Structure-Activity Relationship and Substrate-Dependent Phenomena in Effects of Ginsenosides on Activities of Drug-Metabolizing P450 Enzymes

Ginseng, a traditional herbal medicine, may interact with several co-administered drugs in clinical settings, and ginsenosides, the major active components of ginseng, may be responsible for these ginseng-drug interactions (GDIs). Results from previous studies on ginsenosides' effects on human drug-metabolizing P450 enzymes are inconsistent and confusing. Herein, we first evaluated the inhibitory effects of fifteen ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by using commercially available fluorescent probes. The structure-activity relationship of their effects on the P450s was also explored and a pharmacophore model was established for CYP3A4. Moreover, substrate-dependent phenomena were found in ginsenosides' effects on CYP3A4 when another fluorescent probe was used, and were further confirmed in tests with conventional drug probes and human liver microsomes. These substrate-dependent effects of the ginsenosides may provide an explanation for the inconsistent results obtained in previous GDI reports

Genetic Variants on Chromosome 8q24 and Colorectal Neoplasia Risk: A Case-Control Study in China and a Meta-Analysis of the Published Literature

Previous studies have found that common genetic variants on chromosome 8q24 are associated with the risk of developing colorectal neoplasia. We conducted a hospital-based case-control study, including 435 cases and 788 unrelated controls to investigate the associations between common variants on 8q24 and the risk of colorectal cancer in a Chinese population. We also evaluated the association of rs6983267 with colorectal neoplasia in the published literature via a meta-analysis study. We found that rs6983267 was significantly associated with the risk of colorectal cancer in the Chinese population, with an adjusted odds-ratio (OR) for the GT heterozygotes and GG homozygotes of 1.30 (95% CI  = 0.98–1.71, P = 0.069) and 1.66 (95% CI  = 1.18–2.34, P = 0.004), respectively, compared to the TT homozygotes, with a P-trend value of 0.003. No association was found for the other three loci (rs16901979, rs1447295 and rs7837688). In the meta-analysis of the published genetic association studies, the rs6983267 variant was found to be associated with an increased risk of colorectal neoplasia. The heterozygous GT carriers showed a 20% increased risk of colorectal neoplasia (OR  = 1.20, 95% CI  = 1.16–1.25; random effects model) with a summary OR for homozygous GG carriers of 1.39 (95% CI  = 1.32–1.48; random effects model) compared to the TT genotype carriers. We found no significant differences between the association of rs6983267 and colorectal cancer and colorectal adenomas. In summary, our study confirms that the variant rs6983267 is a risk factor for colorectal neoplasia in various populations, including the Chinese population

Characterization of gene expression profiles in HBV-related liver fibrosis patients and identification of ITGBL1 as a key regulator of fibrogenesis

Although hepatitis B virus (HBV) infection is the leading cause of liver fibrosis (LF), the mechanisms underlying liver fibrotic progression remain unclear. Here, we investigated the gene expression profiles of HBV-related LF patients. Whole genome expression arrays were used to detect gene expression in liver biopsy samples from chronically HBV infected patients. Through integrative data analysis, we identified several pathways and key genes involved in the initiation and exacerbation of liver fibrosis. Weight gene co-expression analysis revealed that integrin subunit β-like 1 (ITGBL1) was a key regulator of fibrogenesis. Functional experiments demonstrated that ITGBL1 was an upstream regulator of LF via interactions with transforming growth factor β1. In summary, we investigated the gene expression profiles of HBV-related LF patients and identified a key regulator ITGBL1. Our findings provide a foundation for future studies of gene functions and promote the development of novel antifibrotic therapies

Patient-derived rectal cancer organoids—applications in basic and translational cancer research

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and among the leading causes of death in both men and women. Rectal cancer (RC) is particularly challenging compared with colon cancer as the treatment after diagnosis of RC is more complex on account of its narrow anatomical location in the pelvis adjacent to the urogenital organs. More and more existing studies have begun to refine the research on RC and colon cancer separately. Early diagnosis and multiple treatment strategies optimize outcomes for individual patients. However, the need for more accurate and precise models to facilitate RC research is underscored due to the heterogeneity of clinical response and morbidity interrelated with radical surgery. Organoids generated from biopsies of patients have developed as powerful models to recapitulate many aspects of their primary tissue, consisting of 3-D self-organizing structures, which shed great light on the applications in both biomedical and clinical research. As the preclinical research models for RC are usually confused with colon cancer, research on patient-derived RC organoid models enable personalized analysis of cancer pathobiology, organizational function, and tumor initiation and progression. In this review, we discuss the various applications of patient-derived RC organoids over the past two years in basic cancer biology and clinical translation, including sequencing analysis, drug screening, precision therapy practice, tumor microenvironment studies, and genetic engineering opportunities

Effects of obesity with reduced 25(OH)D levels on bone health in elderly Chinese people: a nationwide cross-sectional study

BackgroundObesity is often accompanied by lower 25(OH)D levels, whereas these two parameters exhibit opposite effects on bone health. It is uncertain what are the effects of lower 25(OH)D levels in obesity on bone health in elderly Chinese people.MethodsA nationally representative cross-sectional analysis of China Community-based Cohort of Osteoporosis (CCCO) was performed from 2016 to 2021, which consisted of 22,081 participants. Demographic data, disease history, Body mass index (BMI), bone mineral density (BMD), the levels of the biomarkers of vitamin D status and those of bone metabolism markers were measured for all participants (N = 22,081). The genes (rs12785878, rs10741657, rs4588, rs7041, rs2282679 and rs6013897) related to 25(OH)D transportation and metabolism were performed in a selected subgroup (N = 6008).ResultsObese subjects exhibited lower 25(OH)D levels (p < 0.05) and higher BMD (p < 0.001) compared with those of normal subjects following adjustment. The genotypes and allele frequency of rs12785878, rs10741657, rs6013897, rs2282679, rs4588 and rs7041 indicated no significant differences among three BMI groups following correction by the Bonferroni’s method (p > 0.05). The levels of total 25(OH)D (ToVD) were significantly different among the GC1F, GC1S and GC2 haplotype groups (p < 0.05). Correlation analysis indicated that ToVD levels were significantly correlated with parathyroid hormone levels, BMD, risk of osteoporosis (OP) and the concentration levels of other bone metabolism markers (p < 0.05). Generalized varying coefficient models demonstrated that the increasing BMI, ToVD levels and their interactions were positively associated with BMD outcomes (p < 0.001), whereas the reduced levels of ToVD and BMI increased the risk of OP, which was noted notably for the subjects with reduced ToVD levels (less than 20.69 ng/ml) combined with decreased BMI (less than 24.05 kg/m2).ConclusionThere was a non-linear interaction of BMI and 25(OH)D. And higher BMI accompanied by decreased 25(OH)D levels is associated with increased BMD and decreased incidence of OP, optimal ranges exist for BMI and 25(OH)D levels. The cutoff value of BMI at approximately 24.05 kg/m2 combined with an approximate value of 25(OH)D at 20.69 ng/ml are beneficial for Chinese elderly subjects

Major depression disorder may causally associate with the increased breast cancer risk: Evidence from two‐sample mendelian randomization analyses

Abstract Introduction Major depression disorder (MDD) has been associated with increased breast cancer risk in epidemiological studies; however, it is still unknown whether this association is causal or not. The aim of this study is to determine the causal relationship between MDD and breast cancer risk. Methods Two‐sample Mendelian randomization (MR) analyses with 92 single‐nucleotide polymorphisms (SNPs) significantly associated with MDD as instrumental variables (IVs) were performed. Effects of these SNPs on breast cancer in women were estimated in the Breast Cancer Association Consortium (122,977 cases and 105,974 controls) using inverse variance weighted (IVW), weighted median and multivariable MR models. Heterogeneity and pleiotropy effects were assessed based on IVW and MR‐Egger regression model, respectively. Results An 8.7% increased risk of overall breast cancer [odds ratio (OR) = 1.087; 95% confidence interval (CI) 1.011–1.170; P = 0.025] per log‐odds ratio increment of MDD risk based on the IVW model was noticed. Similar results were obtained with the multivariable MR model (OR = 1.118, 95% CI = 1.010–1.237; P = 0.031). An increment but not statistically significant causality association was noticed between MDD and risk of ER+ (OR = 1.098, 95% CI = 0.984–1.227; P = 0.093) or ER‐ (OR = 1.129, 95% CI = 0.982–1.297; P = 0.089) breast cancer under multivariable MR model. No significant pleiotropy effects were observed for the IVs in the two‐sample MR studies. Conclusions The results suggested that a genetic predisposition of MDD is causally associated with overall breast cancer risk; however, the underlying biological mechanisms are worthy of further study

Serum Glycocholic Acid-to-Total Bile Acid Ratio Is Independently Associated with Nonalcoholic Fatty Liver Disease: A Retrospective Cross-Sectional Study

Introduction and Aims. Bile acids play an essential role in the progression of nonalcoholic fatty liver disease (NAFLD). This study was aimed at investigating the association of the serum glycocholic acid- (GCA-) to-total bile acid (TBA) ratio with NAFLD in the general population. Materials and Methods. A total of 6708 subjects (2859 cases with NAFLD and 3849 controls) were enrolled in the development cohort and additional 1568 subjects (784 cases with NAFLD and 784 controls) in an independent validation cohort. Demographic characteristics and biochemical data were compared between subjects with NAFLD and controls. Multivariate logistic regression analysis was performed to determine the association of the GCA-to-TBA ratio with NAFLD. A novel model incorporating the GCA-to-TBA ratio was developed for screening NAFLD from the general population. Results. The serum TBA and GCA levels were significantly higher in subjects with NAFLD than in those without NAFLD (2.8 (2.0-4.2) μmol/L vs. 2.5 (1.8-3.7) μmol/L and 1.30 (1.10-1.53) μg/mL vs. 1.28 (1.08-1.50) μg/mL, respectively, all p≤0.01), whereas the serum GCA-to-TBA ratio was significantly lower in subjects with NAFLD than in subjects without NAFLD (0.44 (0.33-0.60) vs. 0.48 (0.36-0.64), p≤0.01). Logistic regression analysis showed that the GCA-to-TBA ratio was independently associated with NAFLD after adjustment for confounding factors (odds ratio: 0.81, 95% confidence interval (CI): 0.71-0.92, p≤0.01). The area under the receiver operating characteristic curve of the novel developed GCA-to-TBA ratio score model in discriminating NAFLD was 0.84 (95% CI: 0.83-0.85) in the development cohort and was 0.91 (95% CI: 0.36-0.65) in the validation cohort. Conclusion. The serum GCA-to-TBA ratio is independently associated with NAFLD. A simple novel model incorporating the GCA-to-TBA ratio score has a good performance in discriminating NAFLD from the general population

MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin

The long non-coding RNA maternally expressed gene 3 (MEG3) is frequently dysregulated in human cancers; however, its roles in colorectal cancer (CRC) development are largely unknown. Here, we reported that MEG3 was down-regulated in CRC tissues and CRC patients with lower MEG3 showed poorer overall survival and disease-free survival than those with higher MEG3 level. MEG3 over-expression represses CRC cells proliferation and migration in vivo and in vitro, while MEG3 knockdown leads to the enhanced proliferation and metastasis of CRC cells. In CRC cells, MEG3 over-expression is related to decreased Clusterin mRNA and the corresponding protein levels, and it also directly binds to Clusterin protein through its 732–1174 region. In further, Clusterin over-expression rescues the compromised abilities of proliferation and metastasis induced by MEG3 over-expression, suggesting that MEG3 inhibits the CRC progression through regulating the Clusterin activities. Additionally, we found that 1α,25-(OH)2D and vitamin D receptor (VDR) stimulate MEG3 expression in CRC cells through directly binding to its promoter. These results suggested that MEG3 functions as a tumor suppressor in CRC via regulating the Clusterin activities and may underlie the anticancer activities of vitamin D on CRC cells. The VDR/MEG3/Clusterin signaling pathway may serve as potential therapeutic targets and prognosis biomarkers for CRC patients in future. Keywords: lncRNA, CRC, MEG3, Clusterin, Vitamin

Bioavailable 25(OH)D but Not Total 25(OH)D Is an Independent Determinant for Bone Mineral Density in Chinese Postmenopausal Women

Total 25(OH)D levels were determined to assess bone health in elderly populations; however, the bioavailability of 25(OH)D is regulated by the albumin and vitamin D binding protein (DBP) levels and DBP variations. Whether bioavailable 25(OH)D level is a superior biomarker for vitamin D than total 25(OH)D level regarding the BMD and the bone metabolism were not yet fully understood. With a community based cross-sectional study of 967 postmenopausal women, we found that the variant rs7041, but not rs4588, of DBP was significantly associated with the blood DBP level, which was positively correlated with the total 25(OH)D level but negatively associated with bioavailable 25(OH)D levels. Both total and bioavailable 25(OH)D levels were significantly correlated with the BMD value in postmenopausal women; however, only the bioavailable 25(OH)D level was an independent determinant of the BMD values when adjusted for age, body mass index and bone turnover biomarkers (OST and β-CTX). The bioavailable and total 25(OH)D were negatively correlated with bone formation biomarkers (OST, PINP and ALP) and PTH levels, while they were positively correlated with osteoprotegerin (OPG) level; however, the bone resorption biomarker (β-CTX) was not correlated with the 25(OH)D levels. An increment of PTH level, along with reduced bioavailable 25(OH)D levels, was evident when the bioavailable 25(OH)D level was <5 ng/mL, which may be the optimal cutpoint for sufficient vitamin D in Chinese elderly women. The blood calcium, magnesium, ALP, TSH, FGF23, and phosphorus levels were not correlated with the total or the bioavailable 25(OH)D levels. These results suggested that high bioavailable 25(OH)D levels were correlated with reduced bone turnover processes and were a biomarker superior to total 25(OH)D for vitamin D in assessing the risks of bone-related diseases. The results indicate that the bioavailable 25(OH)D level should be determined in assessing the bone health