Levels of vitamin a and cellular retinol binding protein in human hepatocellular carcinoma and adjacent normal tissue

The levels of vitamin A (retinol) and vitamin E were measured in the blood, in tissues of human hepatocellular carcinoma (HCC), and in adjacent liver parenchyma. The median values of vitamin A were 11.5 μg/g (ranging 0–82.5 μg/g) in HCC and 52.1 μg/g (ranging 0.4–895.2 μg/g) in normal liver tissues; the difference was statistically significant (p < 0.05). By contrast, there was no significant difference in vitamin E levels between the two tissues. Although the levels of vitamin A were significantly lower in HCC in 10 patients, no significant difference was noted in the cellular retinol binding protein levels in the normal and malignant tissues. These results suggest that the decreased levels of vitamin A in HCC are not due to altered cellular retinol binding protein levels in tumors end the different vitamin A blood supply system. We conclude that either the decreased uptake of vitamin A, but not vitamin E, by HCC cells or the lack of vitamin A‐storing cells in tumors might be responsible for the low levels of vitamin A in HCC.     

Presence of cellular retinol and retinoic acid binding proteins in human uterus.

Human uterine cells contain two separate soluble proteins, one binding retinol and one binding retinoic acid with high specifity. This suggests that both retinol and retinoic acid may be required for normal uterine function.     

Effect of vitamin A status at the end of term pregnancy on the saturation of retinol binding protein with retinol

BACKGROUND: Vitamin A (retinol), which is required for normal fetal development and successful gestation, circulates in the blood bound to a specific protein, the retinol binding protein (RBP). Little is known about the transport and metabolism of this complex protein or about retinol status during normal human pregnancy. OBJECTIVE: The aim of this study was to assess retinol status and transport modalities of retinol in well-nourished women with normal pregnancies, a population poorly investigated compared with pathologic and malnourished pregnant women. DESIGN: The maternal blood and cord blood concentrations of retinol, vitamin E, beta-carotene, RBP, and transthyretin of pregnant French women at term (n = 27) were measured and compared with values from a nonpregnant control group (n = 27). In addition, holo-RBP (retinol bound), apo-RBP (retinol free), and total protein were assessed in both groups to enable the hemodilution occurring during pregnancy to be taken into consideration and to evaluate the extent of saturation of RBP with retinol. RESULTS: Healthy pregnant women at term had normal serum circulatory amounts of retinol, vitamin E, binding proteins, and beta-carotene. However, they had less binding of retinol to RBP (holo-RBP: 49.9% in pregnant women, 54.0% in cord blood, and 77.5% in the control group). CONCLUSION: The results of this study suggest that retinol homeostasis and transport are modified during normal human pregnancy.     

Selective removal of retinoids and palmitic acid from microsomes by fatty acid binding protein and cellular retinol binding protein

Studies were conducted to explore the effect of mouse liver cytosolic proteins enriched in fatty acid binding protein or cellular retinol binding protein on the removal of palmitic acid and retinoids from microsomal membranes. When the soluble proteins were incubated with mouse liver microsomes containing (14C)palmitic acid or (3H)retinoids, it was observed that fatty acid binding protein removed selectively the fatty acid and retinyl ester, whereas the retinol was mainly removed by cellular retinol binding protein.     

Vitamin A, vitamin E, retinol binding protein (RBP), and prealbumin in digestive cancers

The existence of a relation between vitamin A and vitamin E and human cancers is supported by epidemiologic investigations. The aim of this study is to link the level of these vitamins to those of plasmatic protein carriers like retinol binding protein (RBP) and prealbumin (TTR), in three groups of subjects: healthy patients (n = 78), polyp (n = 34) and digestive cancer patients (n = 70). A paired t-test did not reveal any significant variation in any parameter between the polyp group and controls, but did evidence a significant decrease in serum levels of retinol (p less than 2.10(-4], RBP (p less than 2.10(-4), TTR (p less than 10(-5), and alpha-tocopherol (p less than 2.10(-3), in cancer cases as against control subjects. Comparison of RBP renal clearance and retinol tissue clearance in cancer and healthy patients indicates that the decrease in circulating retinol levels cannot be attributed to an increase in peripheral consumption. The simultaneous reduction of RBP and TTR serum levels is to be considered as a sign of protein denutrition. Thus our results suggest that the decrease serum levels of vitamins A and E observed in digestive cancers are a consequence of this nutritional deficiency.     

人体肝癌和正常肝脏细胞内硒与氧化应激机制的初步探讨

目的　探讨微量元素硒和氧化应激水平在肝癌发展中的作用。方法　采集了数例肝癌晚期切除样品及其癌旁正常组织 ,测定了正常肝脏组织和癌组织不同细胞器中硒的含量以及超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GSH -Px)、硫氧还蛋白还原酶 (TrxR)活性及谷胱甘肽 (GSH)和蛋白总巯基的含量。结果　Se在肝癌溶酶体 (P <0 0 5 )、微粒体 (P <0 0 5 )、细胞质中的含量高于正常肝组织 ,几种抗氧化酶酶的活性和巯基含量均高于正常肝。癌细胞中的Se含量要明显高于相应的癌旁周围正常肝细胞 ,尤其是细胞核、线粒体和细胞质。癌细胞线粒体、细胞质中几种抗氧化酶的活性以及巯基含量均高于相应的癌旁正常肝细胞。结论　癌细胞代谢旺盛 ,摄取更多的营养物质 ,从而造成周围正常细胞营养素的缺乏 ,抗氧化能力的下降 ,其机制还有待进一步研究     

Biochemical but not clinical vitamin A deficiency results from mutations in the gene for retinol binding protein

BACKGROUND: Two German sisters aged 14 and 17 y were admitted to the Tübingen eye hospital with a history of night blindness. In both siblings, plasma retinol binding protein (RBP) concentrations were below the limit of detection (<0.6 micromol/L) and plasma retinol concentrations were extremely low (0.19 micromol/L). Interestingly, intestinal absorption of retinyl esters was normal. In addition, other factors associated with low retinol concentrations (eg, low plasma transthyretin or zinc concentrations or mutations in the transthyretin gene) were not present. Neither sibling had a history of systemic disease. OBJECTIVE: Our aim was to investigate the cause of the retinol deficiency in these 2 siblings. DESIGN: The 2 siblings and their mother were examined clinically, including administration of the relative-dose-response test, DNA sequencing of the RBP gene, and routine laboratory testing. RESULTS: Genomic DNA sequence analysis revealed 2 point mutations in the RBP gene: a T-to-A substitution at nucleotide 1282 of exon 3 and a G-to-A substitution at nucleotide 1549 of exon 4. These mutations resulted in amino acid substitutions of asparagine for isoleucine at position 41 (Ile41-->Asn) and of aspartate for glycine at position 74 (Gly74-->Asp). Sequence analysis of cloned polymerase chain reaction products spanning exons 3 and 4 showed that these mutations were localized on different alleles. The genetic defect induced severe biochemical vitamin A deficiency but only mild clinical symptoms (night blindness and a modest retinal dystrophy without effects on growth). CONCLUSIONS: We conclude that the cellular supply of vitamin A to target tissues might be bypassed in these siblings via circulating retinyl esters, beta-carotene, or retinoic acid, thereby maintaining the health of peripheral tissues.     

Serum levels of vitamin A and retinol binding protein in chronic renal patients treated by continuous ambulatorial peritoneal dialysis.

The possible causes and consequences of hypervitaminosis A and retinol binding protein (RBP) levels were investigated in patients with chronic renal disease submitted or not to dialysis treatment. The study was conducted on 20 patients divided into two groups: 10 patients with chronic renal failure (CRF) treated by continuous ambulatorial peritoneal dialysis (CAPD), and 10 CRF patients with no dialysis treatment. Ten normal subjects formed the control group. Retinol levels were determined by HPLC, and RBP levels by immunoassay in plasma and in post-dialysis fluid at different periods of time. Laboratory tests were carried out on all subjects, and dietary history was taken. Patients on dialysis had higher retinol levels than untreated patients. Retinol levels were found to be correlated with RBP levels. Serum retinol and RBP levels did not vary with diet, age or time of disease, dialysis group or time of dialysis, nor were they correlated with the levels measured in the dialysis fluid (CAPD). There was no significant correlation in retinol levels between chronic patients and controls. It is suggested that vitamin A and RBP clearances during dialysis do not accompany urea or creatinine clearance. Hypervitaminosis A did not show any toxic effect.     

Vitamin A, retinol binding protein and lipids in type 1 diabetes mellitus

OBJECTIVE: A case-control study was conducted to evaluate the effects of type 1 diabetes mellitus (IDDM) on plasma levels of vitamin A (retinol) and serum levels of retinol-binding protein (RBP) and their relationship with the atherogenic indicators. SUBJECTS: A total of 47 randomised IDDM children were recruited from those treated at the Endocrinology Unit of the University Hospital of Granada (Spain). They were matched for age and sex with 16 healthy children. METHODS: The following parameters were measured in all patients: serum concentrations of total cholesterol, triglycerides, high (HDL, spectrophotometry), very low (VLDL) and low (LDL) density lipoprotein cholesterol (Friedewald's formula); serum levels of RBP (kinetic nephelometry); plasma vitamin A and glycosilated haemoglobin (HbA1c; high performance chromatography). RESULTS: Higher RBP concentrations in IDDM children (P=0.05), lower retinol levels (P=0.05) and lower vitamin A/cholesterol ratio (P=0.02) than in the control group were found; no differences in the atherogenic indicators were observed. There was a correlation between RBP and vitamin A (P=0.0001). Relationships between retinol, RBP and atherogenic indicators were demonstrated in the IDDM group (A-LDLc/HDLc (P=0.01); A-(VLDL+LDL)c/HDLc (P=0.007); RBP-LDLc/HDLc (P=0.05); RBP-(VLDL+LDL)c/HDLc (P=0.02)), and an inverse relationship was found between the vitamin A/TG ratio and HbA1c (P=0.004). The children with HbA1c>8% showed increased atherogenic indicators and lower vitamin A/CHOL and vitamin A/TG ratios than those with good control of the illness. CONCLUSIONS: The IDDM children with poor metabolic control face a higher atherogenic risk and vitamin A 'relative deficiency' risk than those with good metabolic control of their illness. Relationships between retinol and RBP with atherogenic indicators were found. The results suggest that vitamin A therapeutic supplements in IDDM children may reduce or prevent atherogenic risk.     

Anticonvulsant medication use and circulating levels of total thyroxine, retinol binding protein, and vitamin A in children with delayed cognitive development

Circulating thyroxine (T4), retinol binding protein (RBP), and vitamin A were measured in conjunction with nutritional status assessment of 707 cognitively delayed children, ages 3.0-9.0 y. Twenty percent were receiving anticonvulsant (AC) medication. T4 was lower and RBP and vitamin A were higher (p less than 0.0001) among AC than non-AC subjects. Molar ratios of vitamin A:RBP did not differ between the two groups nor did intakes of protein or vitamin A. Lower T4 and higher RBP were found among children who received diphenylhydantoin (DPH), phenobarbital, or AC combinations, but vitamin A was higher only among those who received DPH. RBP and vitamin A were lower (p less than 0.05) among children with infections and vitamin A was lower (p less than 0.05) among those with serum zinc less than 70 micrograms/dL (less than 10.7 mumol/L); differences between AC and non-AC subjects remained when other variables were considered.     

Influence of vitamin A form and protein nature on the retinol status in the rat

In comparison with soybean proteins, the acid casein increases the blood and liver concentrations of retinol when the diet contains 1 mg of retinol/kg. The effect of the acid casein is more important when the vitamin A is supplied to rats as retinal: with the alcohol form, the amount of liver retinol is 88.7 micrograms; with the aldehyde form, it reaches 137 micrograms.     

Effects of timing and dose of vitamin A on tissue retinol concentrations and antibody production in the previously vitamin A-depleted rats.

The effect of retinol repletion in previously vitamin A-depleted Lewis rats on antibody production to pneumococcal polysaccharide (SSS-III) was studied. When vitamin A-depleted rats were given either 0.35 mumol (0.1 mg) or 5.2 mumol (1.5 mg) retinol, plasma retinol became normal within 8 h. Liver and lymphoid-organ retinol concentrations were normalized by 1 d after repletion with 5.2 mumol but not 0.35 mumol retinol. Antibody production to SSS-III was compared after administering 5.2 mumol retinol either as a divided dose (half given 4 d before and half given on the day of immunization) or as a single dose concurrent with immunization. Vitamin A-depleted rats produced very little SSS-III-specific antibody. The divided dose of retinol consistently restored anti-SSS-III production whereas the single concurrent dose was less effective despite equal effects on tissue retinol concentrations. Interestingly, normalization of plasma retinol was not always a good predictor of the immune response to pneumococcal polysaccharide.     

Rapid determination of vitamin A (retinol) and vitamin E (alpha-tocopherol) in human serum by isocratic adsorption HPLC

The simultaneous determination of alpha-tocopherol and retinol in human serum is reported. The separation is carried out by means of isocratic HPLC on adsorption columns. UV-Detection is possible by using either one wavelength for both compounds (300 nm), or after a lambda change mode with typical wavelengths for alpha-tocopherol (292 nm) and retinol (325 nm). According to short retention times (10 min) and rapid extraction the method is useful for clinical research and allows about 50 analyses per day and operator. Blood from 176 human volunteers was collected and alpha-tocopherol and retinol levels in serum determined with this method. Statistical evaluation of different selected groups shows typical significant differences of alpha-tocopherol and retinol concentrations in smokers and oral contraceptive users.     

Localization of retinol (vitamin A) in rat testes

The purpose of the study was to determine the intracellular location of exogenously injected labeled vitamin A (retinol) in rat testes by light and electron microscopic autoradiography. Tritium-labeled vitamin A mixed in vitamin A-free rat serum was injected intracapsularly in one testis in adult rats. At intervals of 30 minutes, 2 hours, and 4 hours following injection the treated testes were removed the processed for autoradiography. The results show that in the testes vitamin A is localized at three sites: within the macrophages of the interstitial tissue, in the lipid droplets of the Sertoli cells, and in the spermatids in association with Golgi saccules. To confirm the autoradiographic localization of vitamin A, the cellular retinol-binding protein (CRBP) assay demonstrates the presence of CRBP in the interstitial tissue and seminiferous tubules. The results of the study suggest a possible role of vitamin A in spermiogenesis in rat testes.     

视黄醇结合蛋白、前白蛋白对胎儿宫内营养状况评估价值研究

目的 探讨视黄醇结合蛋白(RBP)、前白蛋白(PA)评价胎儿宫内营养状况的临床价值.方法 选择2015年在淮北市妇幼保健院分娩的338例新生儿作为研究对象,按胎龄分为早产儿组137例和足月儿组201例,生后12h内取静脉血检测RBP、PA水平,比较不同分组新生儿RBP、PA水平并分析RBP、PA水平对胎儿宫内营养状况的评价效果.结果 足月儿组血清RBP和PA水平均显著高于早产儿组(t值分别为5.548、4.337,均P<0.05),35~36周早产儿组血清RBP、PA水平均显著高于28~34周早产儿组(t值分别为5.097、9.007,均P<0.05),低体重儿组新生儿血清RBP、PA水平均显著低于其他两组RBP:t值分别为5.379、5.882,均P<0.05;PA:t值分别为6.498、7.267,均P<0.05),而巨大儿组新生儿血清RBP、PA水平均显著高于其他两组(t值分别为4.276、5.034,均P<0.05).结论 血清RBP、PA综合评价能够准确快速判断胎儿宫内营养状况,在临床上具有重要应用价值.     

Capacity of proton beams in preserving normal liver tissue during proton beam therapy for hepatocellular carcinoma

Unirradiated liver volume (ULV) preservation rate is an important factor associated with radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) undergoing proton beam therapy (PBT). The purpose of this study is to identify the predictors for ULV preservation and quantify the capacity of proton beams in normal liver sparing during PBT. We reviewed planning data of 92 patients with single intrahepatic HCC tumors undergoing PBT. The potential clinical and planning factors that may affect ULV preservation were involved in multiple linear regression for ULV preservation rate. The significant factors were determined to be predictors and their influences were quantified. The median ULV preservation rate was 62.08%. All the assessed clinical factors showed significant effects on ULV preservation rate: clinical target volume (CTV), P < 0.001; portal vein tumor thrombosis (PVTT), P = 0.010; left lobe tumor, P = 0.010. In contrast, none of the planning factors demonstrated significance. The coefficients of significant factors in multiple linear regression were 60.85 for intercept, −0.02 for CTV, −9.01 for PVTT and 8.31 for left lobe tumors. The capacity of proton beams to spare normal liver tissue during PBT for HCC is mainly affected by clinical factors. The baseline of the ULV preservation rate is 60.85%, decreasing 0.02% with each milliliter of CTV increase and 9.01% for tumors with PVTT, and increasing 8.31% for tumors limited to the left lobe. Further clinical studies should be carried out to correlate our dosimetric findings with clinical outcomes.     

EZH2在原发性肝细胞性肝癌中的表达及其临床意义

目的探讨果蝇zeste基因增强子同源物2（EZH 2）蛋白在原发性肝细胞性肝癌（HCC）中的表达状况及其临床意义。方法应用免疫组化S-P法检测原发性肝细胞性肝癌50例、肝硬化30例、正常肝组织9例中EZH2蛋白的表达。结果EZH2蛋白主要表达于细胞核，原发性肝细胞性肝癌、肝硬化和正常肝组织的EZH2蛋白阳性表达率分别是88.00%（44/50）、46.67%（14/30）、33.33%（3/9），且EZH2蛋白在原发性肝细胞性肝癌组织中的表达明显高于在肝硬化和正常肝组织中的表达（χ2=16.07，10.09，P〈0.01）。结论EZH2异常表达与原发性肝细胞性肝癌的发展密切相关，在原发性肝细胞性肝癌的发展过程中起重要的作用。