Publications by authors named "Xiaomei Liang"

46 Publications

A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy.

Nano Lett 2021 02 21;21(3):1484-1492. Epub 2021 Jan 21.

Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, P.R. China.

Existing nanoparticle-mediated drug delivery systems for glioma systemic chemotherapy remain a great challenge due to poor delivery efficiency resulting from the blood brain barrier/blood-(brain tumor) barrier (BBB/BBTB) and insufficient tumor penetration. Here, we demonstrate a distinct design by patching doxorubicin-loaded heparin-based nanoparticles (DNs) onto the surface of natural grapefruit extracellular vesicles (EVs), to fabricate biomimetic EV-DNs, achieving efficient drug delivery and thus significantly enhancing antiglioma efficacy. The patching strategy allows the unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs. The biomimetic EV-DNs are enabled to bypass BBB/BBTB and penetrate into glioma tissues by receptor-mediated transcytosis and membrane fusion, greatly promoting cellular internalization and antiproliferation ability as well as extending circulation time. We demonstrate that a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo.
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http://dx.doi.org/10.1021/acs.nanolett.0c04753DOI Listing
February 2021

Advances in Research on the Toxicological Effects of Selenium.

Bull Environ Contam Toxicol 2021 Jan 9. Epub 2021 Jan 9.

College of Biology & Pharmacy, Yulin Normal University, Yulin, 537000, Guangxi, China.

Selenium is a trace element necessary for the growth of organisms. Moreover, selenium supplementation can improve the immunity and fertility of the body, as well as its ability to resist oxidation, tumors, heavy metals, and pathogenic microorganisms. However, owing to the duality of selenium, excessive selenium supplementation can cause certain toxic effects on the growth and development of the body and may even result in death in severe cases. At present, increasing attention is being paid to the development and utilization of selenium as a micronutrient, but its potential toxicity tends to be neglected. This study systematically reviews recent research on the toxicological effects of selenium, aiming to provide theoretical references for selenium toxicology-related research and theoretical support for the development of selenium-containing drugs, selenium-enriched dietary supplements, and selenium-enriched foods.
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http://dx.doi.org/10.1007/s00128-020-03094-3DOI Listing
January 2021

Genetic mapping of a novel powdery mildew resistance gene in wild emmer wheat from "Evolution Canyon" in Mt. Carmel Israel.

Theor Appl Genet 2021 Mar 3;134(3):909-921. Epub 2021 Jan 3.

State Key Laboratory of Crop Biology, Shandong Key Laboratory of Crop Biology, College of Agronomy, Shandong Agricultural University, 271018, Tai'an, China.

Key Message: A single dominant powdery mildew resistance gene MlNFS10 was identified in wild emmer wheat and mapped within a 0.3cM genetic interval spanning a 2.1Mb physical interval on chromosome arm 4AL. Wheat powdery mildew caused by Blumeria graminis forma specialis tritici (Bgt) is a globally devastating disease. The use of powdery mildew resistance genes from wild relatives of wheat is an effective method of disease management. Our previous research has shown that disruptive ecological selection has driven the discrete adaptations of the wild emmer wheat population on the south facing slope (SFS) and north facing slope (NFS) at the microsite of "Evolution Canyon" at Mount Carmel, Israel and demonstrated that 16 accessions in the NFS population display high resistance to 11 powdery mildew isolates (collected from different wheat fields in China). Here, we constructed bi-parental population by crossing the accession NFS-10 (resistant to 22 Bgt races collected from China in seedling resistance screen) and the susceptible line SFS2-12. Genetic analysis indicated that NFS-10 carries a single dominant gene, temporarily designated MlNFS10. Ultimately, 13 markers were successfully located within the long arm of chromosome 4A, thereby delineating MlNFS10 to a 0.3 cM interval covering 2.1 Mb (729275816-731365462) in the Chinese Spring reference sequence. We identified disease resistance-associated genes based on the RNA-seq analysis of both parents. The tightly linked InDel marker XWsdau73447 and SSR marker XWsdau72928 were developed and used for marker-assisted selection when MlNFS10 was introgressed into a hexaploid wheat background. Therefore, MlNFS10 can be used for improvement of germplasm in breeding programs for powdery mildew resistant cultivars.
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http://dx.doi.org/10.1007/s00122-020-03741-7DOI Listing
March 2021

Multimodal analysis of gene expression from postmortem brains and blood identifies synaptic vesicle trafficking genes to be associated with Parkinson's disease.

Brief Bioinform 2020 10 20. Epub 2020 Oct 20.

Head of Department of Neurology, Zhujiang Hospital, Southern Medical University, China.

Objective: We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson's disease (PD) patients and healthy controls (HC).

Methods: We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein-protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson's Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS.

Results: We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P < 0.05), and PPI analysis revealed that SVT genes PPP2CA, SYNJ1, NSF and PPP3CB were the top four hub node genes in MEturquoise (P < 0.001). The levels of these four genes in PD postmortem brains were lower than those in HC brains. We found lower blood levels of PPP2CA, SYNJ1 and NSF in PD compared with HC, and lower SYNJ1 in PD compared with PPS (P < 0.05). SYNJ1, negatively correlated to PD severity, displayed an excellent power to discriminating PD from HC and PPS.

Conclusions: This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.
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http://dx.doi.org/10.1093/bib/bbaa244DOI Listing
October 2020

Predictive Value of Fibrinogen-to-Albumin Ratio for Post-Contrast Acute Kidney Injury in Patients Undergoing Elective Percutaneous Coronary Intervention.

Med Sci Monit 2020 Jul 20;26:e924498. Epub 2020 Jul 20.

Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland).

BACKGROUND Post-contrast acute kidney injury (PC-AKI) is a contributor to adverse outcomes after percutaneous coronary intervention (PCI). This study aimed to investigate whether fibrinogen-to-albumin ratio (FAR), a novel inflammation-based risk index, can predict the occurrence of PC-AKI in patients undergoing elective PCI. MATERIAL AND METHODS We retrospectively enrolled 291 patients who underwent elective PCI from June 2017 to June 2019. PC-AKI was defined as an increase in serum creatinine ≥0.3 mg/dL (≥26.5 μmol/L), or ≥1.5 times baseline within 48 to 72 hours after PCI. The area under the receiver-operating characteristic curve (AUC), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to make comparison for PC-AKI prediction. RESULTS PC-AKI occurred in 43 patients (14.8%). FAR showed an AUC of 0.691 (95% confidence interval: 0.64-0.74; P<0.001) in predicting PC-AKI. In stepwise multivariable logistic regression, FAR was independently associated with the occurrence of PC-AKI along with hypertension, diabetes, hemoglobin, estimated glomerular filtration rate, and left ventricular ejection fraction. FAR significantly improved PC-AKI prediction over Mehran risk score in the continuous NRI and IDI, but not AUC. CONCLUSIONS FAR is independently associated with the occurrence of PC-AKI, and can significantly improve PC-AKI prediction over Mehran risk score in patients undergoing elective PCI.
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http://dx.doi.org/10.12659/MSM.924498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757022PMC
July 2020

Natural and engineered chemokine (C-X-C motif) receptor 4 agonists prevent acute respiratory distress syndrome after lung ischemia-reperfusion injury and hemorrhage.

Sci Rep 2020 07 9;10(1):11359. Epub 2020 Jul 9.

Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

We compared therapeutic properties of natural and engineered chemokine (C-X-C motif) receptor 4 (CXCR4) agonists in a rat acute respiratory distress syndrome (ARDS) model utilizing the PaO/FiO-ratio as a clinically relevant primary outcome criterion. Ventilated rats underwent unilateral lung ischemia from t = 0-70 min plus hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg from t = 40-70 min, followed by reperfusion/fluid resuscitation until t = 300 min. Natural CXCR4 agonists (CXCL12, ubiquitin) and engineered CXCL12 variants (CXCL12, CXCL2, CXCL12K27A/R41A/R47A, CXCL12 (3-68)) were administered within 5 min of fluid resuscitation. Animals treated with vehicle or CXCL12 (3-68) reached criteria for mild and moderate ARDS between t = 90-120 min and t = 120-180 min, respectively, and remained in moderate ARDS until t = 300 min. Ubiquitin, CXCL12, CXCL12 and CXCL12 prevented ARDS development. Potencies of CXCL12/CXCL12/CXCL12 were higher than the potency of ubiquitin. CXCL12K27A/R41A/R47A was inefficacious. CXCL12 > CXCL12 stabilized MAP and reduced fluid requirements. CXCR4 agonists at doses that preserved lung function reduced histological injury of the post-ischemic lung and reduced mortality from 55 to 9%. Our findings suggest that CXCR4 protein agonists prevent development of ARDS and reduce mortality in a rat model, and that development of new engineered protein therapeutics with improved pharmacological properties for ARDS is possible.
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http://dx.doi.org/10.1038/s41598-020-68425-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347544PMC
July 2020

Generation of Transgenic Self-Incompatible Shows a Genus-Specific Preference for Self-Incompatibility Genes.

Plants (Basel) 2019 Dec 4;8(12). Epub 2019 Dec 4.

National Key Laboratory of Crop Genetic Improvement, National Center of Rapeseed Improvement in Wuhan, Huazhong Agricultural University, Wuhan 430070, China.

species employ both self-compatibility and self-incompatibility systems to regulate post-pollination events. is strictly self-incompatible, while the closely related has transitioned to self-compatibility with the loss of functional -locus genes during evolution. The downstream signaling protein, ARC1, is also required for the self-incompatibility response in some and species, and its gene is deleted in the genome. In this study, we attempted to reconstitute the SCR-SRK-ARC1 signaling pathway to restore self-incompatibility in using genes from and , respectively. Several of the transgenic lines expressing the transgenes displayed self-incompatibility, while all the transgenic lines expressing the transgenes failed to show any self-pollen rejection. Furthermore, our results showed that the intensity of the self-incompatibility response in transgenic plants was not associated with the expression levels of the transgenes. Thus, this suggests that there are differences between the and self-incompatibility signaling pathways, which perhaps points to the existence of other factors downstream of that are absent in species.
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http://dx.doi.org/10.3390/plants8120570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963867PMC
December 2019

The differences in the esophageal motility between liquid and solid bolus swallows: A multicenter high-resolution manometry study in Chinese asymptomatic volunteers.

Neurogastroenterol Motil 2019 06 28;31(6):e13574. Epub 2019 Feb 28.

Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: The results of the esophageal body motility differences between liquid and solid swallows from high-resolution manometry (HRM) studies are not consistent. The information of the frequency of ineffective liquid and solid bolus swallows in healthy individuals during HRM procedure is limited. The normative values of the HRM parameters of both liquid and solid swallows for Chinese population are lacking.

Methods: The esophageal HRM data of 101 healthy volunteers from multicenters in China were analyzed. The values of the HRM parameters were summarized and compared between liquid and solid swallows. The frequencies of ineffective liquid and solid swallows were summarized.

Results: Esophagus contracted stronger and slower in solid bolus swallows than water swallows with HREM. Ineffective water swallow (DCI < 450 mm Hg.s.cm) and ineffective bread swallow (DCI < 800 mm Hg.s.cm) were frequently seen in asymptomatic individuals. The adding of bread swallows to the HREM procedure might cause diagnostic change in about 15.8% (16/101) of the asymptomatic individuals.

Conclusions: The vigor and velocity of the esophageal peristalsis between liquid and solid bolus swallows are different. Ineffective water and solid bolus swallows are not rare. Adding solid bolus swallows brings diagnostic change, and it may be needed routinely for the HRM procedure.
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http://dx.doi.org/10.1111/nmo.13574DOI Listing
June 2019

Mechanism of Salt-Induced Self-Compatibility Dissected by Comparative Proteomic Analysis in L.

Int J Mol Sci 2018 Jun 3;19(6). Epub 2018 Jun 3.

National Key Laboratory of Crop Genetic Improvement, National Center of Rapeseed Improvement in Wuhan, Huazhong Agricultural University, Wuhan 430070, China.

Self-incompatibility (SI) in plants genetically prevents self-fertilization to promote outcrossing and genetic diversity. Its hybrids in have been widely cultivated due to the propagation of SI lines by spraying a salt solution. We demonstrated that suppression of SI from edible salt solution treatment was ascribed to sodium chloride and independent of haplotypes, but it did not obviously change the expression of SIrelated genes. Using the isobaric tags for relative and absolute quantitation (iTRAQ) technique, we identified 885 differentially accumulated proteins (DAPs) in stigmas of un-pollinated (UP), pollinated with compatible pollen (PC), pollinated with incompatible pollen (PI), and pollinated with incompatible pollen after edible salt solution treatment (NA). Of the 307 DAPs in NA/UP, 134 were unique and 94 were shared only with PC/UP. In PC and NA, some salt stress protein species, such as , were induced, and these protein species were likely to participate in the self-compatibility (SC) pathway. Most of the identified protein species were related to metabolic pathways, biosynthesis of secondary metabolites, ribosome, and so on. A systematic analysis implied that salt treatment-overcoming SI in was likely conferred by at least five different physiological mechanisms: (i) the use of Ca as signal molecule; (ii) loosening of the cell wall to allow pollen tube penetration; (iii) synthesis of compatibility factor protein species for pollen tube growth; (iv) depolymerization of microtubule networks to facilitate pollen tube movement; and (v) inhibition of protein degradation pathways to restrain the SI response.
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http://dx.doi.org/10.3390/ijms19061652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032146PMC
June 2018

Thymoquinone ameliorates diabetic phenotype in Diet-Induced Obesity mice via activation of SIRT-1-dependent pathways.

PLoS One 2017 26;12(9):e0185374. Epub 2017 Sep 26.

Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, United States of America.

Thymoquinone, a natural occurring quinone and the main bioactive component of plant Nigella sativa, undergoes intracellular redox cycling and re-oxidizes NADH to NAD+. TQ administration (20 mg/kg/bw/day) to the Diet-Induced Obesity (DIO) mice reduced their diabetic phenotype by decreasing fasting blood glucose and fasting insulin levels, and improved glucose tolerance and insulin sensitivity as evaluated by oral glucose and insulin tolerance tests (OGTT and ITT). Furthermore, TQ decreased serum cholesterol levels and liver triglycerides, increased protein expression of phosphorylated Akt, decreased serum levels of inflammatory markers resistin and MCP-1, and decreased NADH/NAD+ ratio. These changes were paralleled by an increase in phosphorylated SIRT-1 and AMPKα in liver and phosphorylated SIRT-1 in skeletal muscle. TQ also increased insulin sensitivity in insulin-resistant HepG2 cells via a SIRT-1-dependent mechanism. These findings are consistent with the TQ-dependent re-oxidation of NADH to NAD+, which stimulates glucose and fatty acid oxidation and activation of SIRT-1-dependent pathways. Taken together, these results demonstrate that TQ ameliorates the diabetic phenotype in the DIO mouse model of type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185374PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614580PMC
October 2017

BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt.

Environ Toxicol Pharmacol 2017 Dec 1;56:29-34. Epub 2017 Sep 1.

Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, 33612, United States. Electronic address:

PBDEs (polybrominated diphenyl ethers) are environmental pollutants that have been linked to the development of type 2 diabetes, however, the precise mechanisms are not clear. Particularly, their direct effect on insulin secretion is unknown. In this study, we show that two PBDE congeners, BDE-47 and BDE-85, potentiate glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells. This effect of BDE-47 and BDE-85 on GSIS was dependent on thyroid receptor (TR). Both BDE-47 and BDE-85 (10μM) activated Akt during an acute exposure. The activation of Akt by BDE-47 and BDE-85 plays a role in their potentiation of GSIS, as pharmacological inhibition of PI3K, an upstream activator of Akt, significantly lowers GSIS compared to compounds alone. This study shows that BDE-47 and BDE-85 directly act on pancreatic β-cells to stimulate GSIS, and that this effect is mediated by the thyroid receptor (TR) and Akt activation.
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http://dx.doi.org/10.1016/j.etap.2017.08.030DOI Listing
December 2017

Mechanisms of Doxorubicin Toxicity in Pancreatic β-Cells.

Toxicol Sci 2016 08 2;152(2):395-405. Epub 2016 Jun 2.

*Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612 Department of Science, United States Coast Guard Academy, New London, Connecticut 06320

Exposure to chemotherapeutic agents has been linked to an increased risk of type 2 diabetes (T2D), a disease characterized by both the peripheral insulin resistance and impaired glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. Using the rat β-cell line INS-1 832/13 and isolated mouse pancreatic islets, we investigated the effect of the chemotherapeutic drug doxorubicin (Adriamycin) on pancreatic β-cell survival and function. Exposure of INS-1 832/13 cells to doxorubicin caused impairment of GSIS, cellular viability, an increase in cellular toxicity, as soon as 6 h post-exposure. Doxorubicin impaired plasma membrane electron transport (PMET), a pathway dependent on reduced equivalents NADH and NADPH, but failed to redox cycle in INS-1 832/13 cells and with their lysates. Although NADPH/NADP(+ )content was unaffected, NADH/NAD(+ )content decreased at 4 h post-exposure to doxorubicin, and was followed by a reduction in ATP content. Previous studies have demonstrated that doxorubicin functions as a topoisomerase II inhibitor via induction of DNA cross-linking, resulting in apoptosis. Doxorubicin induced the expression of mRNA for mdm2, cyclin G1, and fas whereas downregulating p53, and increased the melting temperature of genomic DNA, consistent with DNA damage and induction of apoptosis. Doxorubicin also induced caspase-3 and -7 activity in INS-1 832/13 cells and mouse islets; co-treatment with the pan-caspase inhibitor Z-VAD-FMK temporarily attenuated the doxorubicin-mediated loss of viability in INS-1 832/13 cells. Together, these data suggest that DNA damage, not H2O2 produced via redox cycling, is a major mechanism of doxorubicin toxicity in pancreatic β-cells.
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http://dx.doi.org/10.1093/toxsci/kfw096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960911PMC
August 2016

Synthesis of NAM-thiazoline derivatives as novel O-GlcNAcase inhibitors.

Carbohydr Res 2016 Jun 13;429:54-61. Epub 2016 Apr 13.

Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. Electronic address:

Human O-GlcNAcase (GH 84) and human β-N-acetyl-D-hexosaminidase (GH 20) from Homo sapiens are two therapeutic enzyme targets that share the same catalytic mechanism but play different physiological roles in vivo. Selective inhibition toward one of these enzymes is therefore of importance to regulate the corresponding bioprocess. Here ten new NAM-thiazoline derivatives were synthesized and subsequently characterized by NMR and HRMS. A preliminary bioassay showed that most of the synthesized compounds exhibited obvious selective inhibition against human O-GlcNAcase over human β-N-acetyl-D-hexosaminidase. Among the compounds tested, compound 7d (IC50 = 6.4 µM, hOGA; IC50>1 mM, hHex) and 7f (IC50 = 11.9 µM, hOGA; IC50>1 mM, hHex) proved to be a highly selective and potent inhibitor. Structure-activity relationship analysis indicated a correlation between the inhibitory activity and the size of the groups linked to the thiazoline ring.
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http://dx.doi.org/10.1016/j.carres.2016.04.008DOI Listing
June 2016

A meta-analysis of neoadjuvant chemotherapy plus radiation in the treatment of locally advanced nasopharyngeal carcinoma.

J Cancer Res Ther 2015 Oct;11 Suppl 2:C205-8

Department of Lishui People's Hospital, Zhejiang Province 323000, China.

Objective: We perform this meta-analysis was to evaluate the efficacy of neoadjuvant chemotherapy followed by radiation in the treatment of locally advanced nasopharyngeal carcinoma.

Materials And Methods: We searched the database of Medline and Wanfang to screen and included the prospective, randomized controlled trials of neoadjuvant chemotherapy plus radiation versus radiotherapy in the treatment of locally advanced nasopharyngeal carcinoma. The pooled 5-year overall survival, 5 years disease free survival, recurrence rate, and metastasis rate were calculated by Stata version 11.0 statistical software.

Results: Five prospective clinical studies were included in this meta-analysis. The total number of cases included in this study was 1277. The pooled 5 years overall survival and 5 years disease free survival were not statistical different between the neoadjuvant chemotherapy plus radiation group and radiotherapy group, respectively (P > 0.05). But the recurrence rate (odds ratio [OR] = 0.65, P < 0.05) and metastasis rate (OR = 0.61, P < 0.05) were significantly lower in the neoadjuvant chemotherapy plus radiation group compared to radiotherapy group.

Conclusion: Neoadjuvant chemotherapy followed by radiation can decrease the risk of recurrence and metastasis but not improve the 5 years overall survival and 5 years disease free survival compared to radiotherapy alone in the patients with locally advanced nasopharyngeal carcinoma.
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http://dx.doi.org/10.4103/0973-1482.168186DOI Listing
October 2015

miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin 1-lipin-1 signaling.

Am J Pathol 2015 May 19;185(5):1286-96. Epub 2015 Mar 19.

Department of Pharmaceutical Sciences, Northeast Ohio Medical University, College of Pharmacy, Rootstown, Ohio. Electronic address:

Ethanol-mediated injury, combined with gut-derived lipopolysaccharide (LPS), provokes generation of proinflammatory cytokines in Kupffer cells, causing hepatic inflammation. Among the mediators of these effects, miR-217 aggravates ethanol-induced steatosis in hepatocytes. However, the role of miR-217 in ethanol-induced liver inflammation process is unknown. Here, we examined the role of miR-217 in the responses to ethanol, LPS, or a combination of ethanol and LPS in RAW 264.7 macrophages and in primary Kupffer cells. In macrophages, ethanol substantially exacerbated LPS-mediated induction of miR-217 and production of proinflammatory cytokines compared with LPS or ethanol alone. Consistently, ethanol administration to mice led to increases in miR-217 abundance and increased production of inflammatory cytokines in isolated primary Kupffer cells exposed to the combination of ethanol and LPS. miR-217 promoted combined ethanol and LPS-mediated inhibition of sirtuin 1 expression and activity in macrophages. Moreover, miR-217-mediated sirtuin 1 inhibition was accompanied by increased activities of two vital inflammatory regulators, NF-κB and the nuclear factor of activated T cells c4. Finally, adenovirus-mediated overexpression of miR-217 led to steatosis and inflammation in mice. These findings suggest that miR-217 is a pivotal regulator involved in ethanol-induced hepatic inflammation. Strategies to inhibit hepatic miR-217 could be a viable approach in attenuating alcoholic hepatitis.
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http://dx.doi.org/10.1016/j.ajpath.2015.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419208PMC
May 2015

Design, synthesis and bioactivity of novel glycosylthiadiazole derivatives.

Molecules 2014 Jun 11;19(6):7832-49. Epub 2014 Jun 11.

Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.

A series of novel glycosylthiadiazole derivatives, namely 2-phenylamino-5-glycosyl-1,3,4-thiadiazoles, were designed and synthesized by condensation between sugar aldehydes A/B and substituted thiosemicarbazide C followed by oxidative cyclization by treating with manganese dioxide. The original fungicidal activities results showed that some title compounds exhibited excellent fungicidal activities against Sclerotinia sclerotiorum (Lib.) de Bary and Pyricularia oryzae Cav, especially compounds F-5 and G-8 which displayed better fungicidal activities than the commercial fungicide chlorothalonil. At the same time, the preliminary studies based on the Elson-Morgan method indicated that many compounds exhibited some inhibitory activity toward glucosamine-6-phosphate synthase (GlmS). The structure-activity relationships (SAR) are discussed in terms of the effects of the substituents on both the benzene and the sugar ring.
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http://dx.doi.org/10.3390/molecules19067832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271630PMC
June 2014

Direct 2,3-O-isopropylidenation of α-D-mannopyranosides and the preparation of 3,6-branched mannose trisaccharides.

Molecules 2014 May 22;19(5):6683-93. Epub 2014 May 22.

Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.

A highly efficient, regioselective method for the direct 2,3-O-isopropylidenation of α-D-mannopyranosides is reported. Treatment of various α-D-mannopyranosides with 0.12 equiv of the TsOH·H2O and 2-methoxypropene at 70 °C gave 2,3-O-isopropylidene-α-D-mannopyranosides directly in 80%~90% yields. Based on this method, a 3,6-branched α-D-mannosyl trisaccharide was prepared in 50.4% total yield using p-nitrophenyl 2,3-O-isopropylidene-α-D-mannopyranoside as the starting material.
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http://dx.doi.org/10.3390/molecules19056683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270901PMC
May 2014

Synthesis and plant growth regulation activity of α-d-ManpNAc-(1→2)-[α-L-Rhap-(1→3)-]α-L-Rhap-(1→4)-β-d-GlupNAc-(1→3)-α-L-Rhap, the repeating unit of O-antigen of Rhizobium trifolii 4s.

Carbohydr Res 2014 Mar 12;388:87-93. Epub 2013 Dec 12.

Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.

The synthesis of a pentasaccharide 2 containing acetamido-2-deoxy-d-glucose and acetamido-2-deoxy-d-mannose related to the cell wall polysaccharide of Rhizobium trifolii 4s has been achieved by a [2+3] approach from commercially available l-rhamnose, d-glucose, and d-glucosamine as the starting materials. The target molecule was equipped with a p-methoxylphenyl handle at the reducing terminus to allow for further glycoconjugate formation via selective cleavage of this group. The bioassay suggested that the synthetic pentasaccharide 2 can stimulate the growth of wheat coleoptile similarly to indole-3-acetic acid (IAA), and promote the wheat seedling development before winter by seed treatment at a concentration of 20mg/L.
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http://dx.doi.org/10.1016/j.carres.2013.12.006DOI Listing
March 2014

Novel macrocyclic molecules based on 12a-N substituted 16-membered azalides and azalactams as potential antifungal agents.

Eur J Med Chem 2014 Feb 11;73:286-94. Epub 2013 Dec 11.

Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China. Electronic address:

Novel macrocyclic molecules comprising sulfonyl and acyl moiety at the position N-12a of 16-membered azalides (6a-n) and azalactams (10a-r) scaffold were synthesized from cyclododecanone 1 as starting material via 5 steps and 4 steps, respectively. The antifungal activity of these compounds against Sclerotinia sclerotiorum, Pyricularia oryzae, Botrytis cinerea, Rhizoctonia solani and Phytophthora capsici were evaluated and found that compounds possessing α-exomethylene (6c, 6d, 6e and 6g) showed antifungal activity comparable to commercial fungicide Chlorothalonil against P. oryzae and compounds possessing p-chlorobenzoyl exhibited enhanced antifungal activity than those with other substituents against S. sclerotiorum, P. oryzae, and B. cinerea. These findings suggested that the α-exomethylene and p-chlorobenzoyl may be two potential pharmacological active groups with antifungal activities.
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http://dx.doi.org/10.1016/j.ejmech.2013.11.032DOI Listing
February 2014

Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver.

Gastroenterology 2014 Mar 18;146(3):801-11. Epub 2013 Nov 18.

Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida. Electronic address:

Background & Aims: Sirtuin (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase that regulates hepatic lipid metabolism by modifying histones and transcription factors. Ethanol exposure disrupts SIRT1 activity and contributes to alcoholic liver disease in rodents, but the exact pathogenic mechanism is not clear. We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls).

Methods: We induced alcoholic liver injury in male Sirt1LKO and control mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Liver and serum samples were collected. We also measured messenger RNA levels of SIRT1, SFRS10, and lipin-1β and lipin-1α in liver samples from patients with alcoholic hepatitis and individuals without alcoholic hepatitis (controls).

Results: On the ethanol-containing diet, livers of Sirt1LKO mice accumulated larger amounts of hepatic lipid and expressed higher levels of inflammatory cytokines than control mice; serum of Sirt1LKO mice had increased levels of alanine aminotransferase and aspartate aminotransferase. Hepatic deletion of SIRT1 exacerbated ethanol-mediated defects in lipid metabolism, mainly by altering the function of lipin-1, a transcriptional regulator of lipid metabolism. In cultured mouse AML-12 hepatocytes, transgenic expression of SIRT1 prevented fat accumulation in response to ethanol exposure, largely by reversing the aberrations in lipin-1 signaling induced by ethanol. Liver samples from patients with alcoholic hepatitis had reduced levels of SIRT1 and a higher ratio of Lpin1β/α messenger RNAs than controls.

Conclusions: In mice, hepatic deletion of Sirt1 promotes steatosis, inflammation, and fibrosis in response to ethanol challenge. Ethanol-mediated impairment of hepatic SIRT1 signaling via lipin-1 contributes to development of alcoholic steatosis and inflammation. Reagents designed to increase SIRT1 regulation of lipin-1 can be developed to treat patients with alcoholic fatty liver disease.
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http://dx.doi.org/10.1053/j.gastro.2013.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943758PMC
March 2014

Engineered short branched-chain acyl-CoA synthesis in E. coli and acylation of chloramphenicol to branched-chain derivatives.

Appl Microbiol Biotechnol 2013 Dec 8;97(24):10339-48. Epub 2013 Oct 8.

Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 Xiqidao, Airport Economic Park, Tianjin, 300308, China.

Short branched-chain acyl-CoAs are important building blocks for a wide variety of pharmaceutically valuable natural products. Escherichia coli has been used as a heterologous host for the production of a variety of natural compounds for many years. In the current study, we engineered synthesis of isobutyryl-CoA and isovaleryl-CoA from glucose in E. coli by integration of the branched-chain α-keto acid dehydrogenase complex from Streptomyces avermitilis. In the presence of the chloramphenicol acetyltransferase (cat) gene, chloramphenicol was converted to both chloramphenicol-3-isobutyrate and chloramphenicol-3-isovalerate by the recombinant E. coli strains, which suggested successful synthesis of isobutyryl-CoA and isovaleryl-CoA. Furthermore, we improved the α-keto acid precursor supply by overexpressing the alsS gene from Bacillus subtilis and the ilvC and ilvD genes from E. coli and thus enhanced the synthesis of short branched-chain acyl-CoAs. By feeding 25 mg/L chloramphenicol, 2.96 ± 0.06 mg/L chloramphenicol-3-isobutyrate and 3.94 ± 0.06 mg/L chloramphenicol-3-isovalerate were generated by the engineered E. coli strain, which indicated efficient biosynthesis of short branched-chain acyl-CoAs. HPLC analysis showed that the most efficient E. coli strain produced 80.77 ± 3.83 nmol/g wet weight isovaleryl-CoA. To our knowledge, this is the first report of production of short branched-chain acyl-CoAs in E. coli and opens a way to biosynthesize various valuable natural compounds based on these special building blocks from renewable carbon sources.
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http://dx.doi.org/10.1007/s00253-013-5262-6DOI Listing
December 2013

Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice.

Hepatology 2013 Dec 17;58(6):1953-63. Epub 2013 Oct 17.

Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, FL.

Unlabelled: Lipin-1 regulates lipid metabolism by way of its function as an enzyme in the triglyceride synthesis pathway and as a transcriptional coregulatory protein and is highly up-regulated in alcoholic fatty liver disease. In the present study, using a liver-specific lipin-1-deficient (lipin-1LKO) mouse model, we aimed to investigate the functional role of lipin-1 in the development of alcoholic steatohepatitis and explore the underlying mechanisms. Alcoholic liver injury was achieved by pair feeding wild-type and lipin-1LKO mice with modified Lieber-DeCarli ethanol-containing low-fat diets for 4 weeks. Surprisingly, chronically ethanol-fed lipin-1LKO mice showed markedly greater hepatic triglyceride and cholesterol accumulation, and augmented elevation of serum liver enzymes accompanied by increased hepatic proinflammatory cytokine expression. Our studies further revealed that hepatic removal of lipin-1 in mice augmented ethanol-induced impairment of hepatic fatty acid oxidation and lipoprotein production, likely by way of deactivation of peroxisome proliferator-activated receptor γ coactivator-1 alpha, a prominent transcriptional regulator of lipid metabolism.

Conclusions: Liver-specific lipin-1 deficiency in mice exacerbates the development and progression of experimental alcohol-induced steatohepatitis. Pharmacological or nutritional modulation of hepatic lipin-1 may be beneficial for the prevention or treatment of human alcoholic fatty liver disease.
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http://dx.doi.org/10.1002/hep.26589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835749PMC
December 2013

Efficient synthesis and anti-fungal activity of oleanolic acid oxime esters.

Molecules 2013 Mar 21;18(3):3615-29. Epub 2013 Mar 21.

Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.

In order to develop potential glucosamine-6-phosphate synthase inhibitors and anti-fungal agents, twenty five oleanolic acid oxime esters were synthesized in an efficient way. The structures of the new compounds were confirmed by MS, HRMS, 1H-NMR and 13C-NMR. Preliminary studies based on means of the Elson-Morgan method indicated that many compounds exhibited some inhibitory activity of glucosamine-6-phosphate synthase (GlmS), and the original fungicidal activities results showed that some of the compounds exhibited good fungicidal activities towards Sclerotinia sclerotiorum (Lib.) de Bary, Rhizoctonia solani Kuhn and Botrytis cinerea Pers at the concentration of 50 µg/mL. These compounds would thus merit further study and development as antifungal agents.
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http://dx.doi.org/10.3390/molecules18033615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270060PMC
March 2013

Draft Genome Sequence of Streptomyces bottropensis ATCC 25435, a Bottromycin-Producing Actinomycete.

Genome Announc 2013 Mar 14;1(2):e0001913. Epub 2013 Mar 14.

Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.

A series of bottromycin antibiotics have been isolated and identified from Streptomyces bottropensis strain ATCC 25435. Here, a draft genome sequence of S. bottropensis ATCC 25435 is presented. The genome carries an intact biosynthetic gene cluster for bottromycin antibiotics, which provides insight into the combinatorial biosynthesis of bottromycin antibiotics.
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http://dx.doi.org/10.1128/genomeA.00019-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622962PMC
March 2013

Ethanol administration exacerbates the abnormalities in hepatic lipid oxidation in genetically obese mice.

Am J Physiol Gastrointest Liver Physiol 2013 Jan 8;304(1):G38-47. Epub 2012 Nov 8.

Department of Molecular Pharmacology, University of South Florida Health Sciences Center, Tampa, FL 33612, USA.

Alcohol consumption synergistically increases the risk and severity of liver damage in obese patients. To gain insight into cellular or molecular mechanisms underlying the development of fatty liver caused by ethanol-obesity synergism, we have carried out animal experiments that examine the effects of ethanol administration in genetically obese mice. Lean wild-type (WT) and obese (ob/ob) mice were subjected to ethanol feeding for 4 wk using a modified Lieber-DeCarli diet. After ethanol feeding, the ob/ob mice displayed much more pronounced changes in terms of liver steatosis and elevated plasma levels of alanine aminotransferase and aspartate aminotransferase, indicators of liver injury, compared with control mice. Mechanistic studies showed that ethanol feeding augmented the impairment of hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) signaling in the ob/ob mice. Moreover, the impairment of SIRT1-AMPK signaling was closely associated with altered hepatic functional activity of peroxisome proliferator-activated receptor γ coactivator-α and lipin-1, two vital downstream lipid regulators, which ultimately contributed to aggravated fatty liver observed in ethanol-fed ob/ob mice. Taken together, our novel findings suggest that ethanol administration to obese mice exacerbates fatty liver via impairment of the hepatic lipid metabolism pathways mediated largely by a central signaling system, the SIRT1-AMPK axis.
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http://dx.doi.org/10.1152/ajpgi.00309.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543633PMC
January 2013

Facile syntheses of the disaccharide repeating unit of the O-antigenic polysaccharide of Burkholderia pseudomallei strain 304b and its dimer and trimer.

Carbohydr Res 2011 Nov 9;346(16):2533-9. Epub 2011 Sep 9.

Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.

A highly efficient strategy for the preparation of a disaccharide-repeating unit of the O-antigenic polysaccharide of Burkholderia pseudomallei strain 304b, and its dimer and trimer, has been developed through a regio- and stereoselective manner using p-methoxylphenyl 2,4,6-tri-O-benzoyl-α-D-glucopyranoside and 3-O-allyloxycarbonyl-2,4-di-O-benzoyl-6-deoxy-α-L-talopyranosyl trichloroacetimidate as the key synthons. The target molecules were equipped with a p-methoxylphenyl handle at the reducing terminus to allow for their further functionalization and attachment to a carrier protein.
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http://dx.doi.org/10.1016/j.carres.2011.09.001DOI Listing
November 2011

Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice.

Hepatology 2012 Feb 29;55(2):437-46. Epub 2011 Dec 29.

Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, FL, USA.

Unlabelled: Lipin-1 is a protein that exhibits dual functions as a phosphatidic acid phosphohydrolase enzyme in the triglyceride synthesis pathways and a transcriptional coregulator. Our previous studies have shown that ethanol causes fatty liver by activation of sterol regulatory element-binding protein 1 (SREBP-1) and inhibition of hepatic AMP-activated protein kinase (AMPK) in mice. Here, we tested the hypothesis that AMPK-SREBP-1 signaling may be involved in ethanol-mediated up-regulation of lipin-1 gene expression. The effects of ethanol on lipin-1 were investigated in cultured hepatic cells and in the livers of chronic ethanol-fed mice. Ethanol exposure robustly induced activity of a mouse lipin-1 promoter, promoted cytoplasmic localization of lipin-1, and caused excess lipid accumulation, both in cultured hepatic cells and in mouse livers. Mechanistic studies showed that ethanol-mediated induction of lipin-1 gene expression was inhibited by a known activator of AMPK or overexpression of a constitutively active form of AMPK. Importantly, overexpression of the processed nuclear form of SREBP-1c abolished the ability of 5-aminoimidazole-4-carboxamide ribonucleoside to suppress ethanol-mediated induction of lipin-1 gene-expression level. Chromatin immunoprecipitation assays further revealed that ethanol exposure significantly increased the association of acetylated histone H3 at lysine 9 with the SRE-containing region in the promoter of the lipin-1 gene.

Conclusion: In conclusion, ethanol-induced up-regulation of lipin-1 gene expression is mediated through inhibition of AMPK and activation of SREBP-1.
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http://dx.doi.org/10.1002/hep.24708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253249PMC
February 2012

Two-step synthesis of fatty acid ethyl ester from soybean oil catalyzed by Yarrowia lipolytica lipase.

Biotechnol Biofuels 2011 Mar 2;4(1). Epub 2011 Mar 2.

State Key Laboratories for Agrobiotechnology and College of Biological Sciences, China Agricultural University, Beijing 100193, People's Republic of China.

Background: Enzymatic biodiesel production by transesterification in solvent media has been investigated intensively, but glycerol, as a by-product, could block the immobilized enzyme and excess n-hexane, as a solution aid, would reduce the productivity of the enzyme. Esterification, a solvent-free and no-glycerol-release system for biodiesel production, has been developed, and two-step catalysis of soybean oil, hydrolysis followed by esterification, with Yarrowia lipolytica lipase is reported in this paper.

Results: First, soybean oil was hydrolyzed at 40°C by 100 U of lipase broth per 1 g of oil with approximately 30% to 60% (vol/vol) water. The free fatty acid (FFA) distilled from this hydrolysis mixture was used for the esterification of FFA to fatty acid ethyl ester by immobilized lipase. A mixture of 2.82 g of FFA and equimolar ethanol (addition in three steps) were shaken at 30°C with 18 U of lipase per 1 gram of FFA. The degree of esterification reached 85% after 3 hours. The lipase membranes were taken out, dehydrated and subjected to fresh esterification so that over 82% of esterification was maintained, even though the esterification was repeated every 3 hours for 25 batches.

Conclusion: The two-step enzymatic process without glycerol released and solvent-free demonstrated higher efficiency and safety than enzymatic transesterification, which seems very promising for lipase-catalyzed, large-scale production of biodiesel, especially from high acid value waste oil.
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http://dx.doi.org/10.1186/1754-6834-4-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058029PMC
March 2011

Synthesis and anti-fungal activity of seven oleanolic acid glycosides.

Molecules 2011 Jan 26;16(2):1113-28. Epub 2011 Jan 26.

Key Lab of Pesticide Chemistry and Application Technology, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.

In order to develop potential anti-fungal agents, seven glycoconjugates composed of α-L-rhamnose, 6-deoxy-α-L-talose, β-D-galactose, α-D-mannose, β-D-xylose-(1→4)-6-deoxy-α-L-talose, β-D-galactose-(1→4)-α-L-rhamnose, β-D-galactose-(1→3)-β-D-xylose-(1→4)-6-deoxy-α-L-talose as the glycone and oleanolic acid as the aglycone were synthesized in an efficient and practical way using glycosyl trichloroacetimidates as donors. The structures of the new compounds were confirmed by MS, ¹H-NMR and ¹³C-NMR.Preliminary studies based on means of mycelium growth rate, indicated that all the compounds possess certain fungicidal activity against Sclerotinia sclerotiorum (Lib.) de Bary, Rhizoctonia solani Kuhn, Botrytis cinerea Pers and Phytophthora parasitica Dast.
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http://dx.doi.org/10.3390/molecules16021113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259605PMC
January 2011

Role of SIRT1-FoxO1 signaling in dietary saturated fat-dependent upregulation of liver adiponectin receptor 2 in ethanol-administered mice.

Antioxid Redox Signal 2011 Jul 4;15(2):425-35. Epub 2011 May 4.

Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA.

The aim of the present study is to examine the effects of dietary saturated fatty acids on liver adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) in ethanol-administered animals and in ethanol-exposed cultured hepatic cells, and to explore the underlying molecular mechanisms. The mRNA and protein levels of hepatic AdipoR2 were selectively increased by chronic ethanol feeding to mice consuming a diet high in saturated fat (HSF). Administration of an HSF diet blocked hyperacetylation of forkhead transcription factor 1 (FoxO1), a known target of sirtuin 1 (SIRT1), increased nuclear FoxO1 protein levels, and enhanced association of FoxO1 with the AdipoR2 promoter in the livers of ethanol-fed mice. Treatment of cultured hepatic cells with palmitic acid (a major saturated fatty acid in HSF diet) in the presence of ethanol robustly increased AdipoR2 mRNA expression and enhanced activity of a mouse AdipoR2 promoter. Knocking down SIRT1 or FoxO1 using the small silencing SIRT1 or FoxO1 plasmid blunted the palmitic acid effect. Taken together, these results reveal that dietary saturated fat selectively upregulates hepatic AdipoR2 through modulation of SIRT1-FoxO1 signaling in ethanol fed mice, and this effect may contribute to the protective effect of the HSF diet against alcoholic fatty liver.
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http://dx.doi.org/10.1089/ars.2010.3780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118604PMC
July 2011