Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynt...Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynthetic origins, natural products can be divided into three major groups: the isoprenoids, alkaloids, and phenolic compounds. Isoprenoids are structurally the most diverse group of secondary natural metabolites with different roles in the growth, development, and reproduction of a diverse range of prokaryotic and eukaryotes cells. Mevalonate and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways are known to be responsible for biosynthesis of numerous isoprenoids. HMG-CoA reductase is a rate-determining enzyme in mevalonate pathway, producing intermediates such as farnesyl and geranylgeranyl pyrophosphates, which lead to by-products such as cholesterol. Earlier studies have demonstrated that the inhibition of HMG-CoA reductase is one of the most effective approaches for treating hypercholesterolemia and eventually cardiovascular disease (CVD). Statins are HMG-CoA reductase inhibitors and the most prescribed group of drugs worldwide in treating hypercholesterolemia;however the application of this group of drugs may be expensive and has side effects including rashes and gastrointestinal symptoms. For these reasons, there is an important need to examine the viability of natural products as an alternative to statin treatment. This article is a review of different aforementioned areas with a focus on isoprenoids that can be used for the regulation of HMG-CoA reductase.展开更多
Since we had previously demonstrated that siRNAs to tristetraprolin (TTP) markedly inhibited insulin stimulation of hepatic HMG-CoA reductase (HMGR) transcription, we investigated the effects of transfecting rat liver...Since we had previously demonstrated that siRNAs to tristetraprolin (TTP) markedly inhibited insulin stimulation of hepatic HMG-CoA reductase (HMGR) transcription, we investigated the effects of transfecting rat liver with TTP constructs. We found that transfecting diabetic rats with TTP did not increase HMGR transcription but rather led to modest inhibition. We then investigated whether co-transfection with protein kinase B, hepatic form (AKT2), might lead to phosphorylation and result in activation of HMGR transcription. We found that this treatment resulted in near complete inhibition of transcription. Transfection with peroxisome proliferator-activated receptor g coactivator (PGC-1a) also inhibited HMGR transcription. These results show that although TTP is needed for activation of HMGR transcription, it cannot by itself activate this process. AKT2 and PGC-1a, which mediate the activation of gluconeogenic genes by insulin, exert the opposite effect on HMGR.展开更多
Objective: To fractionate and identify polyphenols from Guazuma ulmifolia Lam. leaves, and to explore their antioxidant, 5-hydroxy-3-methylglutaryl-coenzyme A(HMG-Co A) reductase inhibitory, and Nrf2 modulatory activi...Objective: To fractionate and identify polyphenols from Guazuma ulmifolia Lam. leaves, and to explore their antioxidant, 5-hydroxy-3-methylglutaryl-coenzyme A(HMG-Co A) reductase inhibitory, and Nrf2 modulatory activities.Methods: The 1,1-diphenyl-2-picrylhydrazyl assay was used to evaluate the antioxidant activity of a polyphenolic fraction of the extract of Guazuma ulmifolia Lam. leaves. THP-1 gene reporter cell lines constructed with a transcriptional response element specific for Nrf2 and a minimal promoter for the firefly luciferase–green fluorescent protein transgene were used to determine the effect of the polyphenolic fraction on the Nrf2 signaling pathway. Furthermore, an assay of HMG-Co A reductase inhibitory activity was performed by using a commercial enzyme kit. Polyphenolic compounds were identified by liquid chromatographytandem mass spectrometry.Results: The polyphenolic fraction showed fairly strong antioxidant activity [IC50 =(14.90 ± 4.70) μg/m L] and inhibited HMG-Co A reductase activity by 69.10%, which was slightly lower than that by pravastatin(84.37%) and quercetin(84.25%). Additionally, the polyphenolic fraction activated the Nrf2 antioxidant signaling pathway at 500 μg/m L. Eleven subfractions resulting from the column chromatography separation of the polyphenolic fraction also showed relatively strong antioxidant activities(IC50: 17.46–217.14 μg/m L). The subfraction(F6) stimulated the Nrf2 signaling pathway and had HMG-Co A reductase inhibitory activity(65.43%). Moreover, the subfraction contained two main flavonoids: quercetin and quercimeritrin.Conclusions: The polyphenolic fraction of Guazuma ulmifolia could induce antioxidant genes via the Nrf2/antioxidant regulatory elements pathway, and is a promising candidate for an inhibitor of HMG-Co A reductase.展开更多
Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are widely used for the treatment of hypercholesteremia and have showed remarkable activity in preventing cardiovascular morbidity and mort...Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are widely used for the treatment of hypercholesteremia and have showed remarkable activity in preventing cardiovascular morbidity and mortality. Recent studies demonstrated that statins have significant antithrombotic effect in addition to cholesterollowering action. Although the efficacy of statins for reducing cardiovascular events has historically been ascribed to their inhibitory activity on cholesterol synthesis, the degree of low-density lipoprotein cholesterol reduction by statins generally does not correlate with the magnitude of coronary risk reduction.展开更多
Objective To evaluate whether the effects of HMG - CoA reductase inhibitors on patients with hyperlipidemia are closely related to baseline lipid levels. Methods The data analyzed originated from 3 separate multicente...Objective To evaluate whether the effects of HMG - CoA reductase inhibitors on patients with hyperlipidemia are closely related to baseline lipid levels. Methods The data analyzed originated from 3 separate multicenter clinical trials with similar designs during 1994 to 1999. 166 patients with mean age 58. 9±9. 2 years were involved in Simvastatin Clinical Trial with simvastatin 10 mg once daily for 8 weeks. 146 patients with mean age 57. 9±8. 7years were involved in Lovastatin Clinical Trial with lovastatin 20 mg once daily for 8 weeks. 105 patients with mean age 57. 8±9. 3 years were involved in Atorvastatin Clinical Trial with atorvastatin 10 mg once daily for 6 weeks. Baseline total cholesterol (TC) was more than 5. 98 mmol. L - 1, and baseline triglyceride (TG) was less than 4. 52 mmo. L - 1. The patients were grouped by baseline lipid levels. Results The higher the baseline TC, low density lipoprotein cholesterol (LDL - C) and TG levels were, the more effective the simvastatin, lovastatin, or atorvastatin was in reducing serum TC, LDL - C, and TG, respectively. A positive linear correlation was found between baseline values and effects of simvastatin, lovastatin, or atorvastatin in reducing serum TC, LDL - C, and TG, respectively. Conclusion The changes of reduction on serum lipid with HMG - CoA reductase inhibitors in patients with hyperlipidemia were influenced by baseline lipid levels.展开更多
Aldo-keto reductases(AKRs)are a superfamily of enzymes that play crucial roles in various cellular processes,including the metabolism of xenobiotics,steroids,and carbohydrates.A growing body of evidence has unveiled t...Aldo-keto reductases(AKRs)are a superfamily of enzymes that play crucial roles in various cellular processes,including the metabolism of xenobiotics,steroids,and carbohydrates.A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers.AKRs are aberrantly expressed in a wide range of malignant tumors.Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance.AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression.Inhibition of aldose reductase(AR),either alone or in combination with chemotherapeutic drugs,has evolved as a pragmatic therapeutic option for cancer.Several classes of synthetic aldo-keto reductase(AKR)inhibitors have been developed as potential anticancer agents,some of which have shown promise in clinical trials.Many AKR inhibitors from natural sources also exhibit anticancer effects.Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies.These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy.In this review,we discuss the physiological functions of human AKRs,the aberrant expression of AKRs in malignancies,the involvement of AKRs in the acquisition of cancer hallmarks,and the role of AKRs in oncogenic signaling,and drug resistance.Finally,the potential of aldose reductase inhibitors(ARIs)as anticancer drugs is summarized.展开更多
Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chem...Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.展开更多
Salt acclimation, which is induced by previous salt exposure, increases the resistance of plants to future exposure to salt stress. However, little is known about the underlying mechanism, particularly how plants stor...Salt acclimation, which is induced by previous salt exposure, increases the resistance of plants to future exposure to salt stress. However, little is known about the underlying mechanism, particularly how plants store the"memory" of salt exposure. In this study, we established a system to study salt acclimation in Arabidopsis thaliana. Following treatment with a low concentration of salt, seedlings were allowed to recover to allow transitory salt responses to subside while maintaining the sustainable effects of salt acclimation. We performed transcriptome profiling analysis of these seedlings to identify genes related to salt acclimation memory. Notably, the expres-sion of Basic-leucine zipper 17 (bZIP17) and Hmg-CoA reductase degradation 3A (HRD3A), which are important in the unfolded protein response (UPR) and endoplasmic reticulum-associated degradation (ERAD), respectively, increased following treatment with a low concentration of salt and remained at stably high levels after the stimulus was removed, a treatment which improved plant tolerance to future high-salinity challenge. Our findings suggest that the upregulated expression of important genes involved in the UPR and ERAD represents a "memory" of the history of salt exposure and enables more potent responses to future exposure to salt stress, providing new insights into the mechanisms underlying salt acclimation in plants.展开更多
AIM:To investigate the aldose reductase(AR)inhibition capacity of astragalin(AST)against streptozoticin-induced diabetic cataracts(DCs)in rats.METHODS:Ex vivo investigations were conducted by treating the lens of a go...AIM:To investigate the aldose reductase(AR)inhibition capacity of astragalin(AST)against streptozoticin-induced diabetic cataracts(DCs)in rats.METHODS:Ex vivo investigations were conducted by treating the lens of a goat placed for 72h in artificial aqueous humor(AAH)of pH 7.8 at room temperature with cataract-causing substance(55 mmol/L of galactose)and in vivo studies were performed on rats via induction with streptozotocin.AST was administered at different dose levels and scrutinize for DC activity.RESULTS:In diabetic rats,AST improved the body weight,blood insulin,and glucose as well as the levels of galactitol in a dose-dependent way,other biochemical parameters i.e.inflammatory mediators and cytokines,and also suppress AR activity.The level of the antioxidant parameters such as superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)activity were also altered on a diabetic lens after the administration of the AST.CONCLUSION:AST protects against lens opacification to avoid cataracts and polyols formation,indicating that it could be used as a potential therapeutic agent for diabetes.展开更多
Aim: To analyze the distribution of the single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene in 355 infertile Chinese patients with idiopathic azoospermia or severe o...Aim: To analyze the distribution of the single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene in 355 infertile Chinese patients with idiopathic azoospermia or severe oligozoospermia and 252 fertile Chinese men as controls to explore the possible association of the SNP and male infertility. Methods: Using the polymerase chain reaction (PCR)-restriction fragment length polymorphism technique, the allele and genotype distribution of SNP C677T in the MTHFR gene were investigated in both patients and controls. Results: The frequencies of allele T (40.9% vs 30.4%, P = 0.002, odds ration [OR] = 1.58, 95% confidence interval [CI]: 1.24-2.02) and mutant homozygote (TT) (18.3% vs. 11.5%, P = 0.023, OR = 1.72, 95% CI: 1.07-2.76) as well as carrier with allele (TT + CT) (63.4% vs. 49.2%, P = 0.0005, OR = 1.79, 95% CI: 1.29-2.48) in infertile patients were significantly higher than those in controls. After patient stratification, the significant differences in distribution of the SNP between each patient subgroup and control group still remained. Conclusion: Our findings indicate that there is an association of SNP C677T in the MTHFR gene with male infertility, suggesting that this polymorphism might be a genetic risk factor for male infertility in Chinese men.展开更多
The objective is to study whether the accumulation and utilization of plant N are controlled by Mo status in winter wheat cultivars. Mo-efficient cultivar 97003 (eft) and Mo-inefficient cultivar 97014 (ineff) were...The objective is to study whether the accumulation and utilization of plant N are controlled by Mo status in winter wheat cultivars. Mo-efficient cultivar 97003 (eft) and Mo-inefficient cultivar 97014 (ineff) were grown in severely Mo-deficient acidic soil (Tamm-reagent-extractable Mo 0.112 mg kg^-1) with (+Mo) and without (-Mo) the application of 0.13 mg kg^-1 Mo. The accumulation and use efficiency of plant total N were significantly higher in +Mo than that in -Mo and in eft than that in ineff under Mo deficiency. N use efficiency was remarkably higher in maturity but it was forwarded to jointing stage after Mo supply, thus indicating that Mo supply promoted the N use efficiency besides N uptake and eff was efficient in N uptake and utilization. The overall activity of nitrate reductase (NR, EC 1.6.6.1) was significantly higher in +Mo than in -Mo and ratio of +Mo/-Mo was even to 14.8 at filleting stage for ineff. Activity of glutamine synthetase (GS, EC 6.3.1.2) was significantly lower in +Mo than in -Mo. Concentration of nitrate and glutamate were also significantly lower in +Mo than in -Mo, thus provided evidences for enhancing N use efficiency by Mo supply. Activities of NR and GS were significantly higher and concentrations of nitrate and glutamate were significantly lower in eff than ineff under Mo deficiency, thus indicated eff was more efficient in N reduction and utilization. It is therefore concluded that Mo could promote N accumulation and utilization in winter wheat which was directly related to NR and feedback regulated by GS. Higher Mo status also results in higher accumulation and utilization of plant N in eft.展开更多
AIM: To identify the association between methylenetetrahydrofolate reductase(MTHFR) polymorphisms and gastric cancer(GC) susceptibility.METHODS: Systematic searches were performed on the electronic databases PubMed, I...AIM: To identify the association between methylenetetrahydrofolate reductase(MTHFR) polymorphisms and gastric cancer(GC) susceptibility.METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio(OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I2 statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed.RESULTS: Increased risk was found for the MTHFRC677T polymorphism under four genetic models(TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677 T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677 T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677 T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298 C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations(CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04). CONCLUSION: MTHFR C677 T polymorphism is a risk factor for GC, and the A1298 C polymorphism may be a protective factor against GC in eastern populations.展开更多
Objective:To assesse the inhibitor) effect of alcoholic extract of two Indian medicinal plants namely Ceasalpinia digyna Rottler and.Alangium lamarckii Thwaits on aldose reductase(AR) of rat lens.Methods:Rats lens w...Objective:To assesse the inhibitor) effect of alcoholic extract of two Indian medicinal plants namely Ceasalpinia digyna Rottler and.Alangium lamarckii Thwaits on aldose reductase(AR) of rat lens.Methods:Rats lens were enucleated through posterior approach and their homogenate was prepared and centrifuged to obtain a clear supernatant for the determination of AR activity and protein content.Results:The alcoholic extract of Ceasalpirda digyna and Alangium lamarckii had a potent inhibitory effect on the lens AR enzyme.The IC<sub>50</sub> values of alcoholic extract of the selected plants were calculated and were(46.29±11.17) and(106.00±5.11)μg/mL,respectively. Quercetin was used as a positive control and its IC<sub>50</sub> value was(2.95±1.53)μg/mL.Conclusions:Thus,it is concluded that alcoholic extracts of the selected plant exhibit significant inhibitory effects on AR in the rat lens in vitro.展开更多
In China, nitrogen fertilizer application rates in intensive agricultural systems have increased dramatically in recent years, especially in protected vegetable production systems. This excessive use of nitrogen ferti...In China, nitrogen fertilizer application rates in intensive agricultural systems have increased dramatically in recent years, especially in protected vegetable production systems. This excessive use of nitrogen fertilizer has resulted in soil secondary salinization, which has become a significant environmental stress for crops such as cucumber, in the protected farmland of China. So it is necessary to illuminate how crops respond to nitrate stress. The objective of this work was to examine the effects of increased nitrate concentration [14 (CK) and 140 mmol L^-1 (T)] on NO3- concentration, and in vitro and in vivo nitrate reductase activities in the roots and leaves of cucumber (Cucumis sativus L. cv. Xintaimici) seedlings with hydroponic culture. The results showed that the NO3- concentration in the roots and leaves of T seedlings significantly increased over treatment course, and at 12 d increased by 1.08 and 1.72 times with respect to CK seedlings, respectively; in vitro nitrate reductase activity of T was increased dramatically to 1.74 times of CK in the roots at 2 d and 1.56 times of CK in the leaves at 6 d, and then decreased. At 12 d, in vitro activity was still 24.3% higher in the roots and only 9.9% lower in the leaves than CK. Compared with in vitro nitrate reductase activity, in vivo activity responded differently to the increase of treatment time. At the beginning, in vivo nitrate reductase activity in the roots and leaves of T had no significant difference from CK, whereas with the increase of treatment duration, the activity decreased. At 12 d, in vivo activity in the roots and leaves of T lowered by 20.1 and 52.8% with respect to CK, respectively. This evidence suggests that posttranslational activation of nitrate reductase in cucumber seedlings may be seriously inhibited by nitrate stress.展开更多
Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas ma...Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas made it an important target for the development ofantiviral and anticancer drugs. Taking account of the re-cent developments in this field of research, this reviewfocuses on the role of thioredoxin and glutaredoxin sys-tems in the redox reactions of the RNR catalysis.展开更多
Background:Cytochrome b5 reductase 2(CYB5R2) is a potential tumor suppressor that inhibits cell proliferation and motility in nasopharyngeal carcinoma(NPC).Inactivation of CYB5R2 is associated with lymph node metastas...Background:Cytochrome b5 reductase 2(CYB5R2) is a potential tumor suppressor that inhibits cell proliferation and motility in nasopharyngeal carcinoma(NPC).Inactivation of CYB5R2 is associated with lymph node metastasis in NPC.This study aimed to explore the mechanisms contributing to the anti-neoplastic effects of CYB5R2.Methods:Polymerase chain reaction(PCR) assays were used to analyze the transcription of 84 genes known to be involved in representative cancer pathways in the NPC cell line HONE1.NPC cell lines CNE2 and HONE1 were transiently transfected with CYB5R2,and data was validated by real-time PCR.A chick chorioallantoic membrane(CAM)embryo model was implanted with CYB5R2-expressing CNE2 and HONE1 cells to evaluate the effect of CYB5R2 on angiogenesis.An immunohistochemical assay of the CAM model was used to analyze the protein expression of vascular endothelial growth factor(VEGF).Results:In CYB5R2-transfected NPC cells,PCR assays revealed up-regulated mRNA levels of Fas cell surface death receptor(FAS),FBJ murine osteosarcoma viral oncogene homolog(FOS),phosphoinositide-3-kinase regulatory subunit 1(PIK3R1),integrin beta 3(ITGB3),metastasis suppressor 1(MTSSl),interferon beta 1(IFNB1),and cyclin-dependent kinase inhibitor 2A(CDKN2A) and down-regulated levels of integrin beta 5(ITGB5),insulin-like growth factor 1(IGF1),TEK tyrosine kinase(TEK),transforming growth factor beta receptor 1(TGFBRl),and VEGF.The angiogenesis in the CAM model implanted with CYB5R2-transfected NPC cells was inhibited.Down-regulation of VEGF by CYB5R2 in NPC cells was confirmed by immunohistochemical staining in the CAM model.Conclusion:CYB5R2 up-regulates the expression of genes that negatively modulate angiogenesis in NPC cells and down-regulates the expression of VEGF to reduce angiogenesis,thereby suppressing tumor formation.展开更多
Objective:To evaluate the aldose reductase inhibitory(ARI)activity of different fractions of Hybanthus enneaspermus for potential use in diabetic cataract.Methods:Total phenol and flavonoid content of different fracti...Objective:To evaluate the aldose reductase inhibitory(ARI)activity of different fractions of Hybanthus enneaspermus for potential use in diabetic cataract.Methods:Total phenol and flavonoid content of different fractions was determined.ARI activity of different fractions in rat lens was investigated in vitro.Results:The results showed significant level of phenolic and flavonoid content in ethyl acetate fraction[total phenol(212.15±0.79 mg/g),total flavonoid(39.11±2.27mg/g)]and aqueous fraction[total phenol(140.62±0.57mg/g),total flavonoid(26.07±1.49 mg/g)]as compared with the chloroform fraction[total phenol(68.56±0.51mg/g),total flavonoid(13.41±0.82mg/g)]and petrolium ether fraction[total phenol(36.68±0.43mg/g),total flavonoid(11.55±1.06mg/g)].There was a significant difference in the ARI activity of each fraction,and it was found to be the highest in ethyl acetate fraction[IC_(50)(49.26±1.76μg/mL)]followed by aqueous extract[IC_(50)(70.83±2.82μg/mL)]and it was least in the petroleum ether fraction[IC_(50)(118.89±0.71μg/mL)].Chloroform fraction showed moderate activity[IC_(50)(98.52±1.80μg/mL)].Conclusions:Different fractions showed significanct amount of ARI activity,where in ethyl acetate fraction it was found to be maximum which may be due to its high phenolic and flavonoid content.The extract after further evaluation may be used in the treatment of diabetic cataract.展开更多
文摘Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynthetic origins, natural products can be divided into three major groups: the isoprenoids, alkaloids, and phenolic compounds. Isoprenoids are structurally the most diverse group of secondary natural metabolites with different roles in the growth, development, and reproduction of a diverse range of prokaryotic and eukaryotes cells. Mevalonate and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways are known to be responsible for biosynthesis of numerous isoprenoids. HMG-CoA reductase is a rate-determining enzyme in mevalonate pathway, producing intermediates such as farnesyl and geranylgeranyl pyrophosphates, which lead to by-products such as cholesterol. Earlier studies have demonstrated that the inhibition of HMG-CoA reductase is one of the most effective approaches for treating hypercholesterolemia and eventually cardiovascular disease (CVD). Statins are HMG-CoA reductase inhibitors and the most prescribed group of drugs worldwide in treating hypercholesterolemia;however the application of this group of drugs may be expensive and has side effects including rashes and gastrointestinal symptoms. For these reasons, there is an important need to examine the viability of natural products as an alternative to statin treatment. This article is a review of different aforementioned areas with a focus on isoprenoids that can be used for the regulation of HMG-CoA reductase.
文摘Since we had previously demonstrated that siRNAs to tristetraprolin (TTP) markedly inhibited insulin stimulation of hepatic HMG-CoA reductase (HMGR) transcription, we investigated the effects of transfecting rat liver with TTP constructs. We found that transfecting diabetic rats with TTP did not increase HMGR transcription but rather led to modest inhibition. We then investigated whether co-transfection with protein kinase B, hepatic form (AKT2), might lead to phosphorylation and result in activation of HMGR transcription. We found that this treatment resulted in near complete inhibition of transcription. Transfection with peroxisome proliferator-activated receptor g coactivator (PGC-1a) also inhibited HMGR transcription. These results show that although TTP is needed for activation of HMGR transcription, it cannot by itself activate this process. AKT2 and PGC-1a, which mediate the activation of gluconeogenic genes by insulin, exert the opposite effect on HMGR.
基金funded by International Collaboration Research Grant under the Ministry of Research, Technology and Higher Education of the Republic of Indonesia (No. 011/SP2H/LT/DRPM/VIII/2017)University of Missouri-Columbia, MO(USA)
文摘Objective: To fractionate and identify polyphenols from Guazuma ulmifolia Lam. leaves, and to explore their antioxidant, 5-hydroxy-3-methylglutaryl-coenzyme A(HMG-Co A) reductase inhibitory, and Nrf2 modulatory activities.Methods: The 1,1-diphenyl-2-picrylhydrazyl assay was used to evaluate the antioxidant activity of a polyphenolic fraction of the extract of Guazuma ulmifolia Lam. leaves. THP-1 gene reporter cell lines constructed with a transcriptional response element specific for Nrf2 and a minimal promoter for the firefly luciferase–green fluorescent protein transgene were used to determine the effect of the polyphenolic fraction on the Nrf2 signaling pathway. Furthermore, an assay of HMG-Co A reductase inhibitory activity was performed by using a commercial enzyme kit. Polyphenolic compounds were identified by liquid chromatographytandem mass spectrometry.Results: The polyphenolic fraction showed fairly strong antioxidant activity [IC50 =(14.90 ± 4.70) μg/m L] and inhibited HMG-Co A reductase activity by 69.10%, which was slightly lower than that by pravastatin(84.37%) and quercetin(84.25%). Additionally, the polyphenolic fraction activated the Nrf2 antioxidant signaling pathway at 500 μg/m L. Eleven subfractions resulting from the column chromatography separation of the polyphenolic fraction also showed relatively strong antioxidant activities(IC50: 17.46–217.14 μg/m L). The subfraction(F6) stimulated the Nrf2 signaling pathway and had HMG-Co A reductase inhibitory activity(65.43%). Moreover, the subfraction contained two main flavonoids: quercetin and quercimeritrin.Conclusions: The polyphenolic fraction of Guazuma ulmifolia could induce antioxidant genes via the Nrf2/antioxidant regulatory elements pathway, and is a promising candidate for an inhibitor of HMG-Co A reductase.
文摘Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are widely used for the treatment of hypercholesteremia and have showed remarkable activity in preventing cardiovascular morbidity and mortality. Recent studies demonstrated that statins have significant antithrombotic effect in addition to cholesterollowering action. Although the efficacy of statins for reducing cardiovascular events has historically been ascribed to their inhibitory activity on cholesterol synthesis, the degree of low-density lipoprotein cholesterol reduction by statins generally does not correlate with the magnitude of coronary risk reduction.
文摘Objective To evaluate whether the effects of HMG - CoA reductase inhibitors on patients with hyperlipidemia are closely related to baseline lipid levels. Methods The data analyzed originated from 3 separate multicenter clinical trials with similar designs during 1994 to 1999. 166 patients with mean age 58. 9±9. 2 years were involved in Simvastatin Clinical Trial with simvastatin 10 mg once daily for 8 weeks. 146 patients with mean age 57. 9±8. 7years were involved in Lovastatin Clinical Trial with lovastatin 20 mg once daily for 8 weeks. 105 patients with mean age 57. 8±9. 3 years were involved in Atorvastatin Clinical Trial with atorvastatin 10 mg once daily for 6 weeks. Baseline total cholesterol (TC) was more than 5. 98 mmol. L - 1, and baseline triglyceride (TG) was less than 4. 52 mmo. L - 1. The patients were grouped by baseline lipid levels. Results The higher the baseline TC, low density lipoprotein cholesterol (LDL - C) and TG levels were, the more effective the simvastatin, lovastatin, or atorvastatin was in reducing serum TC, LDL - C, and TG, respectively. A positive linear correlation was found between baseline values and effects of simvastatin, lovastatin, or atorvastatin in reducing serum TC, LDL - C, and TG, respectively. Conclusion The changes of reduction on serum lipid with HMG - CoA reductase inhibitors in patients with hyperlipidemia were influenced by baseline lipid levels.
基金SN and GBR are supported by grants from the Science and Engineering Research Board,Government of India(EMR/2016/001984)Indian Council of Medical Research.
文摘Aldo-keto reductases(AKRs)are a superfamily of enzymes that play crucial roles in various cellular processes,including the metabolism of xenobiotics,steroids,and carbohydrates.A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers.AKRs are aberrantly expressed in a wide range of malignant tumors.Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance.AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression.Inhibition of aldose reductase(AR),either alone or in combination with chemotherapeutic drugs,has evolved as a pragmatic therapeutic option for cancer.Several classes of synthetic aldo-keto reductase(AKR)inhibitors have been developed as potential anticancer agents,some of which have shown promise in clinical trials.Many AKR inhibitors from natural sources also exhibit anticancer effects.Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies.These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy.In this review,we discuss the physiological functions of human AKRs,the aberrant expression of AKRs in malignancies,the involvement of AKRs in the acquisition of cancer hallmarks,and the role of AKRs in oncogenic signaling,and drug resistance.Finally,the potential of aldose reductase inhibitors(ARIs)as anticancer drugs is summarized.
基金National Yang Ming Chiao Tung University Far Eastern Memorial Hospital Joint Research Programs(NYCU-FEMH 109DN03,110DN06,111DN04,112DN05).
文摘Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.
基金supported by the National Natural Science Foundation of China (31771489 and 31571384)
文摘Salt acclimation, which is induced by previous salt exposure, increases the resistance of plants to future exposure to salt stress. However, little is known about the underlying mechanism, particularly how plants store the"memory" of salt exposure. In this study, we established a system to study salt acclimation in Arabidopsis thaliana. Following treatment with a low concentration of salt, seedlings were allowed to recover to allow transitory salt responses to subside while maintaining the sustainable effects of salt acclimation. We performed transcriptome profiling analysis of these seedlings to identify genes related to salt acclimation memory. Notably, the expres-sion of Basic-leucine zipper 17 (bZIP17) and Hmg-CoA reductase degradation 3A (HRD3A), which are important in the unfolded protein response (UPR) and endoplasmic reticulum-associated degradation (ERAD), respectively, increased following treatment with a low concentration of salt and remained at stably high levels after the stimulus was removed, a treatment which improved plant tolerance to future high-salinity challenge. Our findings suggest that the upregulated expression of important genes involved in the UPR and ERAD represents a "memory" of the history of salt exposure and enables more potent responses to future exposure to salt stress, providing new insights into the mechanisms underlying salt acclimation in plants.
文摘AIM:To investigate the aldose reductase(AR)inhibition capacity of astragalin(AST)against streptozoticin-induced diabetic cataracts(DCs)in rats.METHODS:Ex vivo investigations were conducted by treating the lens of a goat placed for 72h in artificial aqueous humor(AAH)of pH 7.8 at room temperature with cataract-causing substance(55 mmol/L of galactose)and in vivo studies were performed on rats via induction with streptozotocin.AST was administered at different dose levels and scrutinize for DC activity.RESULTS:In diabetic rats,AST improved the body weight,blood insulin,and glucose as well as the levels of galactitol in a dose-dependent way,other biochemical parameters i.e.inflammatory mediators and cytokines,and also suppress AR activity.The level of the antioxidant parameters such as superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)activity were also altered on a diabetic lens after the administration of the AST.CONCLUSION:AST protects against lens opacification to avoid cataracts and polyols formation,indicating that it could be used as a potential therapeutic agent for diabetes.
基金Acknowledgment This work was supported by the National High Tech- nology Research and Development Program of China (Grants 2004AA216090 and 2002BA711A08), National Basic Research Program of China (Grant 2004Cb518805), the Natural National Science Foundation of China (Grant 30470960) and the China Medical Board of New York.
文摘Aim: To analyze the distribution of the single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene in 355 infertile Chinese patients with idiopathic azoospermia or severe oligozoospermia and 252 fertile Chinese men as controls to explore the possible association of the SNP and male infertility. Methods: Using the polymerase chain reaction (PCR)-restriction fragment length polymorphism technique, the allele and genotype distribution of SNP C677T in the MTHFR gene were investigated in both patients and controls. Results: The frequencies of allele T (40.9% vs 30.4%, P = 0.002, odds ration [OR] = 1.58, 95% confidence interval [CI]: 1.24-2.02) and mutant homozygote (TT) (18.3% vs. 11.5%, P = 0.023, OR = 1.72, 95% CI: 1.07-2.76) as well as carrier with allele (TT + CT) (63.4% vs. 49.2%, P = 0.0005, OR = 1.79, 95% CI: 1.29-2.48) in infertile patients were significantly higher than those in controls. After patient stratification, the significant differences in distribution of the SNP between each patient subgroup and control group still remained. Conclusion: Our findings indicate that there is an association of SNP C677T in the MTHFR gene with male infertility, suggesting that this polymorphism might be a genetic risk factor for male infertility in Chinese men.
基金Financial supports by the National Natural Science Foun-dation of China (30070431)the Key Technologies R&D Program of China during the 9th Five-Year Plan period(95-Agric-18-04)+1 种基金the Doctoral Fund of Ministry of Edu-cation of China (200805041061)the Earmarked Fund for Modern Agro-Industry Technology Research System, China
文摘The objective is to study whether the accumulation and utilization of plant N are controlled by Mo status in winter wheat cultivars. Mo-efficient cultivar 97003 (eft) and Mo-inefficient cultivar 97014 (ineff) were grown in severely Mo-deficient acidic soil (Tamm-reagent-extractable Mo 0.112 mg kg^-1) with (+Mo) and without (-Mo) the application of 0.13 mg kg^-1 Mo. The accumulation and use efficiency of plant total N were significantly higher in +Mo than that in -Mo and in eft than that in ineff under Mo deficiency. N use efficiency was remarkably higher in maturity but it was forwarded to jointing stage after Mo supply, thus indicating that Mo supply promoted the N use efficiency besides N uptake and eff was efficient in N uptake and utilization. The overall activity of nitrate reductase (NR, EC 1.6.6.1) was significantly higher in +Mo than in -Mo and ratio of +Mo/-Mo was even to 14.8 at filleting stage for ineff. Activity of glutamine synthetase (GS, EC 6.3.1.2) was significantly lower in +Mo than in -Mo. Concentration of nitrate and glutamate were also significantly lower in +Mo than in -Mo, thus provided evidences for enhancing N use efficiency by Mo supply. Activities of NR and GS were significantly higher and concentrations of nitrate and glutamate were significantly lower in eff than ineff under Mo deficiency, thus indicated eff was more efficient in N reduction and utilization. It is therefore concluded that Mo could promote N accumulation and utilization in winter wheat which was directly related to NR and feedback regulated by GS. Higher Mo status also results in higher accumulation and utilization of plant N in eft.
文摘AIM: To identify the association between methylenetetrahydrofolate reductase(MTHFR) polymorphisms and gastric cancer(GC) susceptibility.METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio(OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I2 statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed.RESULTS: Increased risk was found for the MTHFRC677T polymorphism under four genetic models(TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677 T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677 T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677 T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298 C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations(CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04). CONCLUSION: MTHFR C677 T polymorphism is a risk factor for GC, and the A1298 C polymorphism may be a protective factor against GC in eastern populations.
文摘Objective:To assesse the inhibitor) effect of alcoholic extract of two Indian medicinal plants namely Ceasalpinia digyna Rottler and.Alangium lamarckii Thwaits on aldose reductase(AR) of rat lens.Methods:Rats lens were enucleated through posterior approach and their homogenate was prepared and centrifuged to obtain a clear supernatant for the determination of AR activity and protein content.Results:The alcoholic extract of Ceasalpirda digyna and Alangium lamarckii had a potent inhibitory effect on the lens AR enzyme.The IC<sub>50</sub> values of alcoholic extract of the selected plants were calculated and were(46.29±11.17) and(106.00±5.11)μg/mL,respectively. Quercetin was used as a positive control and its IC<sub>50</sub> value was(2.95±1.53)μg/mL.Conclusions:Thus,it is concluded that alcoholic extracts of the selected plant exhibit significant inhibitory effects on AR in the rat lens in vitro.
基金supported by the National Natural Science Foundation of China (30471187)
文摘In China, nitrogen fertilizer application rates in intensive agricultural systems have increased dramatically in recent years, especially in protected vegetable production systems. This excessive use of nitrogen fertilizer has resulted in soil secondary salinization, which has become a significant environmental stress for crops such as cucumber, in the protected farmland of China. So it is necessary to illuminate how crops respond to nitrate stress. The objective of this work was to examine the effects of increased nitrate concentration [14 (CK) and 140 mmol L^-1 (T)] on NO3- concentration, and in vitro and in vivo nitrate reductase activities in the roots and leaves of cucumber (Cucumis sativus L. cv. Xintaimici) seedlings with hydroponic culture. The results showed that the NO3- concentration in the roots and leaves of T seedlings significantly increased over treatment course, and at 12 d increased by 1.08 and 1.72 times with respect to CK seedlings, respectively; in vitro nitrate reductase activity of T was increased dramatically to 1.74 times of CK in the roots at 2 d and 1.56 times of CK in the leaves at 6 d, and then decreased. At 12 d, in vitro activity was still 24.3% higher in the roots and only 9.9% lower in the leaves than CK. Compared with in vitro nitrate reductase activity, in vivo activity responded differently to the increase of treatment time. At the beginning, in vivo nitrate reductase activity in the roots and leaves of T had no significant difference from CK, whereas with the increase of treatment duration, the activity decreased. At 12 d, in vivo activity in the roots and leaves of T lowered by 20.1 and 52.8% with respect to CK, respectively. This evidence suggests that posttranslational activation of nitrate reductase in cucumber seedlings may be seriously inhibited by nitrate stress.
基金Supported by The Swedish Research Council Medicine,No.3529The Swedish Cancer Society,No.961The Wallenberg Foundation
文摘Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas made it an important target for the development ofantiviral and anticancer drugs. Taking account of the re-cent developments in this field of research, this reviewfocuses on the role of thioredoxin and glutaredoxin sys-tems in the redox reactions of the RNR catalysis.
基金supported by Grants from the National Basic Research Program of China(No.2011CB504300)the Program for New Century Excellent Talents in University(No.NCET-12-0654)the Department of Education of the Guangxi Zhuang Autonomous Region(No.201203YB051)
文摘Background:Cytochrome b5 reductase 2(CYB5R2) is a potential tumor suppressor that inhibits cell proliferation and motility in nasopharyngeal carcinoma(NPC).Inactivation of CYB5R2 is associated with lymph node metastasis in NPC.This study aimed to explore the mechanisms contributing to the anti-neoplastic effects of CYB5R2.Methods:Polymerase chain reaction(PCR) assays were used to analyze the transcription of 84 genes known to be involved in representative cancer pathways in the NPC cell line HONE1.NPC cell lines CNE2 and HONE1 were transiently transfected with CYB5R2,and data was validated by real-time PCR.A chick chorioallantoic membrane(CAM)embryo model was implanted with CYB5R2-expressing CNE2 and HONE1 cells to evaluate the effect of CYB5R2 on angiogenesis.An immunohistochemical assay of the CAM model was used to analyze the protein expression of vascular endothelial growth factor(VEGF).Results:In CYB5R2-transfected NPC cells,PCR assays revealed up-regulated mRNA levels of Fas cell surface death receptor(FAS),FBJ murine osteosarcoma viral oncogene homolog(FOS),phosphoinositide-3-kinase regulatory subunit 1(PIK3R1),integrin beta 3(ITGB3),metastasis suppressor 1(MTSSl),interferon beta 1(IFNB1),and cyclin-dependent kinase inhibitor 2A(CDKN2A) and down-regulated levels of integrin beta 5(ITGB5),insulin-like growth factor 1(IGF1),TEK tyrosine kinase(TEK),transforming growth factor beta receptor 1(TGFBRl),and VEGF.The angiogenesis in the CAM model implanted with CYB5R2-transfected NPC cells was inhibited.Down-regulation of VEGF by CYB5R2 in NPC cells was confirmed by immunohistochemical staining in the CAM model.Conclusion:CYB5R2 up-regulates the expression of genes that negatively modulate angiogenesis in NPC cells and down-regulates the expression of VEGF to reduce angiogenesis,thereby suppressing tumor formation.
基金supported by University Grants Commission,New Delhi(grant No.IT/DEV/08-09/3252/L)
文摘Objective:To evaluate the aldose reductase inhibitory(ARI)activity of different fractions of Hybanthus enneaspermus for potential use in diabetic cataract.Methods:Total phenol and flavonoid content of different fractions was determined.ARI activity of different fractions in rat lens was investigated in vitro.Results:The results showed significant level of phenolic and flavonoid content in ethyl acetate fraction[total phenol(212.15±0.79 mg/g),total flavonoid(39.11±2.27mg/g)]and aqueous fraction[total phenol(140.62±0.57mg/g),total flavonoid(26.07±1.49 mg/g)]as compared with the chloroform fraction[total phenol(68.56±0.51mg/g),total flavonoid(13.41±0.82mg/g)]and petrolium ether fraction[total phenol(36.68±0.43mg/g),total flavonoid(11.55±1.06mg/g)].There was a significant difference in the ARI activity of each fraction,and it was found to be the highest in ethyl acetate fraction[IC_(50)(49.26±1.76μg/mL)]followed by aqueous extract[IC_(50)(70.83±2.82μg/mL)]and it was least in the petroleum ether fraction[IC_(50)(118.89±0.71μg/mL)].Chloroform fraction showed moderate activity[IC_(50)(98.52±1.80μg/mL)].Conclusions:Different fractions showed significanct amount of ARI activity,where in ethyl acetate fraction it was found to be maximum which may be due to its high phenolic and flavonoid content.The extract after further evaluation may be used in the treatment of diabetic cataract.