OBJECTIVE: To screen for differentially expressed circular RNAs (circRNAs) in the serum of preterm infants with intraventricular hemorrhage (IVH) and explore the competitive endogenous RNA (ceRNA) mechanism of circRNAs in IVH in these infants. METHODS: Fifty preterm infants (gestational age of 28 to 34 weeks) admitted in our department between January, 2019 and January, 2020 were enrolled in this study, including 25 with a MRI diagnosis of IVH and 25 without IVH. Serum samples were collected from 3 randomly selected infants from each group for profiling differentially expressed circRNAs using circRNA array technique. Gene ontology (GO) and pathway analyses were performed to reveal the function of the identified circRNAs. The circRNA-miRNA-mRNA network was constructed to identify the co-expression network of hsa_circ_ 0087893. RESULTS: A total of 121 differentially expressed circRNAs were identified in the infants with IVH, including 62 up-regulated and 59 down-regulated circRNAs. GO and pathway analyses showed that these circRNAs were involved in multiple biological processes and pathways, including cell proliferation, activation and death, DNA damage and repair, retinol metabolism, sphingolipid metabolism, cell adhesion molecules. Among these circRNAs, hsa_circ_0087893 was found to have significant down-regulation in IVH group and co-express with 41 miRNAs and 15 mRNAs (such as miR-214-3p, miR-761, miR-183-5p, AKR1B1, KRT34, PPP2CB, and HPRT1). CONCLUSION The circRNA hsa_circ_0087893 may function as a ceRNA and play an important role in the occurrence and progression of IVH in preterm infants.
Infant, Newborn ; Infant ; Humans ; RNA, Circular ; Infant, Premature ; MicroRNAs ; RNA, Messenger ; Cerebral Hemorrhage/genetics* ; Aldehyde Reductase

Aldose reductase (AR) protein, a member of the NADPH-dependent aldo-keto reductase family, reduces a wide range of aldehydes and enhances cell survival by inhibition of oxidative stress. Oxidative stress is known as one of the major pathological factor in ischemia. Since the precise function of AR protein in ischemic injury is fully unclear, we examined the function of AR protein in hippocampal neuronal (HT-22) cells and in an animal model of ischemia in this study. Cell permeable Tat-AR protein was produced by fusion of protein transduction domain in Tat for delivery into the cells. Tat-AR protein transduced into HT-22 cells and significantly inhibited cell death and regulated the mitogen-activate protein kinases (MAPKs), Bcl-2, Bax, and Caspase-3 under oxidative stress condition. In an ischemic animal model, Tat-AR protein transduced into the brain tissues through the blood-brain barrier (BBB) and drastically decreased neuronal cell death in hippocampal CA1 region. These results indicate that transduced Tat-AR protein has protective effects against oxidative stress-induced neuronal cell death in vitro and in vivo, suggesting that Tat-AR protein could be used as potential therapeutic agent in ischemic injury.
Aldehyde Reductase ; Aldehydes ; Blood-Brain Barrier ; Brain ; CA1 Region, Hippocampal ; Caspase 3 ; Cell Death ; Cell Survival ; Humans ; In Vitro Techniques ; Ischemia ; Models, Animal ; Neurons ; Oxidative Stress ; Oxidoreductases ; Protein Kinases

A methanolic extract of Corydalis ternata having aldose reductase inhibitory activity was examined as a possible aldose reductase (ALR2) inhibitor, a key enzyme involved in diabetic complications. Seven alkaloids, tetrahydrocoptisine (1), corydaline (2), tetrahydropalmatine (3), isocorybulbine (4), corybulbine (5), dehydrocorydaline (6), and N-methyltetrahydroberbinium (7) were isolated from CHCl₃ fraction of C. ternata methanol extract. Among them, compounds 1, 5, and 7 exhibited 5.04 ± 1.97%, 5.00 ± 1.26%, and 1.80 ± 2.33% inhibitions, respectively at 40 µM. The activities of the single compounds were not comparable to that of the whole extract, suggesting that the whole combination of each single compound was responsible for the activity of the extract as shown in many cases of natural medicines. Even though this is the second report on aldose reductase inhibition activity of C. ternata, recombinant human aldose reductase was employed in this study unlike in the previous report. Furthermore, the aldose reductase inhibitory activities of isocorybulbine, corybulbine, and N-methyltetrahydroberbinium, to the best of our knowledge, were evaluated for the first time in this study. These results suggest a use of the extract of C. ternata for ameliorating diabetic complications.
Aldehyde Reductase* ; Alkaloids* ; Corydalis* ; Diabetes Complications ; Humans ; Methanol

Naturally occurring coumarin compounds have received substantial attention due to their pharmaceutical effects. Esculetin is a coumarin derivative and a polyphenol compound that is used in a variety of therapeutic and pharmacological strategies. However, its effect on aldose reductase activity remains poorly understood. In this study, the potential beneficial effects of esculetin on lenticular aldose reductase were investigated in galactose-fed (GAL) rats, an animal model of sugar cataracts. Cataracts were induced in Sprague-Dawley (SD) rats via a 50% galactose diet for 2 weeks, and groups of GAL rats were orally treated with esculetin (10 or 50 mg/kg body weight). In vehicle-treated GAL rats, lens opacification was observed, and swelling and membrane rupture of the lens fiber cells were increased. Additionally, aldose reductase was highly expressed in the lens epithelium and superficial cortical fibers during cataract development in the GAL rats. Esculetin reduced rat lens aldose reductase (RLAR) activity in vitro, and esculetin treatment significantly inhibited lens opacity, as well as morphological alterations, such as swelling, vacuolation and liquefaction of lens fibers, via the inhibition of aldose reductase in the GAL rats. These results indicate that esculetin is a useful treatment for galactose-induced cataracts.
Aldehyde Reductase* ; Animals ; Cataract ; Diet ; Epithelium ; Galactose ; Membranes ; Models, Animal ; Rats* ; Rats, Sprague-Dawley ; Rupture

OBJECTIVETo study the effects of p38 MAPK signaling pathway and aldose reductase (AR) on the transforming growth factor (TGF)-β1-induced expression of fibronectin (FN).

METHODSHuman mesangial cells (HMCs) were cultured, and transfected with pCDNA3-AR. AR gene silencing was induced by small interfering RNA (siRNA). AR expression in HMCs was examined by immunofluorescence analysis. RT-PCR and real-time PCR were performed to detect the mRNA expression of AR in the HMCs and Western blotting was used to detect the protein expression of AR, FN and p38. AR inhibitors (ARIs), Sorbinil and Zopolrestat were added and co-incubated, followed by addition of TGF-β1. Western blotting was used to document protein expression of FN and p38 mitogen-activated protein kinases (p38 MAPKs) in the HMCs.

RESULTSImmunofluorescence analysis showed a stronger expression of AR in HMCs transfected with AR than that of normal HMCs and HMCs transfected with blank vector. In comparison with normal HMCs and those transfected with blank vector, HMCs transfected with AR showed stronger protein expression of FN (P<0.05). After incubation of ARIs, protein expression of FN decreased in HMCs transfected with AR (P<0.05). After stimulation of TGF-β1, FN protein expression increased in both normal HMCs and those transfected with AR (P<0.05). After preincubation with ARI, FN protein expression in HMCs transfected decreased significantly (P<0.05). After stimulation of TGF-β1, naïve HMCs showed increased expression of phosphor-p38. In contrast, HMCs preincubated with ARIs showed reduced expression of phosphor-p38, and HMCs transfected with AR showed increased expression of phosphor-p38 (P<0.05).

CONCLUSIONSAR regulates the expression of FN through the stimulation of TGF-β1, which may involve the activation of p38-MAPK signaling pathway. AR may play a role in the pathogenesis of glomerulosclerosis.

Aldehyde Reductase ; metabolism ; Cells, Cultured ; Fibronectins ; metabolism ; Humans ; MAP Kinase Signaling System ; Mesangial Cells ; metabolism ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Transfection ; Transforming Growth Factor beta1 ; pharmacology ; p38 Mitogen-Activated Protein Kinases ; metabolism

Aldose reductase (AR) is known to play a crucial role in the mediation of diabetic and cardiovascular complications. Recently, several studies have demonstrated that allergen-induced airway remodeling and ovalbumin-induced asthma is mediated by AR. Epalrestat is an aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Whether AR is involved in pathogenesis of pulmonary fibrosis and whether epalrestat attenuates pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. The expression of AR, TGF-beta1, alpha-SMA and collagen I was analyzed by immunohistochemisty, real-time PCR or western blot. In vivo, epalrestat treatment significantly ameliorated the bleomycin-mediated histological fibrosis alterations and blocked collagen deposition concomitantly with reversing bleomycin-induced expression up-regulation of TGF-beta1, AR, alpha-SMA and collagen I (both mRNA and protein). In vitro, epalrestat remarkably attenuated proliferation of pulmonary fibroblasts and expression of alpha-SMA and collagen I induced by TGF-beta1, and this inhibitory effect of epalrestat was accompanied by inhibiting AR expression. Knockdown of AR gene expression reversed TGF-beta1-induced proliferation of fibroblasts, up-regulation of alpha-SMA and collagen I expression. These findings suggest that AR plays an important role in bleomycin-induced pulmonary fibrosis, and epalrestat inhibited the progression of bleomycin-induced pulmonary fibrosis is mediated via inhibiting of AR expression.
Airway Remodeling ; Aldehyde Reductase* ; Animals ; Asthma ; Bleomycin ; Blotting, Western ; Bromodeoxyuridine ; Collagen ; Diabetic Neuropathies ; Fibroblasts ; Fibrosis ; Flow Cytometry ; Gene Expression ; Negotiating ; Pulmonary Fibrosis* ; Rats* ; Real-Time Polymerase Chain Reaction ; RNA, Messenger ; Transforming Growth Factor beta1 ; Up-Regulation

BACKGROUND/AIMS: Upregulation of aldo-keto reductase 1B10 (AKR1B10) through the mitogenic activator protein-1 signaling pathway might promote hepatocarcinogenesis and tumor progression. The goal of this study was to evaluate the prognostic significance of AKR1B10 protein expression in patients with hepatocellular carcinoma after surgery. METHODS: A tissue microarray was used to detect the expression level of AKR1B10 protein in tumors from 255 patients with hepatocellular carcinoma who underwent curative hepatectomy. The impact of AKR1B10 expression on the survival of patients was analyzed. The median follow-up period was 119.8 months. RESULTS: High AKR1B10 protein expression was observed in 125 of the 255 patients with hepatocellular carcinoma (49.0%). High AKR1B10 expression was significantly associated with a lack of invasion of the major portal vein (p=0.022), a lack of intrahepatic metastasis (p=0.010), lower the American Joint Committee on Cancer T stage (p=0.016), lower the Barcelona Clinic Liver Cancer stage (p=0.006), and lower alpha-fetoprotein levels (p=0.020). High AKR1B10 expression was also correlated with a lack of early recurrence (p=0.022). Multivariate analyses of survival revealed that intrahepatic metastases and lower albumin levels were independent predictors of both shorter recurrence-free survival and shorter disease-specific survival. High AKR1B10 expression was an independent predictor of both longer recurrence-free survival (p=0.024) and longer disease-specific survival (p=0.046). CONCLUSIONS: High AKR1B10 protein expression might be useful as a marker of a favorable prognosis in patients with hepatocellular carcinoma after curative hepatectomy.
Adolescent ; Adult ; Aged ; Aldehyde Reductase/*metabolism ; Carcinoma, Hepatocellular/*metabolism/surgery ; Disease-Free Survival ; Female ; Hepatectomy ; Humans ; Immunohistochemistry ; Liver Neoplasms/*metabolism/surgery ; Male ; Middle Aged ; Prognosis ; Tumor Markers, Biological/*metabolism ; Young Adult

OBJECTIVETo identify the possible association between C(-106)T polymorphism of the aldose reductase (ALR) gene and diabetic retinopathy (DR) in a cohort of Chinese patients with type 2 diabetes mellitus (T2DM).

METHODSFrom November 2009 to September 2010, patients with T2DM were recruited and assigned to DR group or diabetic without retinopathy (DWR) group according to the duration of diabetes and the grading of 7-field fundus color photographs of both eyes. Genotypes of the C(-106)T polymorphism (rs759853) in ALR gene were analyzed using the MassARRAY genotyping system and an association study was performed.

RESULTSA total of 268 T2DM patients (129 in the DR group and 139 in the DWR group) were included in this study. No statistically significant differences were observed between the 2 groups in the age of diabetes onset (P=0.10) and gender (P=0.78). The success rate of genotyping for the study subjects was 99.6% (267/268), with one case of failure in the DR group. The frequencies of the T allele in the C(-106)T polymorphism were 16.0% (41/256) in the DR group and 19.4% (54/278) in the DWR group (P=0.36). There was no significant difference in the C(-106)T genotypes between the 2 groups (P=0.40). Compared with the wild-type genotype, odds ratio (OR) for the risk of DR was 0.7 (95% CI, 0.38-1.3) for the heterozygous CT genotype and 0.76 (95% CI, 0.18-3.25) for the homozygous TT genotype. The risk of DR was positively associated with microalbuminuria (OR=4.61; 95% CI, 2.34-9.05) and insulin therapy (OR=3.43; 95% CI, 1.94-6.09).

CONCLUSIONSMicroalbuminuria and insulin therapy are associated with the risk of DR in Chinese patients with T2DM. C(-106)T polymorphism of the ALR gene may not be significantly associated with DR in Chinese patients with T2DM.

Albuminuria ; epidemiology ; urine ; Aldehyde Reductase ; genetics ; Asian Continental Ancestry Group ; China ; Cohort Studies ; Diabetes Mellitus, Type 2 ; complications ; drug therapy ; ethnology ; genetics ; Diabetic Retinopathy ; drug therapy ; ethnology ; etiology ; genetics ; Female ; Gene Frequency ; Humans ; Hypoglycemic Agents ; administration & dosage ; adverse effects ; therapeutic use ; Insulin ; administration & dosage ; adverse effects ; therapeutic use ; Logistic Models ; Male ; Multivariate Analysis ; Polymorphism, Single Nucleotide ; Risk

OBJECTIVETo optimize the hydrolysis process of linarin by response surface methodology, and to use the model of aldose reductase to study the acacetin's activity of aldose reductase inhibitory.

METHODThe model of acacetin enzyme in vitro was established by the determination of fluorescence absorption of NADPH, the inhibition rate of acacetin aldose reductase was calculated, and then the IC50 of hydrolysis was obtained. The hydrolysis process of linarin hydrolysis condition was optimized by using response surface method.

RESULTThe results indicated that the IC50 of acacetin (2.74 mg x L(-1)) was less than the IC50 of linarin (3.53 mg x L(-1)). Hydrolyzation time of 7.4 h, sulphuric acid concentration of 0.54 mol x L(-1) and the ratio of material to liquid of 3 : 1 were the optimum conditions.

CONCLUSIONHydrolyzate acacetin has preferable inhibitory activity of aldose reductase. The optimized hydrolysis condition of linarin is convenient to use with good predictability.

Aldehyde Reductase ; antagonists & inhibitors ; metabolism ; Animals ; Diabetic Retinopathy ; enzymology ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Enzyme Inhibitors ; chemistry ; pharmacology ; Flavones ; chemistry ; Glycosides ; chemistry ; pharmacology ; Glycosylation ; Humans ; Hydrolysis ; Male ; Rats ; Rats, Wistar ; Retina ; enzymology

OBJECTIVETo investigate the chemical compounds from the ethanol extract with inhibitory effects against aldose reductase from Thunbergia.

METHODGuided by anti-aldose reductase assay, compounds from the bioactive fraction (ethyl acetate extract) were separated and purified by various chromatographic methods including silica gel, Sephadex LH-20, and reversed-phase HPLC. Their structures were indentified based on analysis of the spectroscopic data including 1D and 2D NMR data.

RESULTEight compounds were obtained and identified as 8-hydroxy-8-methyl-9-methene-cyclopentane [7,11] -1,4, 6-trihydroxy-tetrahydronaphthalene-12-one, named as thunbergia A (1), 3,4-dihydro-4,5,8-trihydroxy-2-(3-methyl-2-butenyl) naphtha[2,3-b] oxiren-1(2H)-one (2), 8-(beta-gluco pyranosyloxy)-3,4-dihydro-2-(3-methyl-2-butenyl)naphtha [2,3-b] oxiren-1(2H)-one (3), galangin (4), quercetin (5), luteolin (6), 5,6,3',4'-tetrahydroxy -3,7-dimethoxy-flavone (7) and upeol (8).

CONCLUSIONThunbergia A was a new derivative of tetrahydronaphthalene, and compounds 2 and 3 were separated from the genus Thunbergia for the first time.

Acanthaceae ; chemistry ; Aldehyde Reductase ; antagonists & inhibitors ; Animals ; Nuclear Magnetic Resonance, Biomolecular ; Plant Extracts ; chemistry ; isolation & purification ; pharmacology ; Plant Roots ; chemistry ; Rats