Publications by authors named "Lizhen Wu"

41 Publications

Overexpression of miR-224-5p alleviates allergic rhinitis in mice via the TLR4/MyD88/NF-κB pathway.

Exp Anim 2021 Jun 7. Epub 2021 Jun 7.

Shandong Institute of Otolaryngology, Shandong Provincial ENT Hospital Affiliated to Shandong University.

Inflammatory allergic reaction is the main cause of allergic rhinitis (AR). Previous studies indicated that miR-224-5p was downregulated in the nasal mucosa of patients with AR, while the function of miR-224-5p in AR remains unclear. To explore this issue, AR mouse model was established using ovalbumin (OVA). For treatment group, lentivirus (LV)-miR-224-5p or its control was intranasally administrated to AR mice. miR-224-5p expression was detected by reverse transcription-quantitative PCR, followed by assessing the immunoglobulin E (IgE) level. Pathological alterations in nasal mucosa were detected using Hematoxylin-Eosin staining and Sirius red staining, followed by assessing the levels of inflammatory cells and factors. The NLRP3 inflammasome and TLR4/MyD88/NF-κB pathway were measured by Western blot, and then the relationship between miR-224-5p and toll-like receptor 4 (TLR4) was verified. The results showed that miR-224-5p was significantly decreased in nasal mucosa of AR mice. AR mice exhibited increased sneezing and nasal rubbing events, IgE level in serum, and pathological alterations in nasal mucosa, while overexpression of miR-224-5p markedly attenuated these changes. The levels of inflammatory cells in nasal lavage fluid and pro-inflammatory factors in serum and nasal mucosa were significantly increased in AR mice, which were reduced by miR-224-5p overexpression. Of note, LV-miR-224-5p treatment remarkably suppressed the activations of NLRP3 inflammasome and the TLR4/MyD88/NF-κB pathway in AR mice. Furthermore, miR-224-5p could bind to 3'-untranslated region (3'-UTR) of TLR4 and negatively regulate TLR4 level. Overall, we conclude that miR-224-5p may relieve AR by negatively regulating TLR4/MyD88/NF-κB pathway, indicating that miR-224-5p may be a promising target for AR treatment.
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http://dx.doi.org/10.1538/expanim.20-0195DOI Listing
June 2021

MC-100093, a novel β-lactam GLT-1 enhancer devoid of antimicrobial properties attenuates cocaine relapse in rats.

J Pharmacol Exp Ther 2021 May 13. Epub 2021 May 13.

School of Pharmacy, Temple University, United States.

Cocaine use disorder (CUD) currently lacks FDA-approved treatments. In rodents, the glutamate transporter-1 (GLT-1) is downregulated in the nucleus accumbens following cocaine self-administration and increasing the expression and function of GLT-1 reduces the reinstatement of cocaine-seeking. The beta-lactam antibiotic ceftriaxone upregulates GLT-1 and attenuates cue- and cocaine-induced cocaine seeking without affecting motivation for natural rewards. While ceftriaxone shows promise for treating CUD, it possesses characteristics that limit successful translation from bench to bedside, including poor brain penetration, a lack of oral bioavailability and a risk of bacterial resistance when used chronically. Thus, we aimed to develop novel molecules that retained the GLT-1 enhancing effects of ceftriaxone but displayed superior drug-like properties. Here we describe a new monocyclic beta-lactam, MC-100093, as a potent up-regulator of GLT-1 that is orally bioavailable and devoid of antimicrobial properties. MC-100093 was synthesized and tested and to determine physiochemical, pharmacokinetic and pharmacodynamic properties. Next, adult male rats underwent cocaine self-administration and extinction training. During extinction training, rats received one of four doses of MC-100093 for 6-8 days prior to a single cue-primed reinstatement test. Separate cohorts of rats were used to assess nucleus accumbens GLT-1 expression and MC-100093 effects on sucrose self-administration. We found that 50 mg/kg MC-100093 attenuated cue-primed reinstatement of cocaine-seeking while upregulating GLT-1 expression in the nucleus accumbens core. This dose did not produce sedation, nor did it decrease sucrose consumption or body weight. Thus, MC-100093 represents a potential treatment to reduce cocaine relapse. Increasing GLT-1 activity reliably reduces drug-seeking across classes of drugs, however, existing GLT1-enhancers have side effects and lack oral bioavailability. To address this issue, novel GLT-1 enhancers were synthesized and the compound with the most favorable pharmacokinetic and pharmacodynamic properties, MC-100093, was selected for further testing. MC-100093 attenuated cued cocaine-seeking without reducing food-seeking or locomotion and upregulated GLT-1 expression in the nucleus accumbens.
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http://dx.doi.org/10.1124/jpet.121.000532DOI Listing
May 2021

5-Fluorouracil efficacy requires anti-tumor immunity triggered by cancer-cell-intrinsic STING.

EMBO J 2021 Apr 22;40(7):e106065. Epub 2021 Feb 22.

Yale Stem Cell Center, New Haven, CT, USA.

5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug, but the mechanisms underlying 5-FU efficacy in immunocompetent hosts in vivo remain largely elusive. Through modeling 5-FU response of murine colon and melanoma tumors, we report that effective reduction of tumor burden by 5-FU is dependent on anti-tumor immunity triggered by the activation of cancer-cell-intrinsic STING. While the loss of STING does not induce 5-FU resistance in vitro, effective 5-FU responsiveness in vivo requires cancer-cell-intrinsic cGAS, STING, and subsequent type I interferon (IFN) production, as well as IFN-sensing by bone-marrow-derived cells. In the absence of cancer-cell-intrinsic STING, a much higher dose of 5-FU is needed to reduce tumor burden. 5-FU treatment leads to increased intratumoral T cells, and T-cell depletion significantly reduces the efficacy of 5-FU in vivo. In human colorectal specimens, higher STING expression is associated with better survival and responsiveness to chemotherapy. Our results support a model in which 5-FU triggers cancer-cell-initiated anti-tumor immunity to reduce tumor burden, and our findings could be harnessed to improve therapeutic effectiveness and toxicity for colon and other cancers.
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http://dx.doi.org/10.15252/embj.2020106065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013832PMC
April 2021

miR-3574 ameliorates intermittent hypoxia-induced cardiomyocyte injury through inhibiting Axin1.

Aging (Albany NY) 2021 02 11;13(6):8068-8077. Epub 2021 Feb 11.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, Taijiang, Fuzhou 350005, China.

Objective: miRNAs play critical roles in the regulation of many cardiovascular diseases. However, its role and potential mechanism in cardiac injury caused by obstructive sleep apnea (OSA) remain poorly elucidated. In the present study, we aimed to investigate the effects of miR-3574 on cardiomyocyte injury under intermittent hypoxia (IH).

Results: We confirmed that IH inhibited cell viability, induced cell apoptosis and suppressed miR-3574 expression in the H9c2. miR-3574 overexpression could ameliorate the effects of IH on the cell viability and cell apoptosis in the H9c2. Axin1 was a target gene of miR-3574, and miR-3574 overexpression reduced the expression of Axin1. miR-3574 could inhibit the IH-induced cardiomyocyte injury via downregulating Axin1. However, Axin1 could partially reverse these effects of miR-3574.

Conclusion: Our study first reveals that miR-3574 could alleviate IH-induced cardiomyocyte injury by targeting Axin1, which may function as a novel and promising therapy target for OSA-associated cardiovascular diseases.

Methods: H9c2 were exposed to IH condition. CCK-8 assay was applied to determine cell viability of H9c2. qRT-PCR was conducted to measure the expression level of mRNA and miRNA. Western blot assay was then performed to detect the protein levels. Finally, we used dual-luciferase reporter assay identify the potential target of miR-3574.
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http://dx.doi.org/10.18632/aging.202480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034950PMC
February 2021

Preoperative computed tomography-assessed skeletal muscle index is a novel prognostic factor in patients with hepatocellular carcinoma following hepatectomy: a meta-analysis.

J Gastrointest Oncol 2020 Oct;11(5):1040-1053

Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Background: Recently, several studies have examined the association between preoperative sarcopenia and prognosis evaluation in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. However, their conclusions remain ambiguous and controversial. Thus, we conducted a meta-analysis to assess the prognostic role of preoperative sarcopenia in patients with HCC undergoing hepatectomy.

Methods: We searched the existing literature reporting on the prognostic value of preoperative computed tomography (CT)-assessed sarcopenia for the survival of patients with HCC undergoing hepatectomy. The pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of overall survival (OS) and disease-free survival (DFS) were used to assess the prognostic value of preoperative sarcopenia in HCC patients. The associations between preoperative sarcopenia and clinicopathological characteristics were also evaluated.

Results: A total of six studies with 1,420 patients (including 458 sarcopenia and 962 non-sarcopenia patients) were included in the meta-analysis. The results showed that preoperative sarcopenia was significantly associated with poor OS (HR =1.572, 95% CI: 1.342-1.840, P=0) and shorter DFS (HR =1.544, 95% CI: 1.178-2.024, P=0.002) in patients with HCC undergoing hepatectomy. Preoperative sarcopenia was also significantly related to larger diameter tumors (WMD =0.598, 95% CI: 0.216-0.980, P=0.002). The results of the sensitivity analysis were stable in this meta-analysis. Egger's tests revealed that there was no significant publication bias.

Conclusions: Sarcopenia appears to have significant adverse impacts on postoperative outcomes in patients with hepatocellular carcinoma following hepatectomy. However, further large-scale prospective studies are needed to confirm our findings.
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http://dx.doi.org/10.21037/jgo-20-122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657831PMC
October 2020

Using rat operant delayed match-to-sample task to identify neural substrates recruited with increased working memory load.

Learn Mem 2020 11 15;27(11):467-476. Epub 2020 Oct 15.

Department of Psychology, University of Florida, Gainesville, Florida 32611, USA.

The delayed match-to-sample task (DMS) is used to probe working memory (WM) across species. While the involvement of the PFC in this task has been established, limited information exists regarding the recruitment of broader circuitry, especially under the low- versus high-WM load. We sought to address this question by using a variable-delay operant DMS task. Male Sprague-Dawley rats were trained and tested to determine their baseline WM performance across all (0- to 24-sec) delays. Next, rats were tested in a single DMS test with either 0- or 24-sec fixed delay, to assess low-/high-load WM performance. - mRNA expression was quantified within cortical and subcortical regions and correlated with WM performance. High WM load up-regulated overall - mRNA expression within the PrL, as well as within a subset of mGlu5+ cells, with load-dependent, local activation of protein kinase C (PKC) as the proposed underlying molecular mechanism. The PrL activity negatively correlated with choice accuracy during high load WM performance. A broader circuitry, including several subcortical regions, was found to be activated under low and/or high load conditions. These findings highlight the role of mGlu5- and/or PKC-dependent signaling within the PrL, and corresponding recruitment of subcortical regions during high-load WM performance.
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http://dx.doi.org/10.1101/lm.052134.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571269PMC
November 2020

Making ends meet in class switch recombination.

Cell Res 2020 09;30(9):711-712

Department of immunobiology, Yale School of Medicine, New Haven, CT, 06519, USA.

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http://dx.doi.org/10.1038/s41422-020-0342-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609326PMC
September 2020

Mitochondrial DNA Stress Signalling Protects the Nuclear Genome.

Nat Metab 2019 12 9;1(12):1209-1218. Epub 2019 Dec 9.

Salk Institute for Biological Studies, La Jolla, CA, USA.

The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by TFAM into higher-order structures called nucleoids1. Mitochondria are also platforms for antiviral signalling2 and, due to their bacterial origin, mtDNA and other mitochondrial components trigger innate immune responses and inflammatory pathology. We showed previously that instability and cytoplasmic release of mtDNA activates the cGAS-STING-TBK1 pathway resulting in interferon stimulated gene (ISG) expression that promotes antiviral immunity4. Here, we find that persistent mtDNA stress is not associated with basally activated NF-κB signalling or interferon gene expression typical of an acute antiviral response. Instead, a specific subset of ISGs, that includes , remains activated by the unphosphorylated form of ISGF3 (U-ISGF3) that enhances nDNA damage and repair responses. In cultured primary fibroblasts and cancer cells, the chemotherapeutic drug doxorubicin causes mtDNA damage and release, which leads to cGAS-STING-dependent ISG activation. In addition, mtDNA stress in TFAM-deficient mouse melanoma cells produces tumours that are more resistant to doxorubicin . Finally, mice exposed to ionizing radiation exhibit enhanced nDNA repair responses in spleen. Therefore, we propose that damage to and subsequent release of mtDNA elicits a protective signalling response that enhances nDNA repair in cells and tissues, suggesting mtDNA is a genotoxic stress sentinel.
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http://dx.doi.org/10.1038/s42255-019-0150-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213273PMC
December 2019

Ceftriaxone and mGlu2/3 interactions in the nucleus accumbens core affect the reinstatement of cocaine-seeking in male and female rats.

Psychopharmacology (Berl) 2020 Jul 7;237(7):2007-2018. Epub 2020 May 7.

Department of Psychology, University of Florida, 114 Psychology, 945 Center Dr, Gainesville, FL, 32611-2250, USA.

Rationale: The beta-lactam antibiotic ceftriaxone reliably attenuates the reinstatement of cocaine seeking. While the restoration of nucleus accumbens core (NA core) GLT-1 expression is necessary for ceftriaxone to attenuate reinstatement, AAV-mediated GLT-1 overexpression is not sufficient to attenuate reinstatement and does not prevent glutamate efflux during reinstatement.

Aims: Here, we test the hypothesis that ceftriaxone attenuates reinstatement through interactions with glutamate autoreceptors mGlu2 and mGlu3 in the NA core.

Methods: Male and female rats self-administered cocaine for 12 days followed by 2-3 weeks of extinction training. During the last 6-10 days of extinction, rats received ceftriaxone (200 mg/kg IP) or vehicle. In experiment 1, rats were killed, and NA core tissue was biotinylated for assessment of total and surface expression of mGlu2 and mGlu3 via western blotting. In experiment 2, we tested the hypothesis that mGlu2/3 signaling is necessary for ceftriaxone to attenuate cue- and cocaine-primed reinstatement by administering bilateral intra-NA core infusion of mGlu2/3 antagonist LY341495 or vehicle immediately prior to reinstatement testing.

Results: mGlu2 expression was reduced by cocaine and restored by ceftriaxone. There were no effects of cocaine or ceftriaxone on mGlu3 expression. We observed no effects of estrus on expression of either protein. The antagonism of mGlu2/3 in the NA core during both cue- and cocaine-primed reinstatement tests prevented ceftriaxone from attenuating reinstatement.

Conclusions: These results indicate that ceftriaxone's effects depend on mGlu2/3 function and possibly mGlu2 receptor expression. Future work will test this hypothesis by manipulating mGlu2 expression in pathways that project to the NA core.
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http://dx.doi.org/10.1007/s00213-020-05514-yDOI Listing
July 2020

An anti-UV superhydrophobic material with photocatalysis, self-cleaning, self-healing and oil/water separation functions.

Nanoscale 2020 Jun;12(21):11455-11459

Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China.

In this work, a superhydrophobic material was successfully prepared with a water contact angle of about 155.5° and a rolling-off angle of about 6.8°, which showed superior UV resistance (365 nm, 5.0 ± 0.6 mW cm-2) for an illumination period of 30 h. The degradation of organic dyes, such as Nile red, methyl blue and orange, could be also achieved with our prepared surface. Anti-UV water-repellency was combined with photocatalysis to realize a self-cleaning surface for both dirt removal and organic degradation. Moreover, the reversible changes with superhydrophobicity and superhydrophilicity were induced by the self-healing property on such a surface, contributing to heavy and light oils/water separation. Because of ultra-long UV-resistance, photocatalysis, self-cleaning, self-healing and oil/water separation functions, our reported surface has potential for application in a variety of fields.
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http://dx.doi.org/10.1039/d0nr01038cDOI Listing
June 2020

Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting.

Eur J Immunol 2020 03 19;50(3):380-395. Epub 2019 Dec 19.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

Secondary diversification of the Ig repertoire occurs through somatic hypermutation (SHM), gene conversion (GCV), and class switch recombination (CSR)-three processes that are initiated by activation-induced cytidine deaminase (AID). AID targets Ig genes at orders of magnitude higher than the rest of the genome, but the basis for this specificity is poorly understood. We have previously demonstrated that enhancers and enhancer-like sequences from Ig genes are capable of stimulating SHM of neighboring genes in a capacity distinct from their roles in increasing transcription. Here, we use an in vitro proteomics approach to identify E-box, MEF2, Ets, and Ikaros transcription factor family members as potential binders of these enhancers. ChIP assays in the hypermutating Ramos B cell line confirmed that many of these factors bound the endogenous Igλ enhancer and/or the IgH intronic enhancer (Eμ) in vivo. Further investigation using SHM reporter assays identified binding sites for E2A and MEF2B in Eμ and demonstrated an association between loss of factor binding and decreases in the SHM stimulating activity of Eμ mutants. Our results provide novel insights into trans-acting factors that dictate SHM targeting and link their activity to specific DNA binding sites within Ig enhancers.
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http://dx.doi.org/10.1002/eji.201948357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202714PMC
March 2020

Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition.

Cancer Res 2020 02 5;80(3):524-535. Epub 2019 Nov 5.

Department of Pathology, Yale School of Medicine, New Haven, Connecticut.

Acquired resistance to HER2-targeted therapies occurs frequently in HER2 breast tumors and new strategies for overcoming resistance are needed. Here, we report that resistance to trastuzumab is reversible, as resistant cells regained sensitivity to the drug after being cultured in drug-free media. RNA-sequencing analysis showed that cells resistant to trastuzumab or trastuzumab + pertuzumab in combination increased expression of oxidative phosphorylation pathway genes. Despite minimal changes in mitochondrial respiration, these cells exhibited increased expression of ATP synthase genes and selective dependency on ATP synthase function. Resistant cells were sensitive to inhibition of ATP synthase by oligomycin A, and knockdown of ATP5J or ATP5B, components of ATP synthase complex, rendered resistant cells responsive to a low dose of trastuzumab. Furthermore, combining ATP synthase inhibitor oligomycin A with trastuzumab led to regression of trastuzumab-resistant tumors . In conclusion, we identify a novel vulnerability of cells with acquired resistance to HER2-targeted antibody therapies and reveal a new therapeutic strategy to overcome resistance. SIGNIFICANCE: These findings implicate ATP synthase as a novel potential target for tumors resistant to HER2-targeted therapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002225PMC
February 2020

Enhanced Capacitance of TiO Nanotubes with a Double-Layer Structure Fabricated in NHF/HPO Mixed Electrolyte.

Langmuir 2019 Apr 2;35(15):5125-5129. Epub 2019 Apr 2.

Key Laboratory of Soft Chemistry and Functional Materials of Education Ministry , Nanjing University of Science and Technology , Nanjing 210094 , China.

TiO is an attractive electrode material in fast charging/discharging supercapacitors because of its high specific surface area. However, the low capacitance of TiO nanotubes as-anodized in the classical electrolyte restricts their further application in supercapacitors. Here, we study the performances of larger-diameter nanotubes with a double-layer structure fabricated in an NHF/phosphoric acid (HPO) mixed electrolyte. Results show that the double-layer structure increased the specific surface area of nanotubes owing to the cavities between the double layers and the porous structure on walls. After soaking in HPO aqueous solution for 40 min, the nanotubes anodized in the mixed electrolyte containing 6 wt % HPO show a specific capacitance of 13.89 mF cm, ∼3.11 times that of the pristine nanotubes in the classical electrolyte. The specific surface area of the soaked nanotubes is up to 113.2 m g, which is ∼2.94 times that of the pristine nanotubes. The values of specific surface area of the anodized nanotubes and the soaked nanotubes fabricated in the mixed electrolyte containing 6 wt % HPO are roughly equal. It demonstrated that the specific surface area increased mainly due to the double-layer structure. The double-layer structure reveals a new strategy to enhance the specific capacitance of TiO nanotubes.
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http://dx.doi.org/10.1021/acs.langmuir.8b04162DOI Listing
April 2019

The effects of clavulanic acid and amoxicillin on cue-primed reinstatement of cocaine seeking.

Behav Neurosci 2019 Apr 4;133(2):247-254. Epub 2019 Feb 4.

Department of Psychology, University of Florida.

Research using the cocaine self-administration and reinstatement animal model of relapse finds that the beta-lactam antibiotic, ceftriaxone, attenuates cocaine-primed reinstatement of cocaine seeking and upregulates two proteins that regulate glutamate release and reuptake (xCT and GLT-1, respectively) in the nucleus accumbens core (NAc). We tested three compounds with beta-lactam rings for their ability to attenuate cue-primed reinstatement and increase GLT-1 and xCT expression in the NAc and prefrontal cortex (PFC). Rats self-administered intravenous cocaine for 1 hr/day for 7 days then 6 hrs/day for 10 days. Cue-primed reinstatement tests began after 8-9 days of extinction training. Rats received oral vehicle, clavulanic acid (CA), amoxicillin (AMX), or CA + AMX (Augmentin; AUG) for 5 days prior to testing. Only AMX-treated rats demonstrated a reduction of cocaine-seeking that trended toward significance, warranting future investigation of a wider range of doses. In the NAc, GLT-1a expression was reduced in vehicle-treated rats relative to cocaine-naïve controls and was not restored by AMX or AUG. CA-treated rats reinstated more than vehicle-treated rats and exhibited GLT-1a and xCT expression intermediate between cocaine-naïve controls and vehicle-treated cocaine rats. In agreement with our previous work, cocaine did not decrease PFC GLT-1a expression. Cocaine reduced xCT expression in the PFC that was unchanged by any of the three compounds. These results indicate that AMX may be another beta-lactam that attenuates cocaine relapse. Furthermore, the upregulation of both GLT-1 and xCT in the NAc may be needed to attenuate cocaine seeking. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508097PMC
April 2019

Berberine, a Traditional Chinese Medicine, Reduces Inflammation in Adipose Tissue, Polarizes M2 Macrophages, and Increases Energy Expenditure in Mice Fed a High-Fat Diet.

Med Sci Monit 2019 Jan 4;25:87-97. Epub 2019 Jan 4.

Department of Endocrinology, Shishi (Overseas Chinese) Hospital, Quanzhou, Fujian, China (mainland).

BACKGROUND The uncoupling protein 1 (UCP1) gene has a role in mitochondrial energy expenditure in brown adipose tissue. This study aimed to investigate the effects of berberine, a benzylisoquinoline alkaloid used in traditional Chinese medicine, on energy expenditure, expression of the UCP1 gene, the cell stress protein inositol-requiring enzyme 1α (IRE1α), apoptosis genes, and macrophage phenotype (M1 and M2) in white and brown adipose tissue in an obese mouse model fed a high-fat diet. MATERIAL AND METHODS Four-week-old C57BL/6J male mice (n=20) were divided into a high-fat diet group, a normal diet group, a group treated with berberine at 100 mg/kg/d in 0.9% normal saline, and a non-treated group. Whole-body fat mass, blood glucose, insulin resistance, and oxygen expenditure during physical activity were measured. After 16 weeks, the mice were euthanized for examination of liver and adipose tissue. The expression of pro-inflammatory cytokines, apoptosis genes, thermogenic genes (including UCP1), and IRE1α, were investigated using immunohistochemistry, Western blot, and quantitative reverse transcription polymerase chain reaction (qRT-PCR), in white and brown adipose tissue. Magnetic cell sorting harvested M1 and M2 macrophages in adipose tissue. Clodronate liposomes were used to inhibit macrophage recruitment. RESULTS Berberine treatment in mice fed a high-fat diet increased energy metabolism, glucose tolerance, and expression of UCP1, and reduced expression of pro-inflammatory cytokines, macrophage recruitment, and resulted in M2 macrophage polarization in white adipose tissue. Polarized M2 macrophages showed reduced expression of apoptotic genes and IRE1α. CONCLUSIONS Berberine improved metabolic function in a mouse model fed a high-fat diet.
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http://dx.doi.org/10.12659/MSM.911849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330261PMC
January 2019

On the Interfacial Adhesion between TiO Nanotube Array Layer and Ti Substrate.

Langmuir 2018 11 7;34(46):13888-13896. Epub 2018 Nov 7.

Key Laboratory of Soft Chemistry and Functional Materials of Education Ministry , Nanjing University of Science and Technology , Nanjing 210094 , P. R. China.

Anodic titania nanotube arrays (TNTAs) with higher aspect ratio are observed to be liable to spontaneous curling or delamination from the underlying titanium (Ti) metal once dried because of the poor interfacial adhesion of the TNTA layer to the underlying Ti, especially when a thin Ti sheet is used. The interfacial adhesion strength was shown to decrease with increasing thickness of the TNTA layer. In this work, although the preparation of TNTAs in a frequently used fluoride-containing solution was completed, different anodization processes were further performed at lower current densities or at lower voltages for a short time in the same electrolyte to increase the adhesion. The mechanical test demonstrated that better adhesion properties have been achieved by applying these anodization posttreatment processes. It is believed that during the fabrication of TNTAs, a large residual stress at the interface of the nanotube layer and the underlying Ti is created. It is the residual stress that leads to the weak interfacial adhesion. The anodization posttreatment processes can reduce or eliminate the residual stress, thereby improving the interfacial adhesion. Further, these processes can also boost the performances of TNTAs for supercapacitors. When the anodization posttreatment processes are implemented at 1 mA cm or at 10 V for 5 min, considerable improvements in the interfacial adhesion are observed. Particularly, both posttreatment processes are also applicable to the very thin Ti sheet (∼18 μm). The realization of robust and adherent TNTAs grown on very thin Ti sheets can not only significantly improve the volumetric capacitances of TNTAs but also make TNTAs an attractive material in flexible supercapacitor applications.
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http://dx.doi.org/10.1021/acs.langmuir.8b03408DOI Listing
November 2018

A novel rat model of comorbid PTSD and addiction reveals intersections between stress susceptibility and enhanced cocaine seeking with a role for mGlu5 receptors.

Transl Psychiatry 2018 10 5;8(1):209. Epub 2018 Oct 5.

Psychology Department, University of Florida, Gainesville, FL, 32611, USA.

PTSD is highly comorbid with cocaine use disorder (CUD), and cocaine users with PTSD + CUD are more resistant to treatment. Here we sought to develop a rat model of PTSD + CUD in order to identify the neurobiological changes underlying such comorbidity and screen potential medications for reducing cocaine seeking in the PTSD population. We utilized a predator scent stress model of PTSD, wherein rats received a single exposure to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). One week after TMT exposure, stress-susceptible (susceptible), intermediate, and resilient phenotypes were detected and were consistent with behavioral, corticosterone, and gene expression profiles 3 weeks post TMT. We assessed phenotypic differences in cocaine self-administration, extinction, and cue-primed reinstatement. Susceptible rats exhibited deficits in extinction learning and increased cue-primed reinstatement that was not prevented by Ceftriaxone, an antibiotic that consistently attenuates the reinstatement of cocaine seeking. TMT-exposed resilient rats displayed increased mGlu5 gene expression in the amygdala and medial prefrontal cortex and did not display the enhanced cocaine seeking observed in susceptible rats. Combined treatment with the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1 H-pyrazol-5-yl)benzamide (CDPPB), fear extinction, and ceftriaxone prevented the reinstatement of cocaine seeking in susceptible rats with fear extinction an important mediating condition. These results highlight the need for animal models of PTSD to consider stress-responsivity, as only a subset of trauma-exposed individuals develop PTSD and these individuals likely exhibit distinct neurobiological changes compared with trauma-exposed populations who are resilient to stress. This work further identifies glutamate homeostasis and mGlu5 as a target for treating relapse in comorbid PTSD-cocaine addiction.
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http://dx.doi.org/10.1038/s41398-018-0265-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173705PMC
October 2018

KDM5 histone demethylases repress immune response via suppression of STING.

PLoS Biol 2018 08 6;16(8):e2006134. Epub 2018 Aug 6.

Department of Pathology, Yale School of Medicine, New Haven, Connecticut, United States of America.

Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases. The induction of STING expression by KDM5 blockade triggered a robust interferon response in a cytosolic DNA-dependent manner in breast cancer cells. This response resulted in resistance to infection by DNA and RNA viruses. In human tumors, KDM5B expression is inversely associated with STING expression in multiple cancer types, with the level of intratumoral CD8+ T cells, and with patient survival in cancers with a high level of cytosolic DNA, such as human papilloma virus (HPV)-positive head and neck cancer. These results demonstrate a novel epigenetic regulatory pathway of immune response and suggest that KDM5 demethylases are potential targets for antipathogen treatment and anticancer immunotherapy.
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http://dx.doi.org/10.1371/journal.pbio.2006134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095604PMC
August 2018

Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A.

J Med Chem 2018 04 23;61(7):3193-3208. Epub 2018 Mar 23.

Department of Molecular and Cellular Oncology , The University of Texas MD Anderson Cancer Center , Houston , Texas 77030 , United States.

Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, ( R)- and ( S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1 H-pyrrolo[3,2- b]pyridine-7-carboxylic acid (compounds N51 and N52) and ( R) - and ( S) -N-(1-(3-isopropyl-1 H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (compounds N54 and N55). In vitro, the S enantiomer of the N51/N52 pair (N52) and the R enantiomer of the N54/N55 pair (N54) exhibited about 4- to 5-fold greater binding affinity. The more potent enzyme inhibition of KDM5A by the R-isoform for the cell-permeable N54/N55 pair translated to differences in growth inhibitory activity. We determined structures of the KDM5A catalytic domain in complex with all 12 inhibitors, which revealed the interactions (or lack thereof) responsible for the differences in binding affinity. These results provide insights to guide improvements in binding potency and avenues for development of cell permeable inhibitors of the KDM5 family.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322411PMC
April 2018

Rab18 promotes lipid droplet (LD) growth by tethering the ER to LDs through SNARE and NRZ interactions.

J Cell Biol 2018 03 24;217(3):975-995. Epub 2018 Jan 24.

State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China

Lipid incorporation from endoplasmic reticulum (ER) to lipid droplet (LD) is important in controlling LD growth and intracellular lipid homeostasis. However, the molecular link mediating ER and LD cross talk remains elusive. Here, we identified Rab18 as an important Rab guanosine triphosphatase in controlling LD growth and maturation. deficiency resulted in a drastically reduced number of mature LDs and decreased lipid storage, and was accompanied by increased ER stress. Rab3GAP1/2, the GEF of Rab18, promoted LD growth by activating and targeting Rab18 to LDs. LD-associated Rab18 bound specifically to the ER-associated NAG-RINT1-ZW10 (NRZ) tethering complex and their associated SNAREs (Syntaxin18, Use1, BNIP1), resulting in the recruitment of ER to LD and the formation of direct ER-LD contact. Cells with defects in the NRZ/SNARE complex function showed reduced LD growth and lipid storage. Overall, our data reveal that the Rab18-NRZ-SNARE complex is critical protein machinery for tethering ER-LD and establishing ER-LD contact to promote LD growth.
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http://dx.doi.org/10.1083/jcb.201704184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839781PMC
March 2018

KDM5 lysine demethylases are involved in maintenance of 3'UTR length.

Sci Adv 2016 Nov 18;2(11):e1501662. Epub 2016 Nov 18.

Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.

The complexity by which cells regulate gene and protein expression is multifaceted and intricate. Regulation of 3' untranslated region (UTR) processing of mRNA has been shown to play a critical role in development and disease. However, the process by which cells select alternative mRNA forms is not well understood. We discovered that the lysine demethylase, Jhd2 (also known as KDM5), recruits 3'UTR processing machinery and promotes alteration of 3'UTR length for some genes in a demethylase-dependent manner. Interaction of Jhd2 with both chromatin and RNA suggests that Jhd2 affects selection of polyadenylation sites through a transcription-coupled mechanism. Furthermore, its mammalian homolog KDM5B (also known as JARID1B or PLU1), but not KDM5A (also known as JARID1A or RBP2), promotes shortening of transcript in breast cancer cells. Consistent with these results, KDM5B expression correlates with shortened in human breast tumor tissues. In contrast, both KDM5A and KDM5B are involved in the lengthening of . Our findings suggest both a novel role for this family of demethylases and a novel targetable mechanism for 3'UTR processing.
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http://dx.doi.org/10.1126/sciadv.1501662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5262454PMC
November 2016

An easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targeting.

Nucleic Acids Res 2016 Nov 25;44(19):e149. Epub 2016 Jul 25.

Department of Pathology, Yale School of Medicine, New Haven, CT, 06520 USA

The CRISPR/Cas9 system is a powerful genome editing tool and has been widely used for biomedical research. However, many challenges, such as off-target effects and lack of easy solutions for multiplex targeting, are still limiting its applications. To overcome these challenges, we first developed a highly efficient doxycycline-inducible Cas9-EGFP vector. This vector allowed us to track the cells for uniform temporal control and efficient gene disruption, even in a polyclonal setting. Furthermore, the inducible CRISPR/Cas9 system dramatically decreased off-target effects with a pulse exposure of the genome to the Cas9/sgRNA complex. To target multiple genes simultaneously, we established simple one-step cloning approaches for expression of multiple sgRNAs with improved vectors. By combining our inducible and multiplex genome editing approaches, we were able to simultaneously delete Lysine Demethylase (KDM) 5A, 5B and 5C efficiently in vitro and in vivo This user friendly and highly efficient toolbox provides a solution for easy genome editing with tight temporal control, minimal off-target effects and multiplex targeting.
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http://dx.doi.org/10.1093/nar/gkw660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100567PMC
November 2016

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.

Cell Chem Biol 2016 07 14;23(7):769-781. Epub 2016 Jul 14.

Department of Biochemistry, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. Electronic address:

The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intramolecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.
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http://dx.doi.org/10.1016/j.chembiol.2016.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958579PMC
July 2016

Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats.

Stress 2016 07 3;19(4):406-18. Epub 2016 Jun 3.

a Department of Psychology , University of Florida , Gainesville , FL , USA ;

Neurobiological mechanisms underlying comorbid posttraumatic stress disorder (PTSD) and cocaine use disorder (CUD) are unknown. We aimed to develop an animal model of PTSD + CUD to examine the neurobiology underlying cocaine-seeking in the presence of PTSD comorbidity. Rats were exposed to cat urine once for 10-minutes and tested for anxiety-like behaviors one week later. Subsequently, rats underwent long-access (LgA) cocaine self-administration and extinction training. Rats were re-exposed to the trauma context and then immediately tested for cue-primed reinstatement of cocaine-seeking. Plasma and brains were collected afterwards for corticosterone assays and real-time qPCR analysis. Urine-exposed (UE; n = 23) and controls not exposed to urine (Ctrl; n = 11) did not differ in elevated plus maze behavior, but UE rats displayed significantly reduced habituation of the acoustic startle response (ASR) relative to Ctrl rats. A median split of ASR habituation scores was used to classify stress-responsive rats. UE rats (n = 10) self-administered more cocaine on Day 1 of LgA than control rats (Ctrl + Coc; n = 8). Re-exposure to the trauma context prevented cocaine reinstatement only in stress-responsive rats. Ctrl + Coc rats had lower plasma corticosterone concentrations than Ctrls, and decreased gene expression of corticotropin releasing hormone (CRH) and Glcci1 in the hippocampus. Rats that self-administered cocaine displayed greater CRH expression in the amygdala that was independent of urine exposure. While we did not find that cat urine exposure induced a PTSD-like phenotype in our rats, the present study underscores the need to separate stressed rats into cohorts based on anxiety-like behavior in order to study individual vulnerability to PTSD + CUD.
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http://dx.doi.org/10.1080/10253890.2016.1189898DOI Listing
July 2016

Differential Roles of Cell Death-inducing DNA Fragmentation Factor-α-like Effector (CIDE) Proteins in Promoting Lipid Droplet Fusion and Growth in Subpopulations of Hepatocytes.

J Biol Chem 2016 Feb 5;291(9):4282-93. Epub 2016 Jan 5.

From the MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China,

Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis. Cell death-inducing DNA fragmentation factor-α-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec (also called Fsp27), play important roles in lipid metabolism. Cidea and Cidec are LD-associated proteins that promote atypical LD fusion in adipocytes. Here, we find that CIDE proteins are all localized to LD-LD contact sites (LDCSs) and promote lipid transfer, LD fusion, and growth in hepatocytes. We have identified two types of hepatocytes, one with small LDs (small LD-containing hepatocytes, SLHs) and one with large LDs (large LD-containing hepatocytes, LLHs) in the liver. Cideb is localized to LDCSs and promotes lipid exchange and LD fusion in both SLHs and LLHs, whereas Cidea and Cidec are specifically localized to the LDCSs and promote lipid exchange and LD fusion in LLHs. Cideb-deficient SLHs have reduced LD sizes and lower lipid exchange activities. Fasting dramatically induces the expression of Cidea/Cidec and increases the percentage of LLHs in the liver. The majority of the hepatocytes from the liver of obese mice are Cidea/Cidec-positive LLHs. Knocking down Cidea or Cidec significantly reduced lipid storage in the livers of obese animals. Our data reveal that CIDE proteins play differential roles in promoting LD fusion and lipid storage; Cideb promotes lipid storage under normal diet conditions, whereas Cidea and Cidec are responsible for liver steatosis under fasting and obese conditions.
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http://dx.doi.org/10.1074/jbc.M115.701094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813457PMC
February 2016

Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice.

Nat Commun 2015 Jan 7;6:5949. Epub 2015 Jan 7.

MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.

Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, 'browning' of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27-null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance. We also observe a striking reduction in adipose inflammation and increase in adiponectin levels in all three models. This appears to reflect reduced activation of the inflammasome and less adipocyte death. These findings highlight the importance of Fsp27 in facilitating optimal energy storage in adipocytes and represent a rare example where adipose inflammation and hepatic insulin resistance are disassociated.
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http://dx.doi.org/10.1038/ncomms6949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354252PMC
January 2015

Rab8a-AS160-MSS4 regulatory circuit controls lipid droplet fusion and growth.

Dev Cell 2014 Aug;30(4):378-93

MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address:

Rab GTPases, by targeting to specific membrane compartments, play essential roles in membrane trafficking. Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis. Fsp27 is shown to be required for LD fusion and growth by enriching at LD-LD contact sites. Here, we identify Rab8a as a direct interactor and regulator of Fsp27 in mediating LD fusion in adipocytes. Knockdown of Rab8a in the livers of ob/ob mice results in the accumulation of smaller LDs and lower hepatic lipid levels. Surprisingly, it is the GDP-bound form of Rab8a that exhibits fusion-promoting activity. We further discover AS160 as the GTPase activating protein (GAP) for Rab8a, which forms a ternary complex with Fsp27 and Rab8a to positively regulate LD fusion. MSS4 antagonizes Fsp27-mediated LD fusion activity through Rab8a. Our results have thus revealed a mechanistic signaling circuit controlling LD fusion and fatty liver formation.
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http://dx.doi.org/10.1016/j.devcel.2014.07.005DOI Listing
August 2014

Cidea controls lipid droplet fusion and lipid storage in brown and white adipose tissue.

Sci China Life Sci 2014 Jan 26;57(1):107-16. Epub 2013 Dec 26.

MOE key laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.

Excess lipid storage in adipose tissue results in the development of obesity and other metabolic disorders including diabetes, fatty liver and cardiovascular diseases. The lipid droplet (LD) is an important subcellular organelle responsible for lipid storage. We previously observed that Fsp27, a member of the CIDE family proteins, is localized to LD-contact sites and promotes atypical LD fusion and growth. Cidea, a close homolog of Fsp27, is expressed at high levels in brown adipose tissue. However, the exact role of Cidea in promoting LD fusion and lipid storage in adipose tissue remains unknown. Here, we expressed Cidea in Fsp27-knockdown adipocytes and observed that Cidea has similar activity to Fsp27 in promoting lipid storage and LD fusion and growth. Next, we generated Cidea and Fsp27 double-deficient mice and observed that these animals had drastically reduced adipose tissue mass and a strong lean phenotype. In addition, Cidea/Fsp27 double-deficient mice had improved insulin sensitivity and were intolerant to cold. Furthermore, we observed that the brown and white adipose tissues of Cidea/Fsp27 double-deficient mice had significantly reduced lipid storage and contained smaller LDs compared to those of Cidea or Fsp27 single deficient mice. Overall, these data reveal an important role of Cidea in controlling lipid droplet fusion, lipid storage in brown and white adipose tissue, and the development of obesity.
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http://dx.doi.org/10.1007/s11427-013-4585-yDOI Listing
January 2014

Imaging lipid droplet fusion and growth.

Methods Cell Biol 2013 ;116:253-68

Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.

Lipid droplets (LDs) are highly dynamic cellular organelles found in most eukaryotic cell types. In white adipocytes, LDs grow into a characteristic unilocular morphology that is well suited for its specialized role as an efficient energy storage organelle. Overexpansion of LDs in white adipocytes results in the development of obesity and insulin resistance. Besides its central role in lipid storage and mobilization, LDs play crucial roles in various cellular processes including virus packaging, host defense, protein storage, and degradation. CIDE proteins, in particular Fsp27, initiates a unique LD fusion process in adipocytes by clustering and enriching at LD contact site and promoting neutral lipid exchange and transfer between contacted LDs. Here, we summarize our approaches to quantitatively measure intracellular LD size and neutral lipid exchange between LDs. Utilization of these methods has greatly facilitated our understanding of molecular pathways governing LD growth in adipocytes.
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http://dx.doi.org/10.1016/B978-0-12-408051-5.00013-9DOI Listing
May 2014

Caesalpins A-H, bioactive cassane-type diterpenes from the seeds of Caesalpinia minax.

J Nat Prod 2013 Jun 12;76(6):1025-31. Epub 2013 Jun 12.

Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, People's Republic of China.

Eight new cassane-type diterpenes, caesalpins A-H (1-8), were isolated from the ethyl acetate extract of Caesalpinia minax. Compound 1 displayed significant antiproliferative activity against HepG-2 (IC50 4.7 μM) and MCF-7 (IC50 2.1 μM) cells, and compounds 2 and 4 exhibited selective cytotoxic activities against MCF-7 (IC50 7.9 μM) and AGS (IC50 6.5 μM) cells.
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http://dx.doi.org/10.1021/np300918qDOI Listing
June 2013