April 2015. All the participants were enrolled at the time of GDM screening and provided fasting blood samples with informed consent. We measured plasma concentrations of fatty acids by gas chromatography-mass spectrometry, and derived potential fatty acid patterns (FAPs) through principal components analysis. Conditional logistic regression and restricted cubic spline model were used to evaluate the associations between individual fatty acids or FAPs and odds of GDM. Results: Twenty individual fatty acids with relative concentrations ≥0.05% were included in the analyses. Compared with control group, GDM group had significantly higher concentrations of total fatty acids, 24:1n-9, and relatively lower levels of 14:0, 15:0, 17:0, 18:0, 24:0, 16:1n-7, 20:1n-9,18:3n-6, 20:2n-6, 18:3n-3, 20:3n-3, 22:5n-3. Two novel patterns of fatty acids were identified to be associated with lower odds of GDM: (1) relatively higher odd-chain fatty acids, 14:0, 18:0, 18:3n-3, 20:2n-6, 20:3n-6 and lower 24:1n-9 and 18:2n-6 [adjusted odds ratio (OR) (95% confidence interval) (CI) for quartiles 4 vs. 1: 0.42 (0.23-0.76), P-trend = 0.002], (2) relatively higher n-3 polyunsaturated fatty acids, 24:0, 18:3n-6 and lower 16:0 and 20:4n-6 [adjusted OR (95% CI) for quartiles 4 vs. 1: 0.48 (0.26-0.90), P-trend = 0.018]. Conclusion: Our findings suggested that two novel FAPs were inversely associated with GDM odds. The combination of circulating fatty acids could be a more significant marker of GDM development than individual fatty acids or their subgroups.

Association between plasma uric acid and insulin resistance in type 2 diabetes: A Mendelian randomization analysis.

OBJECTIVE: Circulating uric acid levels were associated with insulin resistance, but the causality is unclear. We aimed to investigate the association between plasma uric acid and insulin resistance in newly diagnosed type 2 diabetes (T2D). METHODS: We enrolled 1,938 patients who underwent a 75-g oral glucose tolerance test. Insulin resistance was estimated based on the homeostatic model assessment index (HOMA2-IR) and the Matsuda index. Uric acid was measured in fasting plasma by uricase-peroxidase method. We genotyped single nucleotide polymorphisms (SNPs) that were recently identified as top hits in genome-wide association studies of uric acid levels. A weighted genetic risk score (wGRS) was calculated based on the associations between selected SNPs and uric acid levels. RESULTS: The adjusted ß coefficients for Ln-transformed Matsuda index and HOMA2-IR per 1 mg/dL uric acid increment were -0.070 (95%CI: -0.089, -0.052) and 0.057 (95%CI: 0.039, 0.075). These associations were more pronounced among women than men. In Mendelian randomization analysis, the wGRS raised uric acid by 0.225 mg/dL (95%CI: 0.138, 0.312) per SD increase of the score. However, no association was observed between the wGRS and insulin resistance indices whether in men or women. CONCLUSIONS: Elevated plasma uric acid was associated with higher risk of insulin resistance, along with observation of gender difference in such association. However, our study does not support a causal role of plasma uric acid on insulin resistance among newly diagnosed T2D patients.

Association of Gut Microbiota-Dependent Metabolite Trimethylamine N-Oxide with First Ischemic Stroke.

AIM: We aimed to investigate the relationship of trimethylamine N-oxide (TMAO) concentrations with ischemic stroke in a large-scale case-control study conducted among the hospital-based general population. METHODS: We recruited 953 case-control sex- and age-matched pairs, and cases were confined to first acute ischemic stroke in this study. Fasting plasma TMAO was measured using high-performance liquid chromatography-tandem mass spectroscopy. Conditional logistic regression analysis was conducted to calculate odds ratios (OR) for the association of plasma TMAO with ischemic stroke. RESULTS: We found that plasma TMAO concentrations in patients with ischemic stroke were significantly higher than that in the control group (median: 2.85 µmol/L vs. 2.33 µmol/L, P＜0.001). In multivariable conditional logistic regression models, higher plasma TMAO concentrations were associated with increased odds of ischemic stroke [fully adjusted OR for highest vs. lowest TMAO quartile: 1.81; 95% confidence interval (CI): 1.27, 2.59; P for trend ＜0.001]. The multivariable-adjusted OR for ischemic stroke per 1 µmol/L increment of plasma TMAO was 1.05 (95% CI: 1.02, 1.08). Additionally, the positive association also persisted in subgroups stratified by age, sex, body mass index, smoking status, alcohol habits, history of diabetes, and history of hypertension. CONCLUSIONS: This study suggested a positive association between plasma TMAO and ischemic stroke. Further studies are required to explore the role of plasma TMAO concentrations in predicting stroke risk.

U-shaped association between plasma cobalt levels and type 2 diabetes.

AIMS: We aimed to investigate the association of plasma cobalt with newly diagnosed type 2 diabetes (T2D) and further explore the potential interaction effects between cobalt and several redox metals, such as manganese, copper and selenium. DESIGN: A large case-control study including 4564 subjects was conducted. 2282 cases with newly diagnosed T2D and 2282 controls were matched by sex and age. The concentrations of cobalt and other metals in plasma were detected with inductively coupled plasma mass spectrometry (ICPMS). RESULTS: The medians of the cobalt concentrations in plasma were 1.68 µg/dL for controls and T2D. There was a U-shaped relation between T2D and plasma cobalt, which was categorized into quartiles. After multivariable adjusted for the confounding factors, the odds ratios (ORs) of T2D across quartiles were 1.22 (95% CI: 1.01, 1.46), 1.12 (95% CI: 0.94, 1.35), 1.00 (reference) and 1.46 (95% CI: 1.22, 1.75), respectively. The association was almost consistent in subgroup analyses. According to the restricted cubic spline analysis, the lowest ORs of T2D was observed at the plasma cobalt of 2.00 µg/dL. There was a significant interaction between plasma cobalt and copper (P < 0.01). The ORs of T2D in those with medium concentration of plasma cobalt and copper was the lowest. CONCLUSIONS: Higher or lower concentrations of plasma cobalt were related to higher ORs of T2D. The inter-relationship among redox metals in T2D should be further investigated.