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Article ; Online: Distinct roles of arginases 1 and 2 in diabetic nephropathy.

Morris, Sidney M / You, Hanning / Gao, Ting / Vacher, Jean / Cooper, Timothy K / Awad, Alaa S

American journal of physiology. Renal physiology

2017 Volume 313, Issue 4, Page(s) F899–F905

Abstract: Diabetes is the leading cause of end-stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. Because current therapies for progression of diabetic nephropathy (DN) are only moderately ... ...

Abstract	Diabetes is the leading cause of end-stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. Because current therapies for progression of diabetic nephropathy (DN) are only moderately successful, identification of underlying mechanisms of disease is essential to develop more effective therapies. We showed previously that inhibition of arginase using
MeSH term(s)	Albuminuria/enzymology ; Albuminuria/etiology ; Animals ; Arginase/metabolism ; Diabetic Nephropathies/complications ; Diabetic Nephropathies/enzymology ; Fibronectins/metabolism ; Macrophages/enzymology ; Male ; Mice ; Renal Circulation ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Fibronectins ; Tumor Necrosis Factor-alpha ; Arg1 protein, mouse (EC 3.5.3.1) ; Arg2 protein, mouse (EC 3.5.3.1) ; Arginase (EC 3.5.3.1)
Language	English
Publishing date	2017-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00158.2017
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Article ; Online: Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice.

You, Hanning / Gao, Ting / Raup-Konsavage, Wesley M / Cooper, Timothy K / Bronson, Sarah K / Reeves, W Brian / Awad, Alaa S

Kidney international

2017 Volume 91, Issue 3, Page(s) 671–682

Abstract: Inflammation is a central pathophysiologic mechanism that contributes to diabetes mellitus and diabetic nephropathy. Recently, we showed that macrophages directly contribute to diabetic renal injury and that pharmacological blockade or genetic deficiency ...

Abstract	Inflammation is a central pathophysiologic mechanism that contributes to diabetes mellitus and diabetic nephropathy. Recently, we showed that macrophages directly contribute to diabetic renal injury and that pharmacological blockade or genetic deficiency of chemokine (C-C motif) receptor 2 (CCR2) confers kidney protection in diabetic nephropathy. However, the direct role of CCR2 in kidney-derived cells such as podocytes in diabetic nephropathy remains unclear. To study this, we developed a transgenic mouse model expressing CCR2 specifically in podocytes (Tg[NPHS2-Ccr2]) on a nephropathy-prone (DBA/2J) and CCR2-deficient (Ccr2
MeSH term(s)	Albuminuria/genetics ; Albuminuria/metabolism ; Albuminuria/prevention & control ; Animals ; Apoptosis ; Blood Urea Nitrogen ; Collagen Type I/genetics ; Collagen Type I/metabolism ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Type 1/complications ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/pathology ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Diabetic Nephropathies/prevention & control ; Fibronectins/genetics ; Fibronectins/metabolism ; Fibrosis ; Genetic Predisposition to Disease ; Inflammation Mediators/metabolism ; Macrophages/metabolism ; Male ; Mice, Inbred DBA ; Mice, Knockout ; Mice, Transgenic ; Monocytes/metabolism ; Phenotype ; Podocytes/metabolism ; Podocytes/pathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, CCR2/deficiency ; Receptors, CCR2/genetics ; Receptors, CCR2/metabolism ; Signal Transduction ; Streptozocin ; Up-Regulation
Chemical Substances	Ccr2 protein, mouse ; Collagen Type I ; Fibronectins ; Inflammation Mediators ; RNA, Messenger ; Receptors, CCR2 ; Streptozocin (5W494URQ81)
Language	English
Publishing date	2017-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2016.09.042
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Zs.A 797: Show issues

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Article ; Online: The Central Role of Protein Kinase C Epsilon in Cyanide Cardiotoxicity and Its Treatment.

Cheung, Joseph Y / Merali, Salim / Wang, JuFang / Zhang, Xue-Qian / Song, Jianliang / Merali, Carmen / Tomar, Dhanendra / You, Hanning / Judenherc-Haouzi, Annick / Haouzi, Philippe

Toxicological sciences : an official journal of the Society of Toxicology

2019 Volume 171, Issue 1, Page(s) 247–257

Abstract: In adult mouse myocytes, brief exposure to sodium cyanide (CN) in the presence of glucose does not decrease ATP levels, yet produces profound reduction in contractility, intracellular Ca2+ concentration ([Ca2+]i) transient and L-type Ca2+ current (ICa) ... ...

Abstract	In adult mouse myocytes, brief exposure to sodium cyanide (CN) in the presence of glucose does not decrease ATP levels, yet produces profound reduction in contractility, intracellular Ca2+ concentration ([Ca2+]i) transient and L-type Ca2+ current (ICa) amplitudes. We analyzed proteomes from myocytes exposed to CN, focusing on ionic currents associated with excitation-contraction coupling. CN induced phosphorylation of α1c subunit of L-type Ca2+ channel and α2 subunit of Na+-K+-ATPase. Methylene blue (MB), a CN antidote that we previously reported to ameliorate CN-induced reduction in contraction, [Ca2+]i transient and ICa amplitudes, was able to reverse this phosphorylation. CN decreased Na+-K+-ATPase current contributed by α2 but not α1 subunit, an effect that was also counteracted by MB. Peptide consensus sequences suggested CN-induced phosphorylation was mediated by protein kinase C epsilon (PKCε). Indeed, CN stimulated PKC kinase activity and induced PKCε membrane translocation, effects that were prevented by MB. Pretreatment with myristoylated PKCε translocation activator or inhibitor peptides mimicked and inhibited the effects of CN on ICa and myocyte contraction, respectively. We conclude that CN activates PKCε, which phosphorylates L-type Ca2+ channel and Na+-K+-ATPase, resulting in depressed cardiac contractility. We hypothesize that this inhibition of ion fluxes represents a novel mechanism by which the cardiomyocyte reduces its ATP demand (decreased ion fluxes and contractility), diminishes ATP turnover and preserves cell viability. However, this cellular protective effect translates into life-threatening cardiogenic shock in vivo, thereby creating a profound disconnect between survival mechanisms at the cardiomyocyte level from those at the level of the whole organism.
Language	English
Publishing date	2019-05-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfz137
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Zs.A 1709: Show issues

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Article ; Online: The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma.

Steven N Steinway / Hien Dang / Hanning You / C Bart Rountree / Wei Ding

PLoS ONE, Vol 10, Iss 5, p e

2015 Volume 0128159

Abstract: c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted ...

Abstract	c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance.We utilized the human MHCC97-H c-Met positive (c-Met+) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses.We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone.c-Met inhibition monotherapy is not sufficient to eliminate c-Met+ HCC tumor growth. Inhibition of both c-Met and EGFR oncogenic pathways provides superior suppression of HCC tumor growth. Thus, combination of c-Met and EGFR inhibition may represent a superior therapeutic regimen for c-Met+ HCC.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Delayed Treatment with a Small Pigment Epithelium Derived Factor (PEDF) Peptide Prevents the Progression of Diabetic Renal Injury.

Awad, Alaa S / You, Hanning / Gao, Ting / Gvritishvili, Anzor / Cooper, Timothy K / Tombran-Tink, Joyce

PloS one

2015 Volume 10, Issue 7, Page(s) e0133777

Abstract: Our recent publication showed that a small bioactive pigment epithelium derived factor (PEDF) peptide (P78-PEDF) prevents the development of diabetic nephropathy (DN). However, its effects on the progression of established DN were not clear. Therefore, ... ...

Abstract	Our recent publication showed that a small bioactive pigment epithelium derived factor (PEDF) peptide (P78-PEDF) prevents the development of diabetic nephropathy (DN). However, its effects on the progression of established DN were not clear. Therefore, the purpose of this study was to determine the effect of P78-PEDF in the progression of DN and to compare the effects of P78-PEDF and an ACE inhibitor (ACEi), a standard of care in DN. Experiments were conducted in Ins2(Akita) mice treated with P78-PEDF or captopril starting at 6 wks of age for 12 wks (early treatment) or starting at 12 wks of age for 6 wks (late treatment). We first established the optimal dose of the P78-PEDF peptide to ameliorate DN in Ins2(Akita) mouse for a 6 wk study period and found that the peptide was effective at 0.1- 0.5 µg/g/day. We next showed that early or late treatment with P78-PEDF resulted in protection from DN as indicated by reduced albuminuria, kidney macrophage recruitment, histological changes, inflammatory cytokines and fibrotic markers (kidney TNF-α, fibronectin, VEGFA and EGFR), and restored nephrin expression compared with vehicle-treated Ins2(Akita) mice. Interestingly, only early but not late treatment with captopril was as effective as P78-PEDF in reducing most DN complications, despite its lack of effect on nephrin, VEGFA and EGFR expression. These findings highlight the importance of P78-PEDF peptide as a potential therapeutic modality in both the development and progression of diabetic renal injury.
MeSH term(s)	Animals ; Blood Pressure/drug effects ; Captopril/pharmacology ; Captopril/therapeutic use ; Cytokines/metabolism ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetic Nephropathies/drug therapy ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Disease Progression ; Eye Proteins/pharmacology ; Eye Proteins/therapeutic use ; Kidney/drug effects ; Kidney/metabolism ; Kidney/pathology ; Macrophages/drug effects ; Macrophages/metabolism ; Macrophages/pathology ; Male ; Membrane Proteins/metabolism ; Mice ; Nerve Growth Factors/pharmacology ; Nerve Growth Factors/therapeutic use ; Serpins/pharmacology ; Serpins/therapeutic use
Chemical Substances	Cytokines ; Eye Proteins ; Membrane Proteins ; Nerve Growth Factors ; Serpins ; nephrin ; pigment epithelium-derived factor ; Captopril (9G64RSX1XD)
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0133777
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Article ; Online: Arginase inhibition: a new treatment for preventing progression of established diabetic nephropathy.

You, Hanning / Gao, Ting / Cooper, Timothy K / Morris, Sidney M / Awad, Alaa S

American journal of physiology. Renal physiology

2015 Volume 309, Issue 5, Page(s) F447–55

Abstract: Our previous publication showed that inhibition of arginase prevents the development of diabetic nephropathy (DN). However, identification of targets that retard the progression of established DN-which is more clinically relevant-is lacking. Therefore, ... ...

Abstract	Our previous publication showed that inhibition of arginase prevents the development of diabetic nephropathy (DN). However, identification of targets that retard the progression of established DN-which is more clinically relevant-is lacking. Therefore, we tested the hypothesis that arginase inhibition would prevent the progression of established DN. Effects of arginase inhibition were compared with treatment with the angiotensin-converting enzyme inhibitor captopril, a current standard of care in DN. Experiments were conducted in Ins2(Akita) mice treated with the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) or captopril starting at 6 wk of age for 12 wk (early treatment) or starting at 12 wk of age for 6 wk (late treatment). Early and late treatment with BEC resulted in protection from DN as indicated by reduced albuminuria, histological changes, kidney macrophage infiltration, urinary thiobarbituric acid-reactive substances, and restored nephrin expression, kidney nitrate/nitrite, kidney endothelial nitric oxide synthase phosphorylation, and renal medullary blood flow compared with vehicle-treated Ins2(Akita) mice at 18 wk of age. Interestingly, early treatment with captopril reduced albuminuria, histological changes, and kidney macrophage infiltration without affecting the other parameters, but late treatment with captopril was ineffective. These findings highlight the importance of arginase inhibition as a new potential therapeutic intervention in both early and late stages of diabetic renal injury.
MeSH term(s)	Albuminuria/drug therapy ; Albuminuria/metabolism ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Animals ; Arginase/antagonists & inhibitors ; Boronic Acids/pharmacology ; Boronic Acids/therapeutic use ; Captopril/pharmacology ; Captopril/therapeutic use ; Diabetic Nephropathies/drug therapy ; Diabetic Nephropathies/metabolism ; Disease Progression ; Kidney/drug effects ; Kidney/metabolism ; Mice ; Nitric Oxide Synthase Type III/metabolism ; Phosphorylation ; Treatment Outcome
Chemical Substances	(2-boronoethyl)-cysteine ; Angiotensin-Converting Enzyme Inhibitors ; Boronic Acids ; Captopril (9G64RSX1XD) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Arginase (EC 3.5.3.1)
Language	English
Publishing date	2015-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00137.2015
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Article ; Online: The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma.

Steinway, Steven N / Dang, Hien / You, Hanning / Rountree, C Bart / Ding, Wei

PloS one

2015 Volume 10, Issue 5, Page(s) e0128159

Abstract: Background: c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse ... ...

Abstract	Background: c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance. Methods: We utilized the human MHCC97-H c-Met positive (c-Met+) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses. Results: We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone. Conclusion: c-Met inhibition monotherapy is not sufficient to eliminate c-Met+ HCC tumor growth. Inhibition of both c-Met and EGFR oncogenic pathways provides superior suppression of HCC tumor growth. Thus, combination of c-Met and EGFR inhibition may represent a superior therapeutic regimen for c-Met+ HCC.
MeSH term(s)	Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/physiology ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Female ; Hepatocyte Growth Factor/genetics ; Hepatocyte Growth Factor/metabolism ; Humans ; Indoles/pharmacology ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Male ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/genetics ; Proto-Oncogene Proteins c-met/metabolism ; Receptor, ErbB-3/genetics ; Receptor, ErbB-3/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Sulfones/pharmacology
Chemical Substances	5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one ; Indoles ; Sulfones ; Hepatocyte Growth Factor (67256-21-7) ; ERBB3 protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Receptor, ErbB-3 (EC 2.7.10.1)
Language	English
Publishing date	2015-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0128159
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Article ; Online: Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta.

You, Hanning / Ding, Wei / Rountree, C Bart

Hepatology (Baltimore, Md.)

2010 Volume 51, Issue 5, Page(s) 1635–1644

Abstract: Unlabelled: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. CD133, a transmembrane glycoprotein, is an important cell surface marker for both stem cells and cancer stem cells in various tissues including liver. ... ...

Abstract	Unlabelled: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. CD133, a transmembrane glycoprotein, is an important cell surface marker for both stem cells and cancer stem cells in various tissues including liver. CD133 expression has been recently linked to poor prognosis in HCC patients. CD133+ liver cancer cells are characterized by resistance to chemotherapy, self-renewal, multilineage potential, increased colony formation, and in vivo cancer initiation at limited dilution. Recent studies demonstrate that CD133 expression is regulated by DNA methylation. In this study, we explored the role of transforming growth factor beta (TGFbeta), a multifunctional cytokine that plays a critical role in chronic liver injury, in the regulation of CD133 expression. TGFbeta1 is capable of up-regulating CD133 expression specifically within the Huh7 HCC cell line in a time- and dose-dependent manner. Most important, TGFbeta1-induced CD133+ Huh7 cells demonstrate increased tumor initiation in vivo. Forced expression of inhibitory Smads, including Smad6 and Smad7, attenuated TGFbeta1-induced CD133 expression. Within CD133- Huh7 cells, TGFbeta1 stimulation inhibited the expression of DNA methyltransferases (DNMT) 1 and DNMT3beta, which are critical in the maintenance of regional DNA methylation, and global DNMT activity in CD133- Huh7 cells was inhibited by TGFbeta1. DNMT3beta inhibition by TGFbeta1 was partially rescued with overexpression of inhibitory Smads. Lastly, TGFbeta1 treatment led to significant demethylation in CD133 promoter-1 in CD133- Huh7 cells. Conclusion: TGFbeta1 is able to regulate CD133 expression through inhibition of DNMT1 and DNMT3beta expression and subsequent demethylation of promoter-1. TGFbeta1-induced CD133+ Huh7 cells are tumorigenic. The mechanism by which TGFbeta induces CD133 expression is partially dependent on the Smads pathway.
MeSH term(s)	AC133 Antigen ; Antigens, CD/genetics ; Carcinoma, Hepatocellular/metabolism ; Cell Line, Tumor ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/biosynthesis ; Epigenesis, Genetic/physiology ; Glycoproteins/genetics ; Humans ; Liver Neoplasms/metabolism ; Neoplastic Stem Cells/metabolism ; Peptides/genetics ; Smad Proteins/physiology ; Transforming Growth Factor beta/pharmacology ; Up-Regulation ; DNA Methyltransferase 3B
Chemical Substances	AC133 Antigen ; Antigens, CD ; Glycoproteins ; PROM1 protein, human ; Peptides ; Smad Proteins ; Transforming Growth Factor beta ; DNA (Cytosine-5-)-Methyltransferase 1 (EC 2.1.1.37) ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNMT1 protein, human (EC 2.1.1.37)
Language	English
Publishing date	2010-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.23544
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Zs.A 1660: Show issues

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Article ; Online: Antibacterial abilities and biocompatibilities of Ti-Ag alloys with nanotubular coatings.

Liu, Xingwang / Tian, Ang / You, Junhua / Zhang, Hangzhou / Wu, Lin / Bai, Xizhuang / Lei, Zeming / Shi, Xiaoguo / Xue, Xiangxin / Wang, Hanning

International journal of nanomedicine

2016 Volume 11, Page(s) 5743–5755

Abstract: Purpose: To endow implants with both short- and long-term antibacterial activities without impairing their biocompatibility, novel Ti-Ag alloy substrates with different proportions of Ag (1, 2, and 4 wt% Ag) were generated with nanotubular coverings ( ... ...

Abstract	Purpose: To endow implants with both short- and long-term antibacterial activities without impairing their biocompatibility, novel Ti-Ag alloy substrates with different proportions of Ag (1, 2, and 4 wt% Ag) were generated with nanotubular coverings (TiAg-NT). Methods: Unlike commercial pure Ti and titania nanotube, the TiAg-NT samples exhibited short-term antibacterial activity against Results: All of the TiAg-NT samples, particularly the nanotube-coated Ti-Ag alloy with 2 wt% Ag (Ti2%Ag-NT), could effectively inhibit bacterial adhesion and kill the majority of adhered Conclusion: This study indicates that the TiAg-NT samples can prevent biofilm formation and maintain their antibacterial ability for at least 1 month. Ti2%Ag-NT exhibited better antibacterial ability and biocompatibility than commercial pure Ti, which could be attributed to the synergistic effect of the presence of Ag (2 wt%) and the morphology of the nanotubes. Ti2%Ag-NT may offer a potential implant material that is capable of preventing implant-related infection.
MeSH term(s)	Alloys/chemistry ; Alloys/pharmacology ; Anti-Bacterial Agents/pharmacology ; Bacterial Adhesion/drug effects ; Coated Materials, Biocompatible/pharmacology ; Materials Testing ; Microscopy, Electron, Scanning ; Nanotubes/chemistry ; Silver/chemistry ; Staphylococcus aureus/drug effects ; Staphylococcus aureus/growth & development ; Titanium/chemistry
Chemical Substances	Alloys ; Anti-Bacterial Agents ; Coated Materials, Biocompatible ; Silver (3M4G523W1G) ; Titanium (D1JT611TNE)
Language	English
Publishing date	2016
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2364941-0
ISSN	1178-2013 ; 1176-9114
ISSN (online)	1178-2013
ISSN	1176-9114
DOI	10.2147/IJN.S113674
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Zs.A 6606: Show issues

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Article ; Online: Diabetic nephropathy is resistant to oral L-arginine or L-citrulline supplementation.

You, Hanning / Gao, Ting / Cooper, Timothy K / Morris, Sidney M / Awad, Alaa S

American journal of physiology. Renal physiology

2014 Volume 307, Issue 11, Page(s) F1292–301

Abstract: Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide (NO) synthase (NOS)3-dependent mechanism. Arginase competes with endothelial NOS (eNOS) for the common substrate ...

Abstract	Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide (NO) synthase (NOS)3-dependent mechanism. Arginase competes with endothelial NOS (eNOS) for the common substrate L-arginine. Lack of L-arginine results in reduced NO production and eNOS uncoupling, which lead to endothelial dysfunction. Therefore, we hypothesized that L-arginine or L-citrulline supplementation would ameliorate diabetic nephropathy. DBA mice injected with multiple low doses of vehicle or streptozotocin (50 mg/kg ip for 5 days) were provided drinking water with or without L-arginine (1.5%, 6.05 g·kg(-1)·day(-1)) or L-citrulline (1.66%, 5.73 g·kg(-1)·day(-1)) for 9 wk. Nonsupplemented diabetic mice showed significant increases in albuminuria, blood urea nitrogen, glomerular histopathological changes, kidney macrophage recruitment, kidney TNF-α and fibronectin mRNA expression, kidney arginase activity, kidney arginase-2 protein expression, and urinary oxidative stress along with a significant reduction of nephrin and eNOS protein expression and kidney nitrite + nitrate compared with normal mice after 9 wk of diabetes. Surprisingly, L-arginine or L-citrulline supplementation in diabetic mice did not affect any of these parameters despite greatly increasing kidney and plasma arginine levels. These findings demonstrate that chronic L-arginine or L-citrulline supplementation does not prevent or reduce renal injury in a model of type 1 diabetes.
MeSH term(s)	Amino Acids/blood ; Amino Acids/metabolism ; Animals ; Arginase/metabolism ; Arginine/blood ; Arginine/therapeutic use ; Blood Pressure/physiology ; Citrulline/therapeutic use ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetic Nephropathies/drug therapy ; Diabetic Nephropathies/pathology ; Dietary Supplements ; Fibronectins/biosynthesis ; Kidney/pathology ; Male ; Membrane Proteins/biosynthesis ; Mice ; Mice, Inbred DBA ; Nitrates/metabolism ; Nitric Oxide Synthase Type III/biosynthesis ; Nitrites/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis
Chemical Substances	Amino Acids ; Fibronectins ; Membrane Proteins ; Nitrates ; Nitrites ; Tumor Necrosis Factor-alpha ; nephrin ; Citrulline (29VT07BGDA) ; Arginine (94ZLA3W45F) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Arginase (EC 3.5.3.1)
Language	English
Publishing date	2014-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00176.2014
Database	MEDical Literature Analysis and Retrieval System OnLINE

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