Association of circulating MR-proADM with all-cause and cardiovascular mortality in the general population: Results from the KORA F4 cohort study

Background and aim Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort. Methods Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8–9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603–1551). Results MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72–3.26) and 2.31 (1.67–3.20)) and cardiovascular mortality (4.28 (2.19–8.39) and 4.44 (2.25–8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality. Conclusions We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.

Urine β2-Microglobulin and Retinol-Binding Protein and Renal Disease Progression in IgA Nephropathy

Background: Tubulointerstitial involvement has been reported to have a decisive influence on the progression of IgA nephropathy (IgAN). High levels of urine β2-microglobulin (β2-MG) and retinol-binding protein (RBP) were observed in patients with IgAN with tubulointerstitial lesions. However, their roles in disease progression remain unclear. This study aimed to evaluate the associations of urine β2-MG and RBP with the progression of IgAN.Methods: We retrospectively investigated a cohort of 2,153 patients with IgAN. Clinical and pathological features, outcomes, and urine β2-MG, and RBP at the time of biopsy were collected. The associations, of urine β2-MG and RBP with the composite renal outcome, defined as a decline in estimated glomerular filtration rate (eGFR) of ≥50% from baseline or end-stage renal disease (ESRD), were examined using restricted cubic splines and the Cox proportional hazards models.Results: During a median follow-up of 20.40 months, 140 (6.50%) patients reached the composite renal outcomes. Restricted cubic splines showed that patients with higher urinary β2-MG and RBP levels had worse renal outcomes. The Cox regression analysis revealed that urine β2-MG and RBP were associated with a risk of the composite renal outcome in the multivariate adjusted model [+1 SD for log β2-MG, hazard ratio (HR) = 1.462, 95% CI: 1.136–1.882, p = 0.003; +1 SD for log RBP, HR = 1.972, 95% CI: 1.486–2.617, p = 0.001]. The associations were detectable within patients with baseline eGFR <90 ml/min/1.73 m2 (+1 SD for log β2-MG, HR = 1.657, 95% CI: 1.260–2.180, p < 0.001; +1 SD for log RBP, HR = 1.618, 95% CI: 1.199–2.183, p = 0.002), but not among patients with eGFR ≥90 ml/min/1.73 m2.Conclusion: Higher levels of urine β2-MG and RBP were independent risk factors for renal disease progression in IgAN.

Renoprotective Effects of Metformin and Its Relationship with Oxidative Stress in Type 2 Diabetic Mice

Background: Oxidative stress has previously been shown to play critical roles in the development of diabetes and its complications. The purpose of this research was to observe the reno-protective effect of metformin and its effect on oxidative stress in type 2 diabetic mice renal tissue.Methods: Type 2 diabetes mellitus mice model was established by High-fat feed combined with small-dose STZ and randomly divided into diabetes model group, Metformin [MET, 250mg/(kg.d)] group, Glibenclamide (GLIB) [GLIB, 2.5mg/(kg.d)] group, and normal control group (NC). After 8 weeks of intervention, blood and urine samples were collected for detection of FBG, HbA1c, urine albumin (Alb), retinol-binding protein (RBP), podocalyxin (PCX), 8-OHdG, 8-iso-PG, and creatinine (Cr). Renal tissue specimens were preserved for observing renal glomerular basement membrane thickness (GBMT) and foot process fusion rate (FPFR) under electron microscopy.Results: Compared with the NC group, FBG, HbA1c, urinary Alb/Cr (UACR), RBP/Cr (URCR), PCX/Cr (UPCR), 8-OHdG /Cr (UOHCR), and 8-iso-PG /Cr (UISOCR) significantly increased in the T2DM group (P <0.05). Compared with the T2DM group, FBG, HbA1c, UACR, URCR, UPCR, UOHCR, and UISOCR were significantly reduced in the GLIB group and MET group (P <0.05). Compared to the GLIB group, UACR, URCR, UPCR, UOHCR, and UISOCR decreased in the MET group (P <0.05), but FBG and HbA1c were not differenced statistically between the two groups. GBMT and FPFR increased in the T2DM group (P <0.05), which were reduced in the MET group and lighter than those in the GLIB group (P <0.05).Conclusion: Metformin intervention can play a reno-protective effect in type 2 diabetic mice, which may be related to its effect in inhibiting enhanced oxidative stress in vivo.

Association Between Retinol-binding Protein and Sarcopenia in General Inpatient Older Adults: a Cross Sectional Study

Objective: This study aims to evaluate the relationship between serum retinol binding protein levels and sarcopenia in elderly general hospitalized patients. Methods: This cross-sectional study included 682 elderly patients with Barthel-index ≥100 on admission. Sarcopenia was defined according to the recently updated Asian Sarcopenia Working Group 2019 criteria. The skeletal muscle mass index was measured by dual-energy X-ray absorptiometry. Serum prealbumin, albumin, hemoglobin, blood creatinine, alanine aminotransferase, aspartate aminotransferase, and retinol binding protein are also detected. Multivariate logistic regression analysis was used to evaluate the association between serum RBP levels and sarcopenia, and to adjust for potential confounding factors.Results:There are 105 cases of sarcopenia, 56 males and 49 females. The total prevalence of sarcopenia is 15.40% in general inpatients, of which 16.47% are males and 14.33% are females.For men and women, it was observed that the serum retinol binding protein in sarcopenia patients was significantly lower than that without sarcopenia (24.43±8.12 vs 29.98±9.91, P<0.001) and(23.27±5.13 vs 28.35±6.63, P < 0.001),The fully adjusted model showed that male and female low retinol binding protein participants had a 2.341(1.176,4.660) and 2.911(1.324-6.400) times higher risk of sarcopenia than normal retinol binding protein respectively.Conclusion: Low levels of retinol binding protein are associated with an increased risk of sarcopenia in elderly general hospitalized patients.

Methylation-Mediated Silencing of RBP7 Promotes Breast Cancer Progression Through PPAR and PI3K/AKT Pathway

Purpose Retinoid-binding protein (RBP7) is a member of the cellular retinol-binding protein (CRBP) family, which is involved in the pathogenesis of breast cancer (BRCA). The study aims to illustrate the prognostic value and the potential regulatory mechanisms of RBP7 expression in BRCA. Methods We utilized a series of bioinformatics tools, including HPA, GEPIA, UALCAN, ONCOMINE, Kaplan–Meier plotter, PROGeneV2, TISCH, LinkedOmics, UCSC Xena, MethSurv, SMART APP, bc-GenExMiner4.7, OSbrca, STRING, CARE, SwissDock and R software packages, to investigate the expression, prognostic value and functional regulatory networks of RBP7 in BRCA. Results Bioinformatics analysis with the TCGA and CPTAC databases revealed that the mRNA and protein expression levels of RBP7 in normal were higher compared to BRCA tissues. Survival analysis displayed that the lower expression of RBP7, the worse the prognosis in ER-positive (ER+) BRCA patients. Genomic analysis showed that promoter methylation result in transcriptional silencing of RBP7 in BRCA. Functional enrichment analysis demonstrated that downregulation of RBP7 expression may exert its biological influence on BRCA through the PPAR pathway and the PI3K/AKT pathway. Conclusions In summary, we identified RBP7 as a novel biomarker that is helpful for the prognosis of ER+ BRCA patients. Promoter methylation of RBP7 is involved in its gene silencing in BRCA, thus regulating the occurrence and development of ER+ BRCA through the PPAR and PI3K/AKT pathways.

Plasma Retinol Binding Protein 4 as a Biomarker for Detecting Progressive Stroke and Prediction of Early Prognosis in Patients with Acute Ischemic Stroke

Aim and purpose: Progressive stroke (PS) lacks effective treatment measures and leads to serious disability or death. Retinol binding protein 4 (RBP4) could be closely associated with acute ischemic stroke(AIS). We aimed to explore plasma RBP4 as a biomarker for detecting the progression in patients with AIS. Methods: Participants of this retrospective study were 234 patients with AIS within the 48 h onset of disease. The primary endpoint was to ascertain if there was PS through the National Institute of Health stroke scale (NIHSS), early prognosis was confirmed through the modified Rankin scale score (mRS) at discharge or 14 days after the onset of stroke, and determine the significance of demographic characteristics and clinical data . Results: In this study, 43 of 234 patients demonstrated PS. . The level of plasma RBP4 in patients with progressive stroke was significantly lower (29 mg/L, 22.60－40.38 mg/L) than that without progression (38.70 mg/L, 27.28－46.40 mg/L, P = 0.003). In patients with lower plasma RBP4, he proportion of patients with progression (c2 = 9.63, P = 0.008) and with mRS scores ≥2 (c2 = 6.73, P = 0.035) were significantly higher Multivariate logistic regression analysis showed that a lower RBP4 level on admission was an independent risk factor for progressive stroke during hospitalization with an OR value of 2.70 (P = 0.03, 95% CI: 1.12－6.52). Conclusion: A low plasma RBP4 level on admission could be an independent risk factor of PS during hospitalization.

Cellular retinol binding protein-1 inhibits cancer stemness via upregulating WIF1 to suppress Wnt/β-catenin pathway in hepatocellular carcinoma

Background CRBP-1, a cytosolic chaperone of vitamin A, is identified in a serious number of cancers; however, its biological role in hepatocellular carcinoma (HCC) needs to be further explored. The aim of our present study is to explore the roles and mechanisms of CRBP-1 in regulating liver cancer by using in vitro and in vivo biology approaches. Methods The expression level of CRBP-1 was detected using immunohistochemistry in HCC and matching adjacent non-tumorous liver tissues. Following established stable CRBP-1 overexpressed HCC cell lines, the cell growth and tumorigenicity were investigated both in vitro and in vivo. Intracellular retinoic acid was quantified by ELISA. The relationship between CRBP-1 and WIF1 was validated by using dual luciferase and ChIP analyses. Results The low expression of CRBP-1 was observed in HCC tissues compared to the normal liver tissues, while high CRBP-1 expression correlated with clinicopathological characteristics and increased overall survival in HCC patients. Overexpression of CRBP-1 significantly inhibited cell growth and tumorigenicity both in vitro and in vivo. Moreover, overexpression of CRBP-1 suppressed tumorsphere formation and cancer stemness related genes expression in HCC. Mechanically, CRBP-1 inhibited Wnt/β-catenin signaling pathway to suppress cancer cell stemness of HCC. Furthermore, our results revealed that CRBP-1 could increase the intracellular levels of retinoic acid, which induced the activation of RARs/RXRs leading to the transcriptional expression of WIF1, a secreted antagonist of the Wnt/β-catenin signaling pathway, by physically interacting with the region on WIF1 promoter. Conclusion Our findings reveal that CRBP-1 is a crucial player in the initiation and progression of HCC, which provide a novel independent prognostic biomarker and therapeutic target for the diagnosis and treatment of HCC.

Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye

Vitamins are essential compounds obtained through diet that are necessary for normal development and function in an organism. One of the most important vitamins for human physiology is vitamin A, a group of retinoid compounds and carotenoids, which generally function as a mediator for cell growth, differentiation, immunity, and embryonic development, as well as serving as a key component in the phototransduction cycle in the vertebrate retina. For humans, vitamin A is obtained through the diet, where provitamin A carotenoids such as β-carotene from plants or preformed vitamin A such as retinyl esters from animal sources are absorbed into the body via the small intestine and converted into all-trans retinol within the intestinal enterocytes. Specifically, once absorbed, carotenoids are cleaved by carotenoid cleavage oxygenases (CCOs), such as Beta-carotene 15,15’-monooxygenase (BCO1), to produce all-trans retinal that subsequently gets converted into all-trans retinol. CRBP2 bound retinol is then converted into retinyl esters (REs) by the enzyme lecithin retinol acyltransferase (LRAT) in the endoplasmic reticulum, which is then packaged into chylomicrons and sent into the bloodstream for storage in hepatic stellate cells in the liver or for functional use in peripheral tissues such as the retina. All-trans retinol also travels through the bloodstream bound to retinol binding protein 4 (RBP4), where it enters cells with the assistance of the transmembrane transporters, stimulated by retinoic acid 6 (STRA6) in peripheral tissues or retinol binding protein 4 receptor 2 (RBPR2) in systemic tissues (e.g., in the retina and the liver, respectively). Much is known about the intake, metabolism, storage, and function of vitamin A compounds, especially with regard to its impact on eye development and visual function in the retinoid cycle. However, there is much to learn about the role of vitamin A as a transcription factor in development and cell growth, as well as how peripheral cells signal hepatocytes to secrete all-trans retinol into the blood for peripheral cell use. This article aims to review literature regarding the major known pathways of vitamin A intake from dietary sources into hepatocytes, vitamin A excretion by hepatocytes, as well as vitamin A usage within the retinoid cycle in the RPE and retina to provide insight on future directions of novel membrane transporters for vitamin A in retinal cell physiology and visual function.