Rhinebeck, NY, United States


Rhinebeck, NY, United States
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Sinha-Hikim I.,Drew University | Sinha-Hikim I.,University of California at Los Angeles | Sinha-Hikim A.P.,Drew University | Sinha-Hikim A.P.,University of California at Los Angeles | And 9 more authors.
Experimental and Molecular Pathology | Year: 2011

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome. Here, we investigated the molecular mechanisms by which a novel cystine based glutathione precursor with added selenomethionine (F1) prevents hepatic steatosis in a moderate high fat dietary model of NAFLD. Adult (8weeks old), male apolipoprotein E (ApoE)-/- mice were fed with a normal diet (ND) or high fat diet (HFD), consisting of 21% fat and 0.21% cholesterol, with or without dietary supplementation of F1 (3g/kg food) for 16weeks. Compared with ApoE-/- mice fed with ND with or without F1, ApoE-/- mice fed with HFD exhibited significant weight gain, hepatomegaly, and increased serum cholesterol and triglycerides levels with no change in serum albumin levels. High resolution light and electron microscopy revealed micro-and macro-vesicular steatosis in ApoE-/- mice fed on a HFD. HFD-induced obesity also led to increased lipogenesis, oxidative stress, activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), perturbation of the BAX/BCL-2 rheostat, hepatocyte apoptosis, and activation of caspases 9 and 3. F1 fully prevented the adverse effects of HFD on serum triglyceride levels, body and liver weights, and hepatic steatosis and substantially attenuated HFD-induced increase in lipogenesis, oxidative stress, kinase activation, apoptotic signaling, and hepatocyte ultrastructural abnormalities. These results demonstrate that administration of F1, a glutathione precursor, ameliorates HFD-induced hepatic steatosis in ApoE-/- mice and emphasizes the role of oxidative stress in diet-induced obesity and hepatic steatosis. © 2011.

Vaziri N.D.,University of California | Pahl M.V.,University of California | Crum A.,Proimmune | Norris K.,Drew University
Journal of Renal Nutrition | Year: 2012

End-stage renal disease (ESRD) is simultaneously associated with immune activation, marked by systemic inflammation, and immune deficiency. Systemic inflammation contributes to atherosclerosis, cardiovascular disease, cachexia, and anemia, whereas immune deficiency leads to impaired response to vaccination, and increased incidence and severity of microbial infections. ESRD-associated inflammation and immune deficiency are associated with the following: (a) general expansion of monocytes and elevations of their basal integrin, Toll-like receptor (TLR)-2, TLR-4 expression, cytokine production, and reactive oxygen species (ROS) generation and reduced phagocytic capacity, (b) depletion and impaired inhibitory activity of regulatory T cells, (c) spontaneous activation, degranulation, increased basal ROS production, decreased phagocytic capacity, and increased apoptosis of the circulating polymorphonuclear leukocytes, (d) upregulation of ROS production machinery and chemokine expression in the cellular constituents of various tissues, highlighting participation of nonimmune cells in the prevailing inflammatory state, (e) depletion of the antigen-presenting dendritic cells, (f) reduced CD4/CD8 T cell ratio and depletion of naïve and central memory T cells, (g) diffuse B cell lymphopenia leading to impaired humoral immunity, and (h) increased proinflammatory activity of low-density lipoprotein and reduced anti-inflammatory capacity of high-density lipoprotein. Thus, ESRD-associated inflammation is due to activation of innate immune system, orchestrated by monocytes, macrophages, granulocytes, and cellular constituents of other organs/tissues. This is coupled with immune deficiency that is caused by depletion of dendritic cells, naïve and central memory T cells and B cells, and impaired phagocytic function of polymorphonuclear leukocytes and monocytes. © 2012 National Kidney Foundation, Inc.

Sinha-Hikim I.,Drew University | Sinha-Hikim I.,University of California at Los Angeles | Shen R.,Drew University | Lee W.-N.P.,Los Angeles Biomedical Research Institute | And 5 more authors.
American Journal of Physiology - Cell Physiology | Year: 2010

Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and cardiovascular disease, which is largely mediated by oxidative stress. We investigated the effect of three glutathione (GSH) precursors: N-acetyl-cysteine (NAC), cystine as the physiological carrier of cysteine in GSH with added selenomethionine (F1), and NAC fortified with selenomethionine (F2) on oxidative stress induced by spermine (a uremic toxin) in cultured human aortic vascular smooth muscle cells (VSMC). VSMC were exposed to spermine (15 μM) with or without the given antioxidants (dose 50, 100, 200, and 500 μg/ml) or vehicle (control) and assessed for intracellular GSH levels, 4-hydroxy-trans-2-nonenal (4-HNE), and incorporation of 13C from glucose into alanine and protein. Spermine exposure reduced intracellular GSH levels, increased 4-HNE, and impaired glucose metabolism through reduction in pyruvate generation and/or transamination. Treatment with NAC had no effect on intracellular glutathione level. In contrast, F1 maintained intracellular GSH at control levels at all four doses. Subsequent studies performed with 200 μg/ml of F1, F2, or NAC (optimal dose) revealed normalization of 4-HNE, whereas restoration of 13C from glucose to alanine or protein to control values was only noted in the F1 group. Spermine-induced alterations in VSMC ultrastructure were prevented in ∼90% of cells treated with F1 but only ∼50% of cells treated with either NAC or F2. In conclusion, F1 was more effective than NAC or F2 in ameliorating spermine-induced reduction in intracellular GSH levels and cellular alterations in VSMC. The cystine-based GSH precursor (F1) is a promising antioxidant, and further studies are needed to examine the effect of this compound in preventing CKD-associated vascular disease. Copyright © 2010 the American Physiological Society.

Sinha-Hikim I.,Charles R. Drew University of Medicine and Science | Sinha-Hikim I.,University of California at Los Angeles | Sinha-Hikim A.P.,Charles R. Drew University of Medicine and Science | Parveen M.,Charles R. Drew University of Medicine and Science | And 6 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2013

Oxidative stress increases with age and is postulated to be a major causal factor for sarcopenia in aging. Here, we examined whether the administration of a cystine-based antioxidant (F1) can alleviate/delay age-specific changes in skeletal muscles. C57BL6 male mice aged 17 months (middle aged) were fed with normal diet with or without supplementation of F1 (3mg/kg food) for 6 months. Compared with young (5 months old) mice old mice exhibited increased markers of oxidative stress, inflammation, and muscle cell apoptosis and decreased muscle weight. These age-related changes were further associated with inactivation of adenosine-5′-monophosphate-activated protein kinase (AMPK), increased lipogenesis, activation of c-Jun NH2-terminal kinase, and decreased expression of Delta 1, phospho-Akt, and proliferating cell nuclear antigen in aged skeletal muscle. Such alterations were significantly prevented by F1. These results demonstrate the beneficial effects of F1 to attenuate loss of muscle mass associated with aging. © 2013 © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail:

Nicholas S.B.,University of California at Los Angeles | Nicholas S.B.,Charles R. Drew University of Medicine and Science | Yuan J.,University of California at Irvine | Aminzadeh A.,University of California at Irvine | And 4 more authors.
American Journal of Translational Research | Year: 2012

Background: Oxidative stress and inflammation promote the development and progression of chronic kidney disease. Oxidative stress is associated with depletion of tissue glutathione (GSH), the most abundant endogenous intracellular antioxidant, but degradation of oral GSH by digestive enzymes limits its therapeutic use. We hypothesized that GSH repletion with F1, a novel oral GSH precursor containing cystine as a cysteine carrier, would restore tissue GSH and attenuate oxidative stress and inflammation, and thereby reduce the severity of interstitial nephropathy in chronic renal failure (CRF). Methods: Male Sprague-Dawley rats (n=5-8) were assigned to 3 groups: Control (regular rat chow), CRF (rat chow containing 0.7% adenine), and F1-treated CRF (rat chow containing 0.7% adenine and F1, 0.5g/kg/day) for 2-weeks. Animals were switched to regular chow and euthanized after 2 additional weeks. Results: Consumption of 0.7% adenine-containing diet caused azotemia; severe kidney swelling; heavy tubular and glomerular damage; massive tubulointerstitial nephropathy; impaired urinary concentrating capacity; severe anemia; increased markers of oxidative stress, plasma oxidized glutathione disulfide (GSSG); reduced GSH/GSSG ratio and manganese superoxide dismutase; increased expression of inflammatory mediators (cyclooxygenase-2, cytoplasmic NF-κB, p-IκBα, nuclear NF-κB p65), and 3-nitrotyrosine, p<0.05. Co-treatment with F1 significantly attenuated tubulointerstitial inflammation and edema, improved urinary concentrating capacity, azotemia and anemia, and normalized markers of tissue oxidative and nitrosative stress, p<0.05. Conclusions: The novel oxidative stress modulator, F1, markedly attenuated oxidative stress indicators, inflammation, renal injury and dysfunction in the rat model of CRF. Studies to determine the effects of F1 in other models of acute and CRF are warranted.

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