Thiamin (vitamin B1) plays critical roles in normal metabolism and function of all mammalian cells. Pancreatic acinar cells (PACs) import thiamin from circulation via specific carrier-mediated uptake that involves thiamin transporters-1 & -2 (THTR-1 & -2; products of SLC19A2 and SLC19A3, respectively). Our aim in this study was to investigate the effect(s) of pro-inflammatory cytokines on thiamin uptake by PACs. We used human primary (h)PACs, PAC 266-6 cells, and mice in vivo as models in the investigations. First, we examined the level of expression of THTR-1 & -2 mRNA in pancreatic tissues of patients with chronic pancreatitis and observed severe reduction in their expression compared to normal control subjects. Exposing hPACs and PAC 266-6 to pro-inflammatory cytokines (hyper IL-6, TNF-α, and IL-1β) was found to lead to a significant inhibition in thiamin uptake. Focusing on hyper-IL-6 (which also inhibited thiamin uptake by primary mouse PACs), the inhibition in thiamin uptake was found to be associated with significant reduction in THTR-1 & -2 proteins and mRNAs expression as well as in activity of the SLC19A2 and SLC19A3 promoters; it was also associated with reduction in level of expression of the transcription factor Sp1 (which is required for activity of these promoters). Finally, blocking the intracellular Stat3 signaling pathway was found to lead to a significant reversal in the inhibitory effect of hyper IL-6 on thiamin uptake by PAC 266-6. These results show that exposure of PACs to pro-inflammatory cytokines negatively impacts thiamin uptake via (at least in part) transcriptional mechanism(s).

Vitamin B7 (biotin) is essential from normal health and its deficiency/sub-optimal levels occur in a variety of conditions including chronic alcoholism. Mammals, including humans, obtain biotin from diet and gut-microbiota via absorption along the intestinal tract. The absorption process is carrier-mediated and involves the sodium-dependent multivitamin transporter (SMVT; SLC5A6). We have previously shown that chronic alcohol exposure significantly inhibits intestinal/colonic biotin uptake via suppression of Slc5a6 transcription in animal and cell line models.. However, little is known about the transcriptional/epigenetic factors that mediate this suppression. Additionally, the effect of alcohol metabolites (generated via alcohol metabolism by gut microbiota and host tissues) on biotin uptake is still unknown. In order to address these questions, we first demonstrated that chronic alcohol exposure inhibits small intestinal and colonic biotin uptake and SMVT expression in human differentiated enteroid and colonoid monolayers. We then showed that chronic alcohol exposures of both, Caco-2 cells and mice, are associated with a significant suppression in expression of the nuclear factor KLF-4 (needed for Slc5a6 promoter activity), as well as with epigenetic alterations (histone modifications). We also found that chronic exposure of NCM460 human colonic epithelial cells as well as human differentiated colonoid monolayers, to alcohol metabolites (acetaldehyde, ethyl palmitate, ethyl oleate) significantly inhibited biotin uptake and SMVT expression. These findings shed light onto the molecular/epigenetic mechanisms that mediate the inhibitory effect of chronic alcohol exposure on intestinal biotin uptake. They further show that alcohol metabolites are also capable of inhibiting biotin uptake in the gut.

No abstract

Syncope is common, affecting approximately 1 million Americans every year. Although multiple pathophysiological mechanisms regarding its etiology have been documented, neurocardiogenic or vasovagal syncope is the most common cause of these episodes. Other less appreciated etiologies include various cardiac abnormalities in which a structural, electrical, or obstructive disturbance leads to a temporary reduction in blood flow to the brain, resulting in transient loss of consciousness. Cardiac malignancies, while rare, can present with syncope by either disrupting the cardiac conduction apparatus or simply obstructing blood flow through the cardiac chambers. Electrocardiograms and echocardiography are often very helpful in identifying these abnormalities. Here, we report a rare case of late-stage invasive squamous cell carcinoma of the lung presenting with recurrent syncopal events. The cancer invaded the cardiac right atrium causing various dysrhythmias, leading to a very rare cause of cardiogenic syncope. We also discuss how lung cancer can present in a subclinical manner and at times without obvious respiratory symptoms, dramatic physical examination abnormalities, and/or thoracic imaging abnormalities on chest radiograph.