A new theoretical procedure is presented to study the conservation of energy equation with dissip... more A new theoretical procedure is presented to study the conservation of energy equation with dissipation in continuum mechanics in 1D. This procedure is used to transform this nonlinear evolution-diffusion equation into a hyperbolic PDE; specifically, a second order quasi-linear wave equation. An immediate implication of this procedure is the formation of a least action principle for the balance of energy with dissipation. The corresponding action functional enables us to establish a complete analytical mechanics for thermomechanical systems: a Lagrangian-Hamiltonian theory, bracket formalism, and Noether's theorem. Furthermore, we apply our procedure iteratively and produce an infinite sequence of interlocked variational principles, a \emph{variational hierarchy}, where at each level or iteration the full implication of the least action principle can be again shown. Finally we offer comments on the implication of our work to field theories in general.
BackgroundUptake of riboflavin (RF) by intestinal epithelial cells occurs via a specific carrier-... more BackgroundUptake of riboflavin (RF) by intestinal epithelial cells occurs via a specific carrier-mediated process that involves the apically localized RF transporter-3 (RFVT3). Previous studies have shown that sodium butyrate (NaB) affects intestinal uptake of other substrates and expression of their membrane transporters, but its effect on intestinal uptake of RF and expression of RFVT3 has not been examined.AimsTo investigate the effect of NaB on intestinal RF uptake process and expression of the RFVT3.MethodsTwo experimental models were used in this study: Human-derived intestinal epithelial Caco-2 cells and ex vivo mouse colonoids. 3H-RF uptake assay, Western blot, RT-qPCR, and chromatin immunoprecipitation assay were performed.ResultsTreating Caco-2 cells with NaB led to a significant increase in carrier-mediated RF uptake. This increase was associated with a significant induction in the level of expression of the hRFVT3 protein, mRNA, and heterogenous nuclear RNA (hnRNA). Similarly, treating mouse colonoids with NaB led to a marked increase in the level of expression of the mRFVT3 protein, mRNA, and hnRNA. NaB did not affect hRFVT3 mRNA stability, rather it caused significant epigenetic changes (histone modifications) in the SLC52A3 gene where an increase in H3Ac and a reduction in H3K27me3 levels were observed in the NaB-treated Caco-2 cells compared to untreated controls.ConclusionThese findings demonstrate that NaB up-regulates intestinal RF uptake and that the effect appears to be mediated, at least in part, at the level of transcription of the SLC52A3 gene and may involve epigenetic mechanism(s).
American journal of physiology. Gastrointestinal and liver physiology, Jan 6, 2018
Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal v... more Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal vitamin C uptake. Intestinal inflammation and prolonged infection are associated with an increased serum and intestinal mucosa levels of TNF-α, which also exerts profound effects on intestinal absorption process. Elevated levels of TNF-α have been linked to the pathogenesis of IBD and malabsorption of nutrients and these patients have low levels of vitamin C. To date, little is known about the effect of TNF-α on intestinal absorption of vitamin C. We studied the impact of TNF-α on ascorbic acid (AA) transport using variety of intestinal preparations. The expression level of hSVCT-1 mRNA is significantly lower in IBD patients. TNF-α treated Caco-2 cells and mice showed a significant inhibition of intestinal C-AA uptake. This inhibition was associated with significant decreases in SVCT-1 protein, mRNA and hnRNA levels in TNF-α treated Caco-2 cells, mouse jejunum, and enteroids. Also, TNF-α ...
Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar p... more Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar palsies and sensorineural deafness, is mainly associated with defective riboflavin transporters encoded by the SLC52A2 and SLC52A3 genes. Here we present a 16-year-old BVVLS patient belonging to a five generation consanguineous family from Indian ethnicity with two homozygous missense mutations viz., c.421C>A [p.P141T] in SLC52A2 and c.62A>G [p.N21S] in SLC52A3. Functional characterization based on (3)H-riboflavin uptake assay and live-cell confocal imaging revealed that the effect of mutation c.421C>A [p.P141T] identified in SLC52A2 had a slight reduction in riboflavin uptake; on the other hand, the c.62A>G [p.N21S] identified in SLC52A3 showed a drastic reduction in riboflavin uptake, which appeared to be due to impaired trafficking and membrane targeting of the hRFVT-3 protein. This is the first report presenting mutations in both riboflavin transporters hRFVT-2 and hRFVT-3 in the same BVVLS patient. Also, c.62A>G [p.N21S] in SLC52A3 appears to contribute more to the disease phenotype in this patient than c.421C>A [p.P141T] in SLC52A2.
American Journal of Physiology - Cell Physiology, 2016
Vitamin C (ascorbic acid, AA) is indispensable for normal metabolism of all mammalian cells inclu... more Vitamin C (ascorbic acid, AA) is indispensable for normal metabolism of all mammalian cells including pancreatic acinar cells (PACs). PACs obtain AA from their surroundings via transport across the cell membrane. Chronic alcohol exposure negatively affects body AA homeostasis; it also inhibits uptake of other micronutrients into PACs, but its effect on AA uptake is not clear. We examined this issue using both in vitro (266-6 cells) and in vivo (mice) models of chronic alcohol exposure. First, we determined the relative expression of the AA transporters 1 and 2 [i.e., sodium-dependent vitamin C transporter-1 (SVCT-1) and SVCT-2] in mouse and human PACs and found SVCT-2 to be the predominant transporter. Chronic exposure of 266-6 cells to alcohol significantly inhibited AA uptake and caused a marked reduction in SVCT-2 expression at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels. Similarly, chronic alcohol feeding of mice significantly inhibited AA uptake and caused a...
Pancreatic acinar cells take in thiamin by a specific carrier-mediated process that involve both ... more Pancreatic acinar cells take in thiamin by a specific carrier-mediated process that involve both THTR-1 and THTR-2 (encoded by SLC19A2 and SLC19A3, respectively). In this study we examined the effe...
American journal of physiology. Gastrointestinal and liver physiology, 2001
The major cellular pathway for uptake of the vitamin folic acid, including its absorption in the ... more The major cellular pathway for uptake of the vitamin folic acid, including its absorption in the intestine, is via a plasma membrane carrier system, the reduced folate carrier (RFC). Very little is known about the mechanisms that control intracellular trafficking and plasma membrane targeting of RFC. To begin addressing these issues, we used Xenopus oocyte as a model system and examined whether the signal that targets the protein to the plasma membrane is located in the COOH-terminal cytoplasmic tail or in the backbone of the polypeptide. We also examined the role of microtubules and microfilaments in intracellular trafficking of the protein. Confocal imaging of human RFC (hRFC) fused to the enhanced green fluorescent protein (hRFC-EGFP) showed that the protein was expressed at the plasma membrane, with expression confined almost entirely to the animal pole of the oocyte. Localization of hRFC at the plasma membrane was not affected by partial or total truncation of the COOH-terminal...
American journal of physiology. Gastrointestinal and liver physiology, 2001
Thiamine (vitamin B(1)) is essential for normal cellular functions and growth. Mammals cannot syn... more Thiamine (vitamin B(1)) is essential for normal cellular functions and growth. Mammals cannot synthesize thiamine and thus must obtain the vitamin via intestinal absorption. The intestine is exposed to a dietary thiamine source and a bacterial source in which the vitamin is synthesized by the normal microflora of the large intestine. Very little is known about thiamine uptake in the large intestine. The aim of this study was, therefore, to address this issue. Our results with human-derived colonic epithelial NCM460 cells as a model system showed thiamine uptake to be 1) temperature- and energy dependent, 2) Na(+) independent, 3) increased with increasing buffer pH from 5 to 8 and after cell acidification but inhibited by amiloride, 4) saturable as a function of concentration, 5) inhibited by thiamine structural analogs but not by unrelated organic cations, and 6) inhibited by modulators of a Ca(2+)/calmodulin-mediated pathway. NCM460 cells and native human colonic mucosa expressed t...
A new theoretical procedure is presented to study the conservation of energy equation with dissip... more A new theoretical procedure is presented to study the conservation of energy equation with dissipation in continuum mechanics in 1D. This procedure is used to transform this nonlinear evolution-diffusion equation into a hyperbolic PDE; specifically, a second order quasi-linear wave equation. An immediate implication of this procedure is the formation of a least action principle for the balance of energy with dissipation. The corresponding action functional enables us to establish a complete analytical mechanics for thermomechanical systems: a Lagrangian-Hamiltonian theory, bracket formalism, and Noether's theorem. Furthermore, we apply our procedure iteratively and produce an infinite sequence of interlocked variational principles, a \emph{variational hierarchy}, where at each level or iteration the full implication of the least action principle can be again shown. Finally we offer comments on the implication of our work to field theories in general.
BackgroundUptake of riboflavin (RF) by intestinal epithelial cells occurs via a specific carrier-... more BackgroundUptake of riboflavin (RF) by intestinal epithelial cells occurs via a specific carrier-mediated process that involves the apically localized RF transporter-3 (RFVT3). Previous studies have shown that sodium butyrate (NaB) affects intestinal uptake of other substrates and expression of their membrane transporters, but its effect on intestinal uptake of RF and expression of RFVT3 has not been examined.AimsTo investigate the effect of NaB on intestinal RF uptake process and expression of the RFVT3.MethodsTwo experimental models were used in this study: Human-derived intestinal epithelial Caco-2 cells and ex vivo mouse colonoids. 3H-RF uptake assay, Western blot, RT-qPCR, and chromatin immunoprecipitation assay were performed.ResultsTreating Caco-2 cells with NaB led to a significant increase in carrier-mediated RF uptake. This increase was associated with a significant induction in the level of expression of the hRFVT3 protein, mRNA, and heterogenous nuclear RNA (hnRNA). Similarly, treating mouse colonoids with NaB led to a marked increase in the level of expression of the mRFVT3 protein, mRNA, and hnRNA. NaB did not affect hRFVT3 mRNA stability, rather it caused significant epigenetic changes (histone modifications) in the SLC52A3 gene where an increase in H3Ac and a reduction in H3K27me3 levels were observed in the NaB-treated Caco-2 cells compared to untreated controls.ConclusionThese findings demonstrate that NaB up-regulates intestinal RF uptake and that the effect appears to be mediated, at least in part, at the level of transcription of the SLC52A3 gene and may involve epigenetic mechanism(s).
American journal of physiology. Gastrointestinal and liver physiology, Jan 6, 2018
Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal v... more Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal vitamin C uptake. Intestinal inflammation and prolonged infection are associated with an increased serum and intestinal mucosa levels of TNF-α, which also exerts profound effects on intestinal absorption process. Elevated levels of TNF-α have been linked to the pathogenesis of IBD and malabsorption of nutrients and these patients have low levels of vitamin C. To date, little is known about the effect of TNF-α on intestinal absorption of vitamin C. We studied the impact of TNF-α on ascorbic acid (AA) transport using variety of intestinal preparations. The expression level of hSVCT-1 mRNA is significantly lower in IBD patients. TNF-α treated Caco-2 cells and mice showed a significant inhibition of intestinal C-AA uptake. This inhibition was associated with significant decreases in SVCT-1 protein, mRNA and hnRNA levels in TNF-α treated Caco-2 cells, mouse jejunum, and enteroids. Also, TNF-α ...
Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar p... more Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar palsies and sensorineural deafness, is mainly associated with defective riboflavin transporters encoded by the SLC52A2 and SLC52A3 genes. Here we present a 16-year-old BVVLS patient belonging to a five generation consanguineous family from Indian ethnicity with two homozygous missense mutations viz., c.421C>A [p.P141T] in SLC52A2 and c.62A>G [p.N21S] in SLC52A3. Functional characterization based on (3)H-riboflavin uptake assay and live-cell confocal imaging revealed that the effect of mutation c.421C>A [p.P141T] identified in SLC52A2 had a slight reduction in riboflavin uptake; on the other hand, the c.62A>G [p.N21S] identified in SLC52A3 showed a drastic reduction in riboflavin uptake, which appeared to be due to impaired trafficking and membrane targeting of the hRFVT-3 protein. This is the first report presenting mutations in both riboflavin transporters hRFVT-2 and hRFVT-3 in the same BVVLS patient. Also, c.62A>G [p.N21S] in SLC52A3 appears to contribute more to the disease phenotype in this patient than c.421C>A [p.P141T] in SLC52A2.
American Journal of Physiology - Cell Physiology, 2016
Vitamin C (ascorbic acid, AA) is indispensable for normal metabolism of all mammalian cells inclu... more Vitamin C (ascorbic acid, AA) is indispensable for normal metabolism of all mammalian cells including pancreatic acinar cells (PACs). PACs obtain AA from their surroundings via transport across the cell membrane. Chronic alcohol exposure negatively affects body AA homeostasis; it also inhibits uptake of other micronutrients into PACs, but its effect on AA uptake is not clear. We examined this issue using both in vitro (266-6 cells) and in vivo (mice) models of chronic alcohol exposure. First, we determined the relative expression of the AA transporters 1 and 2 [i.e., sodium-dependent vitamin C transporter-1 (SVCT-1) and SVCT-2] in mouse and human PACs and found SVCT-2 to be the predominant transporter. Chronic exposure of 266-6 cells to alcohol significantly inhibited AA uptake and caused a marked reduction in SVCT-2 expression at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels. Similarly, chronic alcohol feeding of mice significantly inhibited AA uptake and caused a...
Pancreatic acinar cells take in thiamin by a specific carrier-mediated process that involve both ... more Pancreatic acinar cells take in thiamin by a specific carrier-mediated process that involve both THTR-1 and THTR-2 (encoded by SLC19A2 and SLC19A3, respectively). In this study we examined the effe...
American journal of physiology. Gastrointestinal and liver physiology, 2001
The major cellular pathway for uptake of the vitamin folic acid, including its absorption in the ... more The major cellular pathway for uptake of the vitamin folic acid, including its absorption in the intestine, is via a plasma membrane carrier system, the reduced folate carrier (RFC). Very little is known about the mechanisms that control intracellular trafficking and plasma membrane targeting of RFC. To begin addressing these issues, we used Xenopus oocyte as a model system and examined whether the signal that targets the protein to the plasma membrane is located in the COOH-terminal cytoplasmic tail or in the backbone of the polypeptide. We also examined the role of microtubules and microfilaments in intracellular trafficking of the protein. Confocal imaging of human RFC (hRFC) fused to the enhanced green fluorescent protein (hRFC-EGFP) showed that the protein was expressed at the plasma membrane, with expression confined almost entirely to the animal pole of the oocyte. Localization of hRFC at the plasma membrane was not affected by partial or total truncation of the COOH-terminal...
American journal of physiology. Gastrointestinal and liver physiology, 2001
Thiamine (vitamin B(1)) is essential for normal cellular functions and growth. Mammals cannot syn... more Thiamine (vitamin B(1)) is essential for normal cellular functions and growth. Mammals cannot synthesize thiamine and thus must obtain the vitamin via intestinal absorption. The intestine is exposed to a dietary thiamine source and a bacterial source in which the vitamin is synthesized by the normal microflora of the large intestine. Very little is known about thiamine uptake in the large intestine. The aim of this study was, therefore, to address this issue. Our results with human-derived colonic epithelial NCM460 cells as a model system showed thiamine uptake to be 1) temperature- and energy dependent, 2) Na(+) independent, 3) increased with increasing buffer pH from 5 to 8 and after cell acidification but inhibited by amiloride, 4) saturable as a function of concentration, 5) inhibited by thiamine structural analogs but not by unrelated organic cations, and 6) inhibited by modulators of a Ca(2+)/calmodulin-mediated pathway. NCM460 cells and native human colonic mucosa expressed t...
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