Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patients.

The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, or in the transcriptionally active form as retinoic acid. The main function of retinol binding protein 4 (RBP4), synthesized in the liver, is to transport hydrophobic vitamin A to various tissues. Vitamin A has an important role in the innate and acquired immune system. In particular, it is involved in the repair of lung tissue after infections. In viral respiratory diseases such as influenza pneumonia, vitamin A supplementation has been shown to reduce mortality in animal models. In critically ill COVID-19 patients, a significant decrease in plasma vitamin A levels and an association with increased mortality have been observed. However, there is no evidence on RBP4 in relation to COVID-19. This prospective, multicenter, observational, cross-sectional study examined RBP4 (enzyme-linked immunosorbent assay) and vitamin A plasma levels (high-performance liquid chromatography) in COVID-19 patients, including 59 hospitalized patients. Of these, 19 developed critical illness (ARDS/ECMO), 20 developed severe illness (oxygenation disorder), and 20 developed moderate illness (no oxygenation disorder). Twenty age-matched convalescent patients following SARS-CoV-2 infection, were used as a control group. Reduced RBP4 plasma levels significantly correlated with impaired liver function and elevated inflammatory markers (CRP, lymphocytopenia). RBP4 levels were decreased in hospitalized patients with critical illness compared to nonpatients (p < 0.01). In comparison, significantly lower vitamin A levels were detected in hospitalized patients regardless of disease severity. Overall, we conclude that RBP4 plasma levels are significantly reduced in critically ill COVID-19 patients during acute inflammation, and vitamin A levels are significantly reduced in patients with moderate/severe/critical illness during the acute phase of illness.

Association between clinicopathological features of breast cancer with adipocytokine levels and oxidative stress markers before and after chemotherapy.

Adipocytokines and markers of oxidative stress have been shown to exhibit potential for detection of advanced stage, HER2/neu status and lymph node metastases in patients with breast cancer, as well as in determining the efficiency of anti-cancer treatments. In the present study, blood concentrations of apelin (APLN), retinol-binding protein 4 (RBP4), 8-hydroxydeoxyguanosine (8-oxo-dG) and total antioxidant capacity (TAC) in women with breast cancer with different clinicopathological features were measured prior to and following adjuvant chemotherapy. The study included 60 women with breast cancer stratified according to tumor grade and size, HER-2/neu expression, and lymph node and hormone receptor status. Blood samples were taken before and after two cycles of adjuvant chemotherapy. None of the clinicopathological features were associated with the baseline concentrations of RBP4, 8-oxo-dG or TAC. An increased baseline concentration of APLN was observed in HER-2/neu positive patients. Moreover, through multivariate logistical regression analysis, APLN was shown to be independently associated with a positive HER/neu status. Chemotherapy treatment did not affect the levels of RBP4 or APLN, or TAC values when assessing all the patients, and when assessing the stratified groups of patients. Only 8-oxo-dG was found to be significantly decreased following drug administration (P=0.0009). This preliminary study demonstrated that APLN is a significant and independent predictor of HER-2/neu positive breast cancer. A significant reduction in 8-oxo-dG levels following chemotherapy may indicate its potential clinical utility in monitoring the effects of chemotherapy in breast cancer patients.

Potassium supplementation blunts the effects of high salt intake on serum retinol-binding protein 4 levels in healthy individuals.

AIMS/INTRODUCTION: Excessive dietary salt or low potassium intakes are strongly correlated with insulin resistance (IR) and type 2 diabetes mellitus. In epidemiological and experimental studies, increased serum retinol-binding protein 4 (RBP4) contributes to the pathogenesis of type 2 diabetes mellitus. Herein, we hypothesized that RBP4 might be an adipocyte-derived "signal" that plays the crucial role in salt-related insulin resistance or type 2 diabetes mellitus. This study aimed to assess whether salt consumption and potassium supplementation influence serum RBP4 levels in healthy individuals. MATERIALS AND METHODS: A total of 42 participants (aged 25-50 years) in a rural area of Northern China were successively provided normal (3 days at baseline), low-salt (7 days; 3 g/day NaCl) and high-salt (7 days; 18 g/day) diets, and a high-salt diet with potassium additive (7 days; 18 g/day NaCl and 4.5 g/day KCl). Urinary sodium and potassium were measured to ensure compliance to dietary intervention. Then, RBP4 levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: High salt intake significantly raised serum RBP4 levels in healthy participants (17.5 ± 0.68 vs 28.6 ± 1.02 µg/mL). This phenomenon was abrogated by potassium supplementation (28.6 ± 1.02 vs 17.6 ± 0.88 µg/mL). In addition, RBP4 levels presented positive (r = 0.528, P < 0.01) and negative (r = -0.506, P < 0.01) associations with 24-h urinary sodium- and potassium excretion levels. CONCLUSIONS: RBP4 synthesis is motivated by high salt intake and revoked by potassium supplementation. Our pioneer work has contributed to the present understanding of salt-induced insulin resistance or type 2 diabetes mellitus.

Clinical study on serum 25-hydroxy vitamin D and retinol binding protein 4 in type 2 diabetic nephropathy / 中华临床营养杂志

Objective:This was a retrospective study to compare the serum 25-hydroxy vitamin D [25(OH)D], retinol binding protein 4(RBP-4) and other clinical data in type 2 diabetes mellitus (T2DM) patients with or without diabetic nephropathy (DN) and to explore the clinical significance of these indicators in DN.Methods:1946 T2DM patients were enrolled in this study. The T2DM patients were divided to group with diabetic nephropathy (DN group) and without diabetic nephropathy (NDN group). According to the urine albumin to creatinine ratio (UACR), DN patients were further divided into microalbuminuria subgroup (UACR 30~300 mg/g) and massive proteinuria subgroup (UACR> /g). Clinical characteristics including serum 25(OH)D, RBP-4 and other biochemical indicators were collected.Results:Compared with NDN group, DN group showed longer disease duration, older age and higher levels of HbA1c, RBP-4, hs-CRP, TC and TG; 25(OH)D and HDL-C in DN group were lower than those in NDN group ( P<0.05). Within DN group, massive proteinuria subgroup showed higher RBP-4, younger age and lower 25(OH)D and HDL-C than microalbuminuria subgroup ( P<0.05). After adjusted for age, gender and disease duration in DN, partial correlation analysis showed that 25(OH)D is positively correlated with eGFR, and negatively correlated with RBP-4 and UACR ( P<0.05). UACR is positively correlated with RBP-4 and TC, and negatively correlated with eGFR (all P<0.05). eGFR is negatively correlated with RBP-4, TC and UACR (all P<0.05). Multivariate logistic regression showed that disease duration, HbA1c, RBP-4 and hs-CRP are risk factors for DN, and 25(OH)D is the protective factor for DN. Conclusions:Decreased 25(OH)D and increased RBP-4 are associated with increased DN risk in T2DM patients, and also associated with exacerbated albuminuria and deteriorated renal function in DN patients. There is a negative correlation between 25(OH)D and RBP-4 in DN. Therefore, it is necessary to strengthen the monitoring of serum 25(OH)D and RBP-4 and enhance vitamin D supplementation in T2DM patients to prevent the occurrence and delay the progression of diabetic nephropathy.

Neutrophil Gelatinase-Associated Lipocalin and Retinol-Binding Protein-4 as Biomarkers for Diabetic Kidney Disease.

AIMS: This study was designed to evaluate the conflicting association between 2 tubular protein markers including neutrophil gelatinase-associated lipocalin (NGAL) and retinol-binding protein-4 (RBP-4) with albuminuria and glomerular filtration rate (GFR) and calculate the accuracy of the role of NGAL and RBP-4 in diagnosis of diabetic nephropathy (DN) in patients with type2 diabetes. METHODS: This is a cross-sectional study that included 133 patients with type 2 diabetes. There were 3 diabetic study groups with normoalbuminuria, moderately increased albuminuria, severely increased albuminuria, and non-diabetic control group without any renal disease. We analyzed the difference of urinary NGAL (uNGAL) and RBP-4 between nondiabetics and diabetics, as well as within the diabetic group. We also assessed the association between albuminuria and NGAL and RBP-4. RESULTS: The urinary levels of NGAL and RBP-4 were higher in patients with type 2 diabetes compared to nondiabetics as well as in albuminuric diabetics compared to nonalbuminuric patients with diabetes (p value <0.001). These 2 proteins were higher in patients with severely increased albuminuria compared to patients with moderately increased albuminuria, even after adjustment for other metabolic factors (all p < 0.01). Moreover, areas under the curve of NGAL and RBP-4 for the diagnosis of chronic kidney disease were 80.6 and 74.6%, respectively. CONCLUSION: uNGAL and RBP-4 are potential markers of tubular damage that may increase before the onset of glomerular markers such as albuminuria and GFR in patients with type 2 diabetes. Therefore, these markers can be used as complementary measurements to albuminuria and GFR in the earlier diagnosis of DN.

Plasma retinol-binding protein-4 and tumor necrosis factor-α are reduced in postmenopausal women after combination of different intensities of circuit resistance training and Zataria supplementation.

PURPOSE: Zataria is a plant with anti-inflammatory properties, which has been used for the treatment of many diseases. This study investigated the effect of different intensities of circuit resistance training and Zataria supplementation on plasma retinol-binding protein-4 (RBP-4) and tumor necrosis factor-α (TNF-α) in postmenopausal women. METHODS: Seventy-two postmenopausal women were divided on randomized order into six groups: Control (McGinley and Bishop in J Appl Physiol 121(6):1290-1305, 2016), Training 35% (T35%), Training 55% (T55%), Zataria (Özgünen et al. in Scand J Med Sci Sports 20:140-147, 2010), Zataria/Training 35% (ZT35%), and Zataria/Training 55% (ZT55%). Resist-ance training program included 12 exercise stations (each: 30 s, intensity: 35% and 55% of 1-RM) for 8 weeks (3 sessions/week). Daily (500 mg) Zataria was used after breakfast by participants in ZG, ZT35%, and ZT55% groups. Blood samples were taken 48 h before and after the first and last sessions of training. RESULTS: After the training period the percentage of body fat decreased significantly (P < 0.001) in all trained groups, whereas muscle mass increased significantly (P < 0.01) only in T55% and ZT55% groups. A significant decrease was observed for RBP-4 values (P < 0.05) after training in all groups except for ZG and CG. Also, RBP-4 was significantly lower (P < 0.05) in all groups as compared to CG at the post-test except for ZG. Moreover, significantly lower values (P < 0.05) were found in T55%, ZT35%, and ZT55% as compared to ZG in post-intervention. TNF-α values decreased significantly (P < 0.05) at the post-test as compared to pre-intervention in ZT35% and ZT55%. Also, TNF-α was significantly lower (P < 0.05) in ZT55% compared to CG and T35% in post-test. CONCLUSIONS: The results demonstrate clearly that in postmenopausal women, circuit resistance training both at low and moderate intensities cause a greater reduction in RBP-4 and TNF-α when Zataria is supplemented in the diet during training.

Ferroportin Expression in Adipocytes Does Not Contribute to Iron Homeostasis or Metabolic Responses to a High Calorie Diet.

BACKGROUND & AIMS: Iron has an increasingly recognized role in the regulation of adipose tissue function, including the expression of adipokines involved in the pathogenesis of nonalcoholic fatty liver disease. The cellular iron exporter, ferroportin, has been proposed as being a key determinant of adipocyte iron homeostasis. METHODS: We studied an adipocyte-specific ferroportin (Fpn1) knockout mouse model, using an Adipoq-Cre recombinase driven Fpn1 deletion and fed mice according to the fast food diet model of nonalcoholic steatohepatitis. RESULTS: We showed successful selective deletion of Fpn1 in adipocytes, but found that this did not lead to increased adipocyte iron stores as measured by atomic absorption spectroscopy or histologically quantified iron granules after staining with 3,3'-diaminobenzidine-enhanced Perls' stain. Mice with adipocyte-specific Fpn1 deletion did not show dysregulation of adiponectin, leptin, resistin, or retinol-binding protein-4 expression. Similarly, adipocyte-specific Fpn1 deletion did not affect insulin sensitivity during hyperinsulinemic-euglycemic clamp studies or lead to histologic evidence of increased liver injury. We have shown, however, that the fast food diet model of nonalcoholic steatohepatitis generates an increase in adipose tissue macrophage infiltration with crown-like structures, as seen in human beings, further validating the utility of this model. CONCLUSIONS: Ferroportin may not be a key determinant of adipocyte iron homeostasis in this knockout model. Further studies are needed to determine the mechanisms of iron metabolism in adipocytes and adipose tissue.

Influence of electroacupuncture intervention in serum RBP4 level in rats with non-alcoholic fatty liver disease and its lipid regulation mechanism / 吉林大学学报(医学版)

Objective To observe the lipid regulation role of electroacupuncture intervention in the rats with non-alcoholic fatty liver disease(NAFLD)induced with high fat and cholesteol forage,and to clarify the regulation mechanism of serum retinol binding protein 4 (RBP4 )level and liver X receptor a (LXR-α)and sterol regulatory element binding protein-1c(SREBP-1c)expressions.Methods 44 female SD rats were fed for 7 d to adapt the environment and were randomly divided into normal group, model group, Dongbaogantai group, electroacupuncture group;11 rats in each group.The rats in normal group got routine feeding,and the others were fed with high fat and high cholesterol forage. After 8 weeks, the models were established, the rats in electroacupuncture group were treated with electroacupuncture method (1.5-2.0 Hz, D.-D.wave, 9V, 1-3 mA)in“Ganshu”,“Pishu”,“Geshu”for 15 min,once a day,lasted for 28 d.The changes of fasting blood-glucose(FBG),serum free fatty acids(FFA)and liver tissue homogenate triglyceride(TG)and total cholesterol (TC)levels of the rats in various groups were tested, and enzyme-linked immunosorbent (ELISA)was used to determine the serum RBP4 levels, and Western blotting method was used to detect the LXR-αand SREBP-1 c protein expression levels in rat liver tissue.Results Compared with normal group,the FBG,serum FFA,TG and TC levels in liver tissue homogenate and serum RBP4 level of the rats in model group were increased (P<0.01);the LXR-αand SREBP-1c protein expression levels were also increased (P<0.01).Compared with model group, the FBG,serum FFA,the TG and TC levels in liver tissue homogenate and serum RBP4 levels of the rats in electroacupuncture group and Dongbaogantai group were decreased (P<0.01);the LXR-αand SREBP-1c protein expression levels were also decreased (P< 0.05 or P< 0.01 ). Conclusion Electroacupuncture method in“Fenglong”,“Zusanli”,“Sanyinjiao”can reduce the serum RBP4 level, regulate the lipid metabolism, and improve the lipid deposition of the NAFLD rats;they have obvious therapeutic effect on NAFLD, and its mechanism may be related to inhibiting the increasing of LXR-αand SREBP-1 c protein expressions in liver tissue.

Recent advances in understanding the anti-diabetic actions of dietary flavonoids.

Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables, and increasing evidence demonstrates a positive relationship between consumption of flavonoid-rich foods and disease prevention. Epidemiological, in vitro and animal studies support the beneficial effects of dietary flavonoids on glucose and lipid homeostasis. It is encouraging that the beneficial effects of some flavonoids are at physiological concentrations and comparable to clinically-used anti-diabetic drugs; however, clinical research in this field and studies on the anti-diabetic effects of flavonoid metabolites are limited. Flavonoids act on various molecular targets and regulate different signaling pathways in pancreatic ß-cells, hepatocytes, adipocytes and skeletal myofibers. Flavonoids may exert beneficial effects in diabetes by (i) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic ß-cells; (ii) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (iii) reducing insulin resistance, inflammation and oxidative stress in muscle and fat and (iv) increasing glucose uptake in skeletal muscle and white adipose tissue. This review highlights recent findings on the anti-diabetic effects of dietary flavonoids, including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones, with particular emphasis on the studies that investigated the cellular and molecular mechanisms involved in the beneficial effects of the compounds.