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1.  The Semen pH Affects Sperm Motility and Capacitation 
PLoS ONE  2015;10(7):e0132974.
As the chemical environment of semen can have a profound effect on sperm quality, we examined the effect of pH on the motility, viability and capacitation of human sperm. The sperm in this study was collected from healthy males to avoid interference from other factors. The spermatozoa cultured in sperm nutrition solution at pH 5.2, 6.2, 7.2 and 8.2 were analyzed for sperm total motility, progressive motility (PR), hypo-osmotic swelling (HOS) rate, and sperm penetration. Our results showed that these parameters were similar in pH 7.2 and 8.2 sperm nutrition solutions, but decreased in pH 5.2 and 6.2 solutions. The HOS rate exhibited positive correlation with the sperm total motility and PR. In addition, the sperm Na+/K+-ATPase activity at different pHs was measured, and the enzyme activity was significantly lower in pH 5.2 and 6.2 media, comparing with that in pH 8.2 and pH 7.2 solutions. Using flow cytometry (FCM) and laser confocal scanning microscopy (LCSM) analysis, the intracellular Ca2+ concentrations of sperm cultured in sperm capacitation solution at pH 5.2, 6.2, 7.2 and 8.2 were determined. Compared with that at pH 7.2, the mean fluorescence intensity of sperm in pH 5.2 and 6.2 media decreased significantly, while that of pH 8.2 group showed no difference. Our results suggested that the declined Na+/K+-ATPase activity at acidic pHs result in decreased sperm movement and capacitation, which could be one of the mechanisms of male infertility.
doi:10.1371/journal.pone.0132974
PMCID: PMC4501804  PMID: 26173069
2.  Molecular characterization of hepatocarcinogenesis using mouse models 
Disease Models & Mechanisms  2015;8(7):743-753.
ABSTRACT
Hepatocellular carcinoma (HCC) is a deadly disease, often unnoticed until the late stages, when treatment options become limited. Thus, there is a crucial need to identify biomarkers for early detection of developing HCC, as well as molecular pathways that would be amenable to therapeutic intervention. Although analysis of human HCC tissues and serum components may serve these purposes, inability of early detection also precludes possibilities of identification of biomarkers or pathways that are sequentially perturbed at earlier phases of disease progression. We have therefore explored the option of utilizing mouse models to understand in a systematic and longitudinal manner the molecular pathways that are progressively deregulated by various etiological factors in contributing to HCC formation, and we report the initial findings in characterizing their validity. Hepatitis B surface antigen transgenic mice, which had been exposed to aflatoxin B1 at various stages in life, were used as a hepatitis model. Our findings confirm a synergistic effect of both these etiological factors, with a gender bias towards males for HCC predisposition. Time-based aflatoxin B1 treatment also demonstrated the requirement of non-quiescent liver for effective transformation. Tumors from these models with various etiologies resemble human HCCs histologically and at the molecular level. Extensive molecular characterization revealed the presence of an 11-gene HCC-expression signature that was able to discern transformed human hepatocytes from primary cells, regardless of etiology, and from other cancer types. Moreover, distinct molecular pathways appear to be deregulated by various etiological agents en route to formation of HCCs, in which common pathways converge, highlighting the existence of etiology-specific as well as common HCC-specific molecular perturbations. This study therefore highlights the utility of these mouse models, which provide a rich resource for the longitudinal analysis of molecular changes and biomarkers associated with HCC that could be exploited further for therapeutic targeting.
Summary: We present initial data from systematic and longitudinal analyses of hepatocarcinogenesis using mouse models that reflect the human disease. This provides a rich resource for the analysis of biomarkers and sequential molecular alterations during disease progression.
doi:10.1242/dmm.017624
PMCID: PMC4486853  PMID: 26035378
Aflatoxin B1; Hepatitis B surface antigen; Hepatocellular carcinoma; Mouse models
3.  Reference genome of wild goat (capra aegagrus) and sequencing of goat breeds provide insight into genic basis of goat domestication 
BMC Genomics  2015;16(1):431.
Background
Domestic goats (Capra hircus) have been selected to play an essential role in agricultural production systems, since being domesticated from their wild progenitor, bezoar (Capra aegagrus). A detailed understanding of the genetic consequences imparted by the domestication process remains a key goal of evolutionary genomics.
Results
We constructed the reference genome of bezoar and sequenced representative breeds of domestic goats to search for genomic changes that likely have accompanied goat domestication and breed formation. Thirteen copy number variation genes associated with coat color were identified in domestic goats, among which ASIP gene duplication contributes to the generation of light coat-color phenotype in domestic goats. Analysis of rapidly evolving genes identified genic changes underlying behavior-related traits, immune response and production-related traits.
Conclusion
Based on the comparison studies of copy number variation genes and rapidly evolving genes between wild and domestic goat, our findings and methodology shed light on the genetic mechanism of animal domestication and will facilitate future goat breeding.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1606-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1606-1
PMCID: PMC4455334  PMID: 26044654
Wild goat genome; Animal domestication; Artificial selection; Coat color evolution; Behavioral evolution
4.  Th1, Th2, and Th17 Cytokine Involvement in Thyroid Associated Ophthalmopathy 
Disease Markers  2015;2015:609593.
To determine serum cytokine profiles in Graves' disease (GD) patients with or without active and inactive thyroid associated ophthalmopathy (TAO), we recruited 65 subjects: 10 GD only (without TAO), 25 GD + active TAO, 20 GD + TAO, and 10 healthy controls. Liquid chip assay was used to measure serum Th1/Th2/Th17 cytokines including IFN-γ (interferon-gamma), TNF-α (tumor necrosis factor-alpha), IL-1α (interleukin-1 alpha), IL-1Ra (IL-1 receptor antagonist), IL-2, IL-4, IL-6, and IL-17 and two chemokines: RANTES (regulated upon activation, normal T cell expressed and secreted) and IP-10 (IFN-γ-induced protein 10). Serum levels of TSH (thyroid stimulating hormone) receptor autoantibodies (TRAb) were measured using an enzyme linked immunosorbent assay. Compared with healthy controls, TAO patients showed significantly elevated serum levels of IFN-γ, TNF-α, IL-1α, IL-4, IL-6, IL-17, and IP-10. Comparing active and inactive TAO, serum Th1 cytokines IFN-γ and TNF-α were elevated in active TAO, while serum Th2 cytokine IL-4 was elevated in inactive TAO. Serum Th17 cytokine IL-17 was elevated in GD but reduced in both active and inactive TAO. A positive correlation was found between TRAb and IFN-γ, TNF-α, IL-1α, IL-2, IL-4, and IL-6. Taken together, serum Th1/Th2/Th17 cytokines and chemokines reflect TAO disease activity and may be implicated in TAO pathogenesis.
doi:10.1155/2015/609593
PMCID: PMC4451372  PMID: 26089587
5.  Targeting DDX3 with a small molecule inhibitor for lung cancer therapy 
EMBO Molecular Medicine  2015;7(5):648-669.
Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3–β-catenin axis and inhibited non-homologous end joining—the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.
doi:10.15252/emmm.201404368
PMCID: PMC4492822  PMID: 25820276
DDX3; DNA repair; lung cancer; radiation-sensitizing agent; small molecule inhibitor
6.  VSTM-v1, a potential myeloid differentiation antigen that is downregulated in bone marrow cells from myeloid leukemia patients 
Leukocyte differentiation antigens often represent important markers for the diagnosis, classification, prognosis, and therapeutic targeting of myeloid leukemia. Herein, we report a potential leukocyte differentiation antigen gene VSTM1 (V-set and transmembrane domain-containing 1) that was downregulated in bone marrow cells from leukemia patients and exhibited a higher degree of promoter methylation. The expression level of its predominant encoded product, VSTM1-v1, was positively correlated with myeloid cell maturation state. Restoration of VSTM1-v1 expression inhibited myeloid leukemia cells’ growth. Therefore, VSTM1-v1 might represent an important myeloid leukocyte differentiation antigen and provide a potential target for the diagnosis and treatment of leukemia.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0118-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13045-015-0118-4
PMCID: PMC4405901  PMID: 25887911
Acute myeloid leukemia; Leukocyte differentiation antigen; VSTM1; Methylation; Biomarker
7.  HDAC Inhibition Blunts Ischemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy 
Circulation  2014;129(10):1139-1151.
Background
Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that SAHA, a histone deacetylase (HDAC) inhibitor FDA-approved for cancer treatment, will blunt reperfusion injury.
Methods and Results
Twenty-one rabbits were randomized into 3 groups: a) vehicle control, b) SAHA pretreatment (one day prior and at surgery), and c) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (I/R, 30min coronary ligation, 24h reperfusion). Additionally cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated I/R (sI/R) to probe mechanism. SAHA reduced infarct (those reduction inhibitor, SAHA, infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during I/R occur, at least in part, through induction of autophagic flux. assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to sI/R, SAHA pretreatment reduced cell death by 40%. This eduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects.
Conclusions
The FDS-approved anti-cancer HDAC inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during I/R occur, at least in part, through induction of autophagic flux.
doi:10.1161/CIRCULATIONAHA.113.002416
PMCID: PMC3984913  PMID: 24396039
ischemia; reperfusion injury; neuroprotection; autophagy; HDAC
8.  MIR34A regulates autophagy and apoptosis by targeting HMGB1 in the retinoblastoma cell 
Autophagy  2014;10(3):442-452.
MIR34A (microRNA 34a) is a tumor suppressor gene, but how it regulates chemotherapy response and resistance is not completely understood. Here, we show that the microRNA MIR34A-dependent high mobility group box 1 (HMGB1) downregulation inhibits autophagy and enhances chemotherapy-induced apoptosis in the retinoblastoma cell. HMGB1 is a multifaceted protein with a key role in autophagy, a self-degradative, homeostatic process with a context-specific role in cancer. MIR34A inhibits HMGB1 expression through a direct MIR34A-binding site within the HMGB1 3′ untranslated region. MIR34A inhibition of HMGB1 leads to a decrease in autophagy under starvation conditions or chemotherapy treatment. Inhibition of autophagy promotes oxidative injury and DNA damage and increases subsequent CASP3 activity, CASP3 cleavage, and PARP1 [poly (ADP-ribose) polymerase 1] cleavage, which are important to the apoptotic process. Finally, upregulation of MIR34A, knockdown of HMGB1, or inhibition of autophagy (e.g., knockdown of ATG5 and BECN1) restores chemosensitivity and enhances tumor cell death in the retinoblastoma cell. These data provide new insights into the mechanisms governing the regulation of HMGB1 expression by microRNA and their possible contribution to autophagy and drug resistance.
doi:10.4161/auto.27418
PMCID: PMC4077883  PMID: 24418846
microRNA; Hmbg1; autophagy; apoptosis; chemotherapy
9.  Small Molecules for Cell Reprogramming and Heart Repair: Progress and Perspective 
ACS chemical biology  2014;9(1):34-44.
Regenerative medicine for heart failure seeks to replace lost cardiomyocytes. Chemical approaches for producing ample supplies of cells, such as pluripotent stem cells and cardiomyocytes, hold promise as practical means to achieve safe, facile cell-based therapy for cardiac repair and regenerative medicine. In this review, we describe recent advances in the application of small molecules to improve the generation and maintenance of pluripotent stem cells. We also describe new directions in heart repair and regeneration in which chemical approaches may find their application.
doi:10.1021/cb400865w
PMCID: PMC3951179  PMID: 24372513
10.  Reactive oxygen species regulate the differentiation of acute promyelocytic leukemia cells through HMGB1-mediated autophagy 
Acute promyelocytic leukemia (APL) results from a blockade of granulocyte differentiation during the promyelocytic stage. As a fusion protein of promyelocytic leukemia (PML) and retinoic acid receptor-α (RARα), PML-RARα oncoprotein is degraded through the differentiation of all-trans retinoic acid (ATRA)-induced cells. Here reactive oxygen species (ROS) and high-mobility group box 1 (HMGB1) were proven essential for the differentiation of APL cells. A down-regulation of ROS by ROS quencher (NAC) blocked the differentiation of APL cell line NB4 while an over-expression of ROS by superoxide dismutase-1 (SOD1) RNA interference (RNAi) increased cell differentiation. HMGB1 was vital for the differentiation of ROS-mediated NB4 cells and its up-regulation promoted ATRA-induced autophagy and the degradation of PML-RARα. Furthermore, ATRA treatment elevated the levels of ROS, enhanced autophagic flux and thereby promoted cytosolic translocation of HMGB1. HMGB1 regulated the interactions between ubiquitin-binding adaptor protein p62/SQSTM and PML-RARα so as to affect the degradation of PML-RARα during ATRA-induced autophagy. Also a depletion of p62/SQSTM1 expression inhibited HMGB1-mediated PML-RARα degradation and cell differentiation. The overall results suggested that HMGB1 is an essential regulator of ROS-induced cell differentiation. And it may become a potential drug target for therapeutic intervention of APL.
PMCID: PMC4396052  PMID: 25973309
HMGB1; ROS; cell differentiation; autophagy
11.  PKM2 Regulates the Warburg Effect and Promotes HMGB1 Release in Sepsis 
Nature communications  2014;5:4436.
Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here, we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1α (HIF1α) and activates the HIF-1α-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1α, and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases.
doi:10.1038/ncomms5436
PMCID: PMC4104986  PMID: 25019241
12.  The Sheep Genome Illuminates Biology of the Rumen and Lipid Metabolism 
Science (New York, N.Y.)  2014;344(6188):1168-1173.
Sheep (Ovis aries) are a major source of meat, milk and fiber in the form of wool, and represent a distinct class of animals that have a specialized digestive organ, the rumen, which carries out the initial digestion of plant material. We have developed and analyzed a high quality reference sheep genome and transcriptomes from 40 different tissues. We identified highly expressed genes encoding keratin cross-linking proteins associated with rumen evolution. We also identified genes involved in lipid metabolism that had been amplified and/or had altered tissue expression patterns. This may be in response to changes in the barrier lipids of the skin, an interaction between lipid metabolism and wool synthesis, and an increased role of volatile fatty acids in ruminants, compared to non-ruminant animals.
doi:10.1126/science.1252806
PMCID: PMC4157056  PMID: 24904168
13.  Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice 
Scientific Reports  2014;4:7158.
Tak1 is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-κB and JNK/p38 MAPKs. Tak1 is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Tak1 is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Tak1 deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Tak1 knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Tak1 deficiency altered the signaling of NF-κB, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Tak1 regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Tak1 mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Tak1−/− monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Tak1 functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners.
doi:10.1038/srep07158
PMCID: PMC4241509  PMID: 25418008
14.  NSE, a Potential Biomarker, Is Closely Connected to Diabetic Peripheral Neuropathy 
Diabetes Care  2013;36(11):3405-3410.
OBJECTIVE
To explore the relationship between serum neuron-specific enolase (NSE) levels and diabetic neuropathy.
RESEARCH DESIGN AND METHODS
Type 1 or 2 diabetic and healthy control subjects (n = 568) were randomly enrolled in a cross-sectional study. Diabetic neuropathy status was documented by the presence of clinical symptoms or signs, electromyography, quantitative sensory tests, and cardiac autonomic neuropathy tests. The severity of the neuropathy was staged by composite scores. Serum NSE was measured using electrochemiluminescence immunoassay. The demographic and clinical variables were obtained through an interviewer questionnaire.
RESULTS
Serum NSE levels increased slightly in diabetic subjects compared with normal subjects (9.1 [1.5] vs. 8.7 [1.7], P = 0.037), and the levels increased greatly in diabetic subjects with neuropathy compared with those without (10.8 [2.8] vs. 9.1 [1.5], P = 0.000). The association of NSE with diabetic neuropathy was independent of the hyperglycemic state (fasting blood glucose, HbA1c, duration, and the type of diabetes) and other potential confounders affecting NSE levels (e.g., age, sex, and renal status) (odds ratio 1.48 [1.13–1.74], P = 0.001). In addition, NSE levels increased with and were closely correlated to the stages of neuropathy (r = 0.63 [0.52–0.74], P = 0.000). The optimal cutoff point for serum NSE levels to distinguish patients with diabetic neuropathy from those without was 10.10 μg/L, with a sensitivity of 66.3% and a specificity of 72.5%.
CONCLUSIONS
Serum NSE levels are closely associated with peripheral neuropathy in patients with diabetes. Future studies are warranted to clarify the relationship.
doi:10.2337/dc13-0590
PMCID: PMC3816869  PMID: 23846809
15.  Filamin A-interacting protein (FILIP) is a region-specific modulator of myosin 2b and controls spine morphology and NMDA receptor accumulation 
Scientific Reports  2014;4:6353.
Learning and memory depend on morphological and functional changes to neural spines. Non-muscle myosin 2b regulates actin dynamics downstream of long-term potentiation induction. However, the mechanism by which myosin 2b is regulated in the spine has not been fully elucidated. Here, we show that filamin A-interacting protein (FILIP) is involved in the control of neural spine morphology and is limitedly expressed in the brain. FILIP bound near the ATPase domain of non-muscle myosin heavy chain IIb, an essential component of myosin 2b, and modified the function of myosin 2b by interfering with its actin-binding activity. In addition, FILIP altered the subcellular distribution of myosin 2b in spines. Moreover, subunits of the NMDA receptor were differently distributed in FILIP-expressing neurons, and excitation propagation was altered in FILIP-knockout mice. These results indicate that FILIP is a novel, region-specific modulator of myosin 2b.
doi:10.1038/srep06353
PMCID: PMC4163676  PMID: 25220605
16.  Pathological Ventricular Remodeling: Therapies 
Circulation  2013;128(9):10.1161/CIRCULATIONAHA.113.001879.
doi:10.1161/CIRCULATIONAHA.113.001879
PMCID: PMC3829603  PMID: 23979628
remodeling; cell death; apoptosis; autophagy; hypertrophy; fibrosis; inflammation; electrophysiological remodeling; stem cells; progenitor cells
17.  HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance 
Nature Communications  2014;5:4602.
Proinflammatory cytokines play important roles in insulin resistance. Here we report that mice with a T-cell-specific conditional knockout of HGK (T-HGK cKO) develop systemic inflammation and insulin resistance. This condition is ameliorated by either IL-6 or IL-17 neutralization. HGK directly phosphorylates TRAF2, leading to its lysosomal degradation and subsequent inhibition of IL-6 production. IL-6-overproducing HGK-deficient T cells accumulate in adipose tissue and further differentiate into IL-6/IL-17 double-positive cells. Moreover, CCL20 neutralization or CCR6 deficiency reduces the Th17 population or insulin resistance in T-HGK cKO mice. In addition, leptin receptor deficiency in T cells inhibits Th17 differentiation and improves the insulin sensitivity in T-HGK cKO mice, which suggests that leptin cooperates with IL-6 to promote Th17 differentiation. Thus, HGK deficiency induces TRAF2/IL-6 upregulation, leading to IL-6/leptin-induced Th17 differentiation in adipose tissue and subsequent insulin resistance. These findings provide insight into the reciprocal regulation between the immune system and the metabolism.
HGK kinase is involved in signalling in many cell types but its function in T cells remains unclear. Here, using T-cell-specific HGK knockout mice, the authors show that HGK prevents the development of systemic inflammation and insulin resistance by inhibiting production of the proinflammatory cytokines IL-6 and IL-17.
doi:10.1038/ncomms5602
PMCID: PMC4143962  PMID: 25098764
18.  HDAC-dependent Ventricular Remodeling 
Trends in cardiovascular medicine  2013;23(6):229-235.
Heart failure, a syndrome culminating the pathogenesis of many forms of heart disease, is highly prevalent and projected to be increasingly so for years to come. Major efforts are directed at identifying means of preventing, slowing, or possibly reversing the unremitting progression of pathological stress leading to myocardial injury and ultimately heart failure. Indeed, despite widespread use of evidence-based therapies, heart failure morbidity and mortality remain high. Recent work has uncovered a fundamental role of reversible protein acetylation in the regulation of many biological processes, including pathological remodeling of the heart. This reversible acetylation is governed by enzymes that attach (histone acetyltransferases, HAT) or remove (histone deacetylases, HDACs) acetyl groups. In the case of the latter, small molecule inhibitors of HDACs are currently being tested for a variety of oncological indications. Now, evidence has revealed that HDAC inhibitors blunt pathological cardiac remodeling in the settings of pressure overload and ischemia/reperfusion, diminishing the emergence of heart failure. Mechanistically, HDAC inhibitors reduce stress-induced cardiomyocyte death, hypertrophy, and ventricular fibrosis. Looking to the future, HDAC inhibitor therapy may emerge as a novel means of arresting the untoward consequences of pathological cardiac stress, conferring clinical benefit to the millions of patients with heart failure.
doi:10.1016/j.tcm.2012.12.006
PMCID: PMC3688696  PMID: 23499301
heart failure; hypertrophy; remodeling; histone deacetylases
19.  Chloroquine Inhibits HMGB1 Inflammatory Signaling and Protects Mice from Lethal Sepsis 
Biochemical pharmacology  2013;86(3):410-418.
Sepsis is caused by an overwhelming immune response to bacterial infection. The discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal sepsis has prompted investigation into the development of new therapeutics which specifically target this protein. Here, we show that chloroquine, an anti-malarial drug, prevents lethality in mice with established endotoxemia or sepsis. This effect is still observed even if administration of chloroquine is delayed. The protective effects of chloroquine were mediated through inhibition of HMGB1 release in macrophages, monocytes, and endothelial cells, thereby preventing its cytokine-like activities. As an inhibitor of autophagy, chloroquine specifically inhibited HMGB1-induced Iκ-B degradation and NF-κB activation. These findings define a novel mechanism for the anti-inflammatory effects of chloroquine and also suggest a new potential clinical use for this drug in the setting of sepsis.
doi:10.1016/j.bcp.2013.05.013
PMCID: PMC3713089  PMID: 23707973
HMGB1; chloroquine; sepsis; autophagy; NF-κB; Beclin 1
20.  Comparative population genomics reveals the domestication history of the peach, Prunus persica, and human influences on perennial fruit crops 
Genome Biology  2014;15(7):415.
Background
Recently, many studies utilizing next generation sequencing have investigated plant evolution and domestication in annual crops. Peach, Prunus persica, is a typical perennial fruit crop that has ornamental and edible varieties. Unlike other fruit crops, cultivated peach includes a large number of phenotypes but few polymorphisms. In this study, we explore the genetic basis of domestication in peach and the influence of humans on its evolution.
Results
We perform large-scale resequencing of 10 wild and 74 cultivated peach varieties, including 9 ornamental, 23 breeding, and 42 landrace lines. We identify 4.6 million SNPs, a large number of which could explain the phenotypic variation in cultivated peach. Population analysis shows a single domestication event, the speciation of P. persica from wild peach. Ornamental and edible peach both belong to P. persica, along with another geographically separated subgroup, Prunus ferganensis.
We identify 147 and 262 genes under edible and ornamental selection, respectively. Some of these genes are associated with important biological features. We perform a population heterozygosity analysis in different plants that indicates that free recombination effects could affect domestication history. By applying artificial selection during the domestication of the peach and facilitating its asexual propagation, humans have caused a sharp decline of the heterozygote ratio of SNPs.
Conclusions
Our analyses enhance our knowledge of the domestication history of perennial fruit crops, and the dataset we generated could be useful for future research on comparative population genomics.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0415-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0415-1
PMCID: PMC4174323  PMID: 25079967
21.  Pathological Ventricular Remodeling: Mechanisms: Part 1 of 2 
Circulation  2013;128(4):388-400.
Despite declines in heart failure morbidity and mortality with current therapies, re-hospitalization rates remain distressingly high, impacting substantially on individuals, society, and the economy. As a result, the need for new therapeutic advances and novel medical devices is urgent. Disease-related left ventricular remodeling is a complex process involving cardiac myocyte growth and death, vascular rarefaction, fibrosis, inflammation, and electrophysiological remodeling. As these events are highly inter-related, targeting one single molecule or process may not be sufficient. Here, we review molecular and cellular mechanisms governing pathological ventricular remodeling.
doi:10.1161/CIRCULATIONAHA.113.001878
PMCID: PMC3801217  PMID: 23877061
remodeling; cell death; apoptosis; autophagy; hypertrophy; fibrosis; inflammation; electrophysiological remodeling; stem cells; progenitor cells
22.  Identification of a novel salt tolerance gene in wild soybean by whole-genome sequencing 
Nature Communications  2014;5:4340.
Using a whole-genome-sequencing approach to explore germplasm resources can serve as an important strategy for crop improvement, especially in investigating wild accessions that may contain useful genetic resources that have been lost during the domestication process. Here we sequence and assemble a draft genome of wild soybean and construct a recombinant inbred population for genotyping-by-sequencing and phenotypic analyses to identify multiple QTLs relevant to traits of interest in agriculture. We use a combination of de novo sequencing data from this work and our previous germplasm re-sequencing data to identify a novel ion transporter gene, GmCHX1, and relate its sequence alterations to salt tolerance. Rapid gain-of-function tests show the protective effects of GmCHX1 towards salt stress. This combination of whole-genome de novo sequencing, high-density-marker QTL mapping by re-sequencing and functional analyses can serve as an effective strategy to unveil novel genomic information in wild soybean to facilitate crop improvement.
The identification of genes that control economically important traits is an essential step towards crop improvement. Here the authors sequence the genome of the wild soybean and, through a combined genetic and functional approach, identify a new gene affecting salt tolerance in soybean.
doi:10.1038/ncomms5340
PMCID: PMC4104456  PMID: 25004933
23.  Fracture is additionally attributed to hyperhomocysteinemia in men and premenopausal women with type 2 diabetes 
Abstract
Aims/Introduction
Data on hyperhomocysteinemia in relation to fractures in diabetes are limited. We aimed to explore the relationship between plasma total homocysteine concentrations and fractures in men and premenopausal women with type 2 diabetes.
Materials and Methods
Diabetic and control participants (n = 292) were enrolled in a cross‐sectional hospital‐based study. Bone mineral density and fractures were documented by dual energy X‐ray absorptiometry and X‐ray film, respectively. Plasma total homocysteine concentrations were measured using fluorescence polarization immunoassay. Risk factors for low bone mineral density or fractures and determinants of homocysteine were obtained from blood samples and the interviewer questionnaire.
Results
Plasma total homocysteine levels were higher in diabetic participants with fractures than without (8.6 [2.1] μmol/L vs 10.3 [3.0] μmol/L, P = 0.000). Diabetic participants with fractures had similar bone mineral densities as control participants. The association of homocysteine with the fracture was independent of possible risk factors for fractures (e.g., age, duration of diabetes, glycated hemoglobin, body mass index, thiazolidenediones and retinopathy) and determinants of homocysteine concentration (e.g., age, sex, serum folate and vitamin B12, renal status and biguanide use; odds ratio 1.41, 95% confidence interval 1.05–2.03, P = 0.020). Furthermore, per increase of 5.0 μmol/L plasma homocysteine was related to the fracture, after controlling for per unit increase of other factors (odds ratio 1.42, 95% confidence interval 1.12–1.78, P = 0.013).
Conclusions
Plasma total homocysteine concentration is independently associated with occurrence of fractures in men and premenopausal women with type 2 diabetes. Future prospective studies are warranted to clarify the relationship.
doi:10.1111/jdi.12149
PMCID: PMC4023589  PMID: 24843766
Fracture; Homocysteine; Men and premenopausal women with type 2 diabetes
24.  Progress in the reprogramming of somatic cells 
Circulation research  2013;112(3):562-574.
Pluripotent stem cells can differentiate into nearly all types of cells in the body. This unique potential provides significant promise for cell-based therapies to restore tissues or organs destroyed by injuries, degenerative diseases, aging, or cancer. The discovery of induced pluripotent stem cell (iPSC) technology offers a possible strategy to generate patient-specific pluripotent stem cells. However, because of concerns about the specificity, efficiency, kinetics, and safety of iPSC reprogramming, improvements or fundamental changes in this process are required before their effective clinical use. A chemical approach is regarded as a promising strategy to improve and change the iPSC process. Dozens of small molecules have been identified that can functionally replace reprogramming factors and significantly improve iPSC reprogramming. In addition to the prospect of deriving patient-specific tissues and organs from iPSCs, another attractive strategy for regenerative medicine is transdifferentiation—the direct conversion of one somatic cell type to another. Recent studies revealed a new paradigm of transdifferentiation: using transcription factors (TFs) employed in iPSC generation to induce transdifferentiation, or iPSC TF-based transdifferentiation. This transdifferentiation not only reveals and utilizes the developmentally plastic intermediates generated during iPSC reprogramming, but also produces a very wide range of cells, including expandable tissue-specific precursor cells. Here, we review recent progress of small-molecule approaches in the generation of iPSCs. In addition, we summarize the new concept of iPSC TF–based transdifferentiation and discuss its application in generating various lineage-specific cells, especially cardiovascular cells.
doi:10.1161/CIRCRESAHA.111.249235
PMCID: PMC3790469  PMID: 23371904
Reprogramming; iPSC; small molecule; transdifferentiation and cardiovascular cell
25.  Bicarbonate efflux via GABAA receptors depolarizes membrane potential and inhibits two-pore domain potassium channels of astrocytes in rat hippocampal slices 
Glia  2012;60(11):1761-1772.
Increasing evidence indicates the functional expression of ionotropic γ-aminobutyric acid receptor (GABAA-R) in astrocytes. However, it remains controversial in regard to the intracellular Cl− concentration ([Cl−]i) and the functional role of anion-selective GABAA-R in astrocytes. In gramicidin perforated-patch recordings from rat hippocampal CA1 astrocytes, GABA and GABAA-R specific agonist THIP depolarized astrocyte membrane potential (Vm), and the THIP induced currents reversed at the voltages between −75.3 to −78.3 mV, corresponding to a [Cl−]i of 3.1 – 3.9 mM that favors a passive distribution of Cl− anions across astrocyte membrane. Further analysis showed that GABAA-R induced Vm depolarization is ascribed to HCO3− efflux, while a passively distributed Cl− mediates no net flux or influx of Cl-that leads to an unchanged or hyperpolarized Vm. In addition to a rapidly activated GABAA-R current component, GABA and THIP also induced a delayed inward current (DIC) in 63% of astrocytes. The DIC became manifest after agonist withdrawal and enhanced in amplitude with increasing agonist application duration or concentrations. Astrocytic two-pore domain K+ channels (K2Ps), especially TWIK-1, appeared to underlie the DIC, because 1) acidic intracellular pH, as a result of HCO3− efflux, inhibited TWIK-1; 2) the DIC remained in the Cs+ recording solutions that inhibited conventional K+ channels and 3) the DIC was completely inhibited by 1 mM quinine but not by blockers for other cation/anion channels. Altogether, HCO3− efflux through activated GABAA-R depolarizes astrocyte Vm and induces a delayed inhibition of K2Ps K+ channels via intracellular acidification.
doi:10.1002/glia.22395
PMCID: PMC3901573  PMID: 22855415
Astrocytes; GABAA receptors; bicarbonate; TWIK-1; patch clamp; hippocampus

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