Integrating Mendelian randomization and single-cell RNA sequencing to identify therapeutic targets of baicalin for type 2 diabetes mellitus.

Background: Alternative and complementary therapies play an imperative role in the clinical management of Type 2 diabetes mellitus (T2DM), and exploring and utilizing natural products from a genetic perspective may yield novel insights into the mechanisms and interventions of the disorder. Methods: To identify the therapeutic target of baicalin for T2DM, we conducted a Mendelian randomization study. Druggable targets of baicalin were obtained by integrating multiple databases, and target-associated cis-expression quantitative trait loci (cis-eQTL) originated from the eQTLGen consortium. Summary statistics for T2DM were derived from two independent genome-wide association studies available through the DIAGRAM Consortium (74,124 cases vs. 824,006 controls) and the FinnGen R9 repository (9,978 cases vs. 12,348 controls). Network construction and enrichment analysis were applied to the therapeutic targets of baicalin. Colocalization analysis was utilized to assess the potential for the therapeutic targets and T2DM to share causative genetic variations. Molecular docking was performed to validate the potency of baicalin. Single-cell RNA sequencing was employed to seek evidence of therapeutic targets' involvement in islet function. Results: Eight baicalin-related targets proved to be significant in the discovery and validation cohorts. Genetic evidence indicated the expression of ANPEP, BECN1, HNF1A, and ST6GAL1 increased the risk of T2DM, and the expression of PGF, RXRA, SREBF1, and USP7 decreased the risk of T2DM. In particular, SREBF1 has significant interaction properties with other therapeutic targets and is supported by strong colocalization. Baicalin had favorable combination activity with eight therapeutic targets. The expression patterns of the therapeutic targets were characterized in cellular clusters of pancreatic tissues that exhibited a pseudo-temporal dependence on islet cell formation and development. Conclusion: This study identified eight potential targets of baicalin for treating T2DM from a genetic perspective, contributing an innovative analytical framework for the development of natural products. We have offered fresh insights into the connections between therapeutic targets and islet cells. Further, fundamental experiments and clinical research are warranted to delve deeper into the molecular mechanisms of T2DM.

Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study.

Background: Increasing evidence indicates that immune response underlies the pathology of type 2 diabetes (T2D). Nevertheless, the specific inflammatory regulators involved in this pathogenesis remain unclear. Methods: We systematically explored circulating inflammatory proteins that are causally associated with T2D via a bidirectional Mendelian randomization (MR) study and further investigated them in prevalent complications of T2D. Genetic instruments for 91 circulating inflammatory proteins were derived from a genome-wide association study (GWAS) that enrolled 14,824 predominantly European participants. Regarding the summary-level GWASs of type 2 diabetes, we adopted the largest meta-analysis of European population (74,124 cases vs. 824,006 controls) and a prospective nested case-cohort study in Europe (9,978 cases vs. 12,348 controls). Summary statistics for five complications of T2D were acquired from the FinnGen R9 repository. The inverse variance-weighted method was applied as the primary method for causal inference. MR-Egger, weighted median and maximum likelihood methods were employed as supplementary analyses. Results from the two T2D studies were combined in a meta-analysis. Sensitivity analyses and phenotype-wide association studies (PheWAS) were performed to detect heterogeneity and potential horizontal pleiotropy in the study. Results: Genetic evidence indicated that elevated levels of TGF-α (OR = 1.16, 95% CI = 1.15-1.17) and CX3CL1 (OR = 1.30, 95% CI = 1.04-1.63) promoted the occurrence of T2D, and increased concentrations of FGF-21 (OR = 0.87, 95% CI = 0.81-0.93) and hGDNF (OR = 0.96, 95% CI = 0.95-0.98) mitigated the risk of developing T2D, while type 2 diabetes did not exert a significant influence on said proteins. Elevated levels of TGF-α were associated with an increased risk of ketoacidosis, neurological complications, and ocular complications in patients with T2D, and increased concentrations of FGF-21 were potentially correlated with a diminished risk of T2D with neurological complications. Higher levels of hGDNF were associated with an increased risk of T2D with peripheral vascular complications, while CX3CL1 did not demonstrate a significant association with T2D complications. Sensitivity analyses and PheWAS further ensure the robustness of our findings. Conclusion: This study determined four circulating inflammatory proteins that affected the occurrence of T2D, providing opportunities for the early prevention and innovative therapy of type 2 diabetes and its complications.

The correlation of two bone turnover markers with bone mineral density: a population-based cross-sectional study.

OBJECTIVE: Exploring the correlation between bone turnover marks (BTMs) with lumbar BMD in middle-aged populations. METHODS: The cross-sectional analysis fetched data came from NHANES. The level of serum bone alkaline phosphatase (sBAP) and urinary N-telopeptide (uNTx) were regarded as representative of bone turnover. Lumbar BMD was the outcome of the study. Multivariable linear regression models were utilized to detect the correlation of sBAP and uNTx with Lumbar BMD. RESULTS: The level of sBAP and uNTx was negatively correlated with lumbar BMD in every multivariable linear regression. For sBAP, this inverse correlation was stable in both men and women (P < 0.01). uNTx indicated a negative association after all relevant covariables were adjusted (P < 0.01). The men group remained the negative correlation in gender subgroup analysis (P < 0.01). CONCLUSION: This study indicated that the increased level of sBAP and uNTx associated with lumbar BMD decreased among middle-aged adults. This correlation could prompt researchers to explore further the relationship between bone turnover rate and BMD, which may provide information for the early detection of BMD loss and provide a new strategy for clinical practice.

Association between fatty acids intake and bone mineral density in adults aged 20-59: NHANES 2011-2018.

Background: Previous studies have investigated the link between fatty acid intake and bone mineral density (BMD), but the results are controversial. This study aims to examine the relationship between fatty acid intake and BMD in adults aged 20-59. Methods: The association between fatty acid consumption and BMD was analyzed using a weighted multiple linear regression model with National Health and Nutrition Examination Survey data from 2011 to 2018. The linearity relationship and saturation value of the connection between fatty acid consumption and BMD were assessed by fitting a smooth curve and a saturation effect analysis model. Results: The study included 8,942 subjects. We found a significant positive correlation between the consumption of saturated fatty acids, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids and BMD. In subgroup analyses that were stratified by gender and race, this association was still shown to be significant. Based on the smooth curve and saturation effect analysis, we found no saturation effect for the three fatty acids and total BMD. However, there was a turning point (20.52 g/d) between MUFAs intake and BMD, and only MUFAs intake >20.52 g/d showed a positive correlation between MUFAs and BMD. Conclusion: We found that fatty acid intake is beneficial for bone density in adults. Therefore, according to our findings, it is recommended that adults consume moderate amounts of fatty acids to ensure adequate bone mass but not metabolic diseases.

Development and validation of a diabetic retinopathy risk prediction model for middle-aged patients with type 2 diabetes mellitus.

Objectives: The study aims to establish a predictive nomogram of diabetic retinopathy(DR) for the middle-aged population with type 2 diabetes mellitus (T2DM). Methods: This retrospective study screened 931 patients with T2DM between 30 and 59 years of age from the 2011-2018 National Health and Nutrition Examination Survey database. The development group comprised 704 participants from the 2011-2016 survey, and the validation group included 227 participants from the 2017-2018 survey. The least absolute shrinkage and selection operator regression model was used to determine the best predictive variables. The logistic regression analysis built three models: the full model, the multiple fractional polynomial (MFP) model, and the stepwise (stepAIC) selected model. Then we decided optimal model based on the receiver operating characteristic curve (ROC). ROC, calibration curve, Hosmer-Lemeshow test, and decision curve analysis (DCA) were used to validate and assess the model. An online dynamic nomogram prediction tool was also constructed. Results: The MFP model was selected to be the final model, including gender, the use of insulin, duration of diabetes, urinary albumin-to-creatinine ratio, and serum phosphorus. The AUC was 0.709 in the development set and 0.704 in the validation set. According to the ROC, calibration curves, and Hosmer-Lemeshow test, the nomogram demonstrated good coherence. The nomogram was clinically helpful, according to DCA. Conclusion: This study established and validated a predictive model for DR in the mid-life T2DM population, which can assist clinicians quickly determining who is prone to develop DR.

The correlation between high-density lipoprotein cholesterol and bone mineral density in adolescents: a cross-sectional study.

Recent studies have shown a correlation between high-density lipoprotein cholesterol (HDL-C) and bone mineral density (BMD) in adults, but their relationship is unclear in adolescents. This study aimed to explore whether a correlation existed between them among adolescents aged 12-19. Data analyzed in our study was fetched from the National Health and Nutrition Examination Survey (NHANES) database 2011-2018. The relationship between HDL-C level and total BMD value was analyzed by multivariate logistic regression models, fitted smoothing curves, and generalized additive models. 3770 participants participated in this analysis. After adjusting for all relevant covariates involved in this study, we found a negative correlation between HDL-C levels and total bone density in male adolescents.Furthermore, the stratified analysis showed that all covariables-adjusted models retained the negative correlation excepting female, black, or Mexican American subgroups. An inverted U-shaped curve represented the correlation of HDL-C and total BMD among adolescents aged 16 to 19, and the turning point was 1.06 mmol/L. After adjusting for all relevant covariates involved in this study, the study found a negative correlation between HDL-C levels and total BMD in male adolescents aged 12 to 19, particularly among those of races other than Black and Mexican. There was a saturation effect between HDL-C level and total BMD in 16-19-year-old adolescents. The turning point was 1.06 mmol/L. Therefore, HDL-C might be a biomarker to detect bone health and further perform a more detailed examination.

Association between urinary nickel with obesity status in adults: A cross-sectional study.

Objectives: The prevalence of obesity is on the rise and is connected to numerous factors. However, the relationship between obesity and nickel has never been investigated. Our study aimed to explore the association between urinary nickel and obesity Status in adults. Methods: From the 2017-2018 National Health and Nutrition Examination Surveys (NHANES), 1,705 participants ≥18 years of age were enrolled. To explore further the relationship among urinary nickel, body mass index (BMI), and waist circumference(WC), Weighted multivariate linear regression analyses and further subgroup analyzes were conducted. Results: Urinary nickel does not correlate with BMI level but positively correlates with WC. In the subgroup analyzed according to sex, Urinary nickel has a positive correlation with BMI and WC in males but has a negative correlation in females. Secondary stratification analysis according to sex and race, Urinary nickel positively correlates with BMI in White males. It also positively correlates with WC in both White and Black males. Conclusions: A correlation was found between urinary nickel levels and BMI and WC in adult males. Adult men, especially those already obese, may need to reduce nickel exposure.

Association between caffeine intake and lumbar spine bone mineral density in adults aged 20-49: A cross-sectional study.

Background: Many epidemiological studies have investigated the connection between coffee intake and bone mineral density (BMD), but the results are controversial. This study aimed to assess the association between caffeine consumption and lumbar BMD in adults aged 20-49. Methods: From a cross-sectional study based on a large sample of the National Health and Nutrition Examination Survey 2011-2018. After controlling for confounders, the weighted multivariate linear regression model was created and stratified by age, gender, and race for subgroup analysis. In addition, we simultaneously stratified analysis by age and sex and divided caffeine intake into quartiles to assess the association between coffee intake and BMD. Results: Caffeine intake was not significantly linked with lumbar BMD in this study of 7041 adults. In subgroup studies stratified by age, there was a significant correlation between lumbar BMD and caffeine consumption in participants aged 30-39 and 40-49. In females, there was a positive correlation between lumbar BMD and coffee consumption stratified by gender. When evaluated by race, the association between lumbar BMD and caffeine intake was independent of race. Consequently, when stratifying for age, sex, and coffee intake quartiles, a significant positive correlation was discovered between the fourth coffee intake quartile and lumbar BMD in females aged 30-39. In addition, a negative correlation was discovered between coffee consumption and lumbar BMD in males aged 40-49. Conclusions: Our research indicates that drinking coffee may benefit 30-39 women's lumbar BMD, but it may adversely affect men aged 40-49.

Identification and validation of immune and prognosis-related genes in hepatocellular carcinoma: A review.

PURPOSE: Bioinformatics methods were used to identify the key genes associated with the immune microenvironment of hepatocellular carcinoma (HCC) to construct an immune risk prognostic model (IRPM) and to study the correlation between IRPM's risk groups and immune characteristics of patients with HCC. METHODS: HCC transcriptome sequencing information was searched for immune-related genes (IRGs) that were regularly expressed in cancer tissues. The IRGs, which were strongly linked to overall survival were screened; the prognostic characteristics model was constructed using Cox regression analysis. IRPM's independent prognostic value was explored; Kaplan-Meier survival and receiver-operating characteristic curves were used to determine the model prediction ability in the led-to queue. RESULTS: Patients in the high-risk group (HRG) showed significantly poor outcomes. Gene Set Enrichment Analysis revealed factors involved in both the HRG and low risk group. Immune-related hub genes (IRHGs) and drug sensitivity expression levels revealed that all IRHGs were correlated with drug sensitivity for certain chemotherapy drugs. CONCLUSION: The study results may serve as a reference for improving prognosis, early screening, and immunotherapy in patients with HCC.

Effect of obesity status on adolescent bone mineral density and saturation effect: A cross-sectional study.

Background: The effect of obesity status on bone mineral density (BMD) in adolescents and whether there is a saturation effect is still insufficient. A cross-sectional study of adolescents aged 12-19 was conducted to investigate them. Methods: Weighted multivariate linear regression models were used to assess the relationship between obesity status and BMD via datasets from the National Health and Nutrition Examination Survey 2011-2018. The nonlinear relationships and saturation values were ascertained by fitting smooth curves and analyzing saturation effects. At the same time, the subgroup stratified analysis was also performed. Results: 4056 adolescents were included in this study. We found that body mass index (BMI) and waist circumference (WC) were significantly associated with total BMD, which remained significant in subgroups stratified by age, gender, standing height, and ethnicity. We also noticed an inverse correlation between left leg fat/lean mass and left leg BMD, which was only significant in males and other races. Fitting smooth curve and saturation effect analysis showed that BMI, WC, left leg fat/lean mass, and BMD had a specific saturation effect. There was a saturation effect on bone mineral density in adolescents with a BMI of 22 kg/m2, a WC of 70.5 cm, or a left leg fat/lean mass of 0.2994. Conclusions: We found a positive saturation effect of BMI and WC with BMD and a negative saturation effect of left leg fat/lean mass with BMD. Appropriate obesity status allows adolescents to have better bone mass development but not excessive obesity.

The correlation between serum albumin and diabetic retinopathy among people with type 2 diabetes mellitus: NHANES 2011-2020.

OBJECTIVES: The objective of this research aimed to investigate the correlation involving serum albumin with diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). METHODS: From 2011 to 2020, the National Health and Nutrition Examination Survey (NHANES) surveyed 45462 participants. We used the relevant data to conduct descriptive statistics, linear regression, and Logistic regression analysis. RESULTS: After adjusting for age, sex, and race, as well as all other variables, serum albumin was significantly negatively related to DR (P<0.001). Furthermore, after controlling for confounding factors, the third quartile (Q3) and the fourth quartile (Q4) had quite a negative significant relationship with the incidence of DR (P<0.01). The second quartile had a significant positive correlation with DR, whereas the observed negative correlations were not statistically meaningful (P>0.05). CONCLUSION: Albumin levels in the serum have a quantitatively significant negative correlation with DR. Serum albumin levels in the blood can be used as a reference point for protracted follow-up of people with T2DM.

The scope and limitations of 1,3-stannyl shift-promoted intramolecular cyclizations of alpha-stannyl radicals with a formyl group.

Alpha-tributylstannyl radicals can be generated from the corresponding bromides or xanthates. These radicals undergo efficient intramolecular 1,5-cyclizations with a formyl group. The resulting beta-stannyl alkoxy radicals proceed through a 1,3-stannyl shift from carbon to oxygen to afford beta-stannyloxy radicals. This novel rearrangement is most likely irreversible and serves as a driving force to promote the cyclizations. Although the cyclization rates can be accelerated when the formyl group carries alpha-dimethyl substituents, unfortunately beta-scission of the alkoxy radicals becomes competitive with the 1,3-stannyl shift. The beta-stannyloxy radicals can be employed in further cyclizations to obtain tandem cyclization products.