Medical Center 151

Pike Road, AL, United States

Medical Center 151

Pike Road, AL, United States

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Davis L.L.,Medical Center 151 | Davis L.L.,University of Alabama at Birmingham | Pilkinton P.,Medical Center 151 | Wisniewski S.R.,University of Pittsburgh | And 7 more authors.
Depression and Anxiety | Year: 2012

Background: The co-occurrence of substance use disorder (SUD) and major depressive disorder (MDD) is common and is often thought to impair response to antidepressant therapy. These patients are often excluded from clinical trials, resulting in a significant knowledge gap regarding optimal pharmacotherapy for the treatment of MDD with concurrent SUD. Methods: In the Combining Medications to Enhance Depression Outcomes study, 665 adult outpatients with chronic and/or recurrent MDD were prospectively treated with either escitalopram monotherapy (escitalopram and placebo) or an antidepressant combination (venalfaxine-XR and mirtazapine or escitalopram and bupropion-SR). Participants with MDD and concurrent SUD (13.1%) were compared to those without SUD (86.9%) on sociodemographic and clinical characteristics at baseline and treatment response at 12- and 28-week endpoints. Results: The participants with MDD and SUD were more likely to be male and have current suicidal thoughts/plans, and had a greater lifetime severity and number of suicide attempts, and a higher number of concurrent Axis I disorders, particularly concurrent anxiety disorders. There were no significant differences between the MDD with or without SUD groups in terms of dose, time in treatment, response or remission at week 12 and 28. Furthermore, no significant differences in response or remission rates were noted between groups on the basis of the presence or absence of SUD and treatment assignment. Conclusions: Although significantbaseline sociodemographic and clinical differences exist, patients with MDD and concurrent SUD are as likely to respond and remit to a single or combination antidepressant treatment as those presenting without SUD. © 2012 Wiley Periodicals, Inc.


Subramanian V.S.,University of California at Irvine | Subramanian V.S.,Medical Center 151 | Subramanya S.B.,University of California at Irvine | Subramanya S.B.,Medical Center 151 | And 3 more authors.
American Journal of Physiology - Renal Physiology | Year: 2010

The renal thiamin reabsorption process plays an important role in regulating thiamin body homeostasis and involves both thiamin transporters-1 and -2 (THTR1 and THTR2). Chronic alcohol use is associated with thiamin deficiency. Although a variety of factors contribute to the development of this deficiency, effects of chronic alcohol use on renal thiamin transport have not been thoroughly examined. We addressed this issue by examining the effect of chronic alcohol feeding of rats with liquid diet on physiological and molecular parameters of renal thiamin transport. Chronic alcohol feeding caused a significant inhibition in carrier-mediated thiamin transport across the renal brush-border membrane and was evident as early as 2 wk after initiation of alcohol feeding. Similarly, thiamin transport across the renal basolateral membrane was significantly inhibited by chronic alcohol feeding. The inhibition in renal thiamin transport was associated with a marked decrease in the level of expression of THTR1 and -2 proteins, mRNAs, and heterogeneous nuclear RNAs. Chronic alcohol feeding also caused a significant reduction in the level of expression of thiamin pyrophosphokinase but not that of the mitochondrial thiamin pyrophosphate transporter. These studies show that chronic alcohol feeding inhibits the entry and exit of thiamin in the polarized renal epithelial cells and that the effect is, at least in part, mediated at the transcriptional level. These findings also suggest that chronic alcohol feeding interferes with the normal homeostasis of thiamin in renal epithelial cells.


Subramanian V.S.,University of California at Irvine | Subramanian V.S.,Medical Center 151 | Subramanya S.B.,University of California at Irvine | Subramanya S.B.,Medical Center 151 | And 5 more authors.
Biochimica et Biophysica Acta - Biomembranes | Year: 2011

Transport of riboflavin (RF) across both the brush border membrane (BBM) and basolateral membrane (BLM) of the polarized enterocyte occurs via specific carrier-mediated mechanisms. Although, three human riboflavin transporters (hRFTs), i.e., hRFT-1, hRFT-2 and hRFT-3 are expressed in the intestine, little is known about the cell surface domain(s) at which these specific hRFTs are expressed. Here, we used live cell confocal imaging of intestinal epithelial Caco-2 and renal MDCK cells to show that the hRFT-1 is mainly expressed at the BLM, hRFT-2 is exclusively expressed at the apical membrane, while hRFT-3 is mostly localized inside intracellular vesicular structures (with some expression at the BLM). Further the level of hRFT-2 mRNA expression in Caco-2 cells and in native human intestine is significantly higher than that of hRFT-1 and -3; hRFT-2 was also more efficient in transporting 3H-RF than hRFT-1 and -3. These findings implied an important role for hRFT-2 in intestinal RF uptake, a conclusion that was further supported by findings of hRFT-2 gene-specific siRNA knockdown investigation. These results show that members of the hRFT family are differentially expressed in polarized epithelia, and that the apically expressed hRFT-2 plays a key role in intestinal RF accumulation. © 2011 Elsevier B.V.


Ghosal A.,University of California at Irvine | Subramanian V.S.,University of California at Irvine | Said H.M.,University of California at Irvine | Said H.M.,Medical Center 151
Biochimica et Biophysica Acta - Biomembranes | Year: 2011

The sodium-dependent multivitamin transporter (SMVT) is a major biotin transporter in a variety of tissues including the small intestine. The human SMVT (hSMVT) polypeptide is predicted to have four N-glycosylation sites and two putative PKC phosphorylation sites but their role in the function and regulation of the protein is not known and was examined in this investigation. Our results showed that the hSMVT protein is glycosylated and that this glycosylation is important for its function. Studies utilizing site-directed mutagenesis revealed that the N-glycosylation sites at positions Asn 138 and Asn489 are important for the function of hSMVT and that mutating these sites significantly reduces the Vmax of the biotin uptake process. Mutating the putative PKC phosphorylation site Thr 286 of hSMVT led to a significant decrease in the PMA-induced inhibition in biotin uptake. The latter effect was not mediated via changes in the level of expression of the hSMVT protein and mRNA or in its level of expression at the cell membrane. These findings demonstrate that the hSMVT protein is glycosylated, and that glycosylation is important for its function. Furthermore, the study shows a role for the putative PKC-phosphorylation site Thr286 of hSMVT in the PKC-mediated regulation of biotin uptake. © 2011 Elsevier B.V.


PubMed | Medical Center 151
Type: Journal Article | Journal: American journal of physiology. Gastrointestinal and liver physiology | Year: 2010

Folate plays an essential role in one-carbon metabolism, and a relationship exists between methyl group metabolism and pancreatic exocrine function. Little, however, is known about the mechanism(s) and regulation of folate uptake by pancreatic acinar cells and the effect of chronic alcohol use on the process. We addressed these issues using the rat-derived pancreatic acinar cell line AR42J and freshly isolated primary rat pancreatic acinar cells as models. We found [(3)H]folic acid uptake to be 1) temperature and pH dependent with a higher uptake at acidic than at neutral/alkaline pH; 2) saturable as a function of substrate concentration at both buffer pH 7.4 and 6.0; 3) inhibited by folate structural analogs and by anion transport inhibitors at both buffer pH 7.4 and 6.0; 4) trans-stimulated by unlabeled folate; 5) adaptively regulated by the prevailing extracellular folate level, and 6) inhibited by modulators of the cAMP/PKA-mediated pathway. Both the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT) were found to be expressed in AR42J and in primary pancreatic acinar cells, as well as in native human pancreas with expression of RFC being higher than PCFT. Chronic alcohol feeding of rats (4 wk; 36% of calories from ethanol) led to a significant decrease in folate uptake by freshly isolated primary pancreatic acinar cells compared with cells from pair-fed controls; this effect was associated with a parallel decrease in the level of expression of RFC and PCFT. These studies reveal that folate uptake by pancreatic acinar cells is via a regulated carrier-mediated process which may involve RFC and PCFT. In addition, chronic alcohol feeding leads to a marked inhibition in folate uptake by pancreatic acinar cells, an effect that is associated with reduction in level of expression of RFC and PCFT.

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