scholarly journals Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Veedamali S. Subramanian ◽  
Trevor Teafatiller ◽  
Anshu Agrawal ◽  
Masashi Kitazawa ◽  
Jonathan S. Marchant
Keyword(s):  
Ascorbic Acid ◽  
Vitamin C ◽  
Inhibitory Effect ◽  
Acid Uptake ◽  
Mrna Levels ◽  
The Central Nervous System ◽  
Factor Α ◽  
And Function

Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-α (TNFα) are increased. Elevated levels of LPS and TNFα have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNFα on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNFα on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH-SY5Y cells with either LPS or TNFα inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNFα also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNFα decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF-κB inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF-κB factors.

scholarly journals Effect of the proinflammatory cytokine TNF-α on intestinal riboflavin uptake: inhibition mediated via transcriptional mechanism(s)

2018 ◽  
Vol 315 (5) ◽  
pp. C653-C663 ◽  
Author(s):  
Kasin Yadunandam Anandam ◽  
Omar A. Alwan ◽  
Veedamali S. Subramanian ◽  
Padmanabhan Srinivasan ◽  
Rubina Kapadia ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Significant Inhibition ◽  
Mrna Levels ◽  
In Vivo Models ◽  
Uptake Inhibition ◽  
Tnf Α ◽  
Vitro Model ◽  
Factor Α

Riboflavin (RF), is essential for normal cellular metabolism/function. Intestinal RF absorption occurs via a specific carrier-mediated process that involves the apical transporter RFVT-3 ( SLC52A3) and the basolateral RFVT-1 (SLC52A1). Previously, we characterized different cellular/molecular aspects of the intestinal RF uptake process, but nothing is known about the effect of proinflammatory cytokines on the uptake event. We addressed this issue using in vitro, ex vivo, and in vivo models. First, we determined the level of mRNA expression of the human (h)RFVT-3 and hRFVT-1 in intestinal tissue of patients with inflammatory bowel disease (IBD) and observed a markedly lower level compared with controls. In the in vitro model, exposing Caco-2 cells to tumor necrosis factor-α (TNF-α) led to a significant inhibition in RF uptake, an effect that was abrogated upon knocking down TNF receptor 1 (TNFR1). The inhibition in RF uptake was associated with a significant reduction in the expression of hRFVT-3 and -1 protein and mRNA levels, as well as in the activity of the SLC52A3 and SLC52A1 promoters. The latter effects appear to involve Sp1 and NF-κB sites in these promoters. Similarly, exposure of mouse small intestinal enteroids and wild-type mice to TNF-α led to a significant inhibition in physiological and molecular parameters of intestinal RF uptake. Collectively, these findings demonstrate that exposure of intestinal epithelial cells to TNF-α leads to inhibition in RF uptake and that this effect is mediated, at least in part, via transcriptional mechanism(s). These findings may explain the significantly low RF levels observed in patients with IBD.

Vitamin C inhibits the activation of the NLRP3 inflammasome by scavenging mitochondrial ROS

Inflammasome ◽  
2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Xuesong Sang ◽  
Hongbin Wang ◽  
Yihui Chen ◽  
Qiuhong Guo ◽  
Ailing Lu ◽  
...  
Keyword(s):  
Vitamin C ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Protein Complexes ◽  
Inhibitory Effect ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Regulatory Effects

AbstractInflammasomes are intracellular protein complexes that mediate maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes have been connected with various diseases, therefore the regulation of inflammasome activation is important for the development of novel therapies for many inflammatory syndromes. Vitamin C is an essential nutrient and has regulatory effects on immune cells. Here we report that vitamin C has an inhibitory effect on the activation of the NLRP3 inflammasome in vitro and in vivo. Mechanistically, this inhibition is through scavenging mitochondrial ROS but not through NF-κB inhibition. Moreover, specificity tests show that the AIM2 inflammasome and the NLRC4 inflammasome can also be inhibited by vitamin C. Our results have thus identified a new inflammasome regulator and provide therapeutic potential for inflammasome-associated diseases.

Sox9-dependent transcriptional regulation of the proprotein convertase furin

2007 ◽  
Vol 293 (1) ◽  
pp. C172-C183 ◽  
Author(s):  
Philippe Guimont ◽  
Francine Grondin ◽  
Claire M. Dubois
Keyword(s):  
High Mobility ◽  
Inhibitory Effect ◽  
Nodule Formation ◽  
Mrna Levels ◽  
Paracrine Factor ◽  
Proprotein Convertase ◽  
Hmg Box ◽  
Repressive Effect

The proprotein convertase furin participates in the maturation/bioactivation of a variety of proproteins involved in chondrogenesis events. These include parathyroid hormone-related peptide (PTHrP), an autocrine/paracrine factor that is crucial to both normal cartilage development and cartilage-related pathological processes. Despite the known importance of furin activity in the bioactivation of the polypeptides, the mechanisms that control furin regulation in chondrogenesis remain unknown. To gain insight into the molecular regulation of furin, we used the mouse prechondrogenic ATDC5 cell line, an established in vitro model of cartilage differentiation. Peak expression of both furin mRNA and furin PTHrP maturation was observed during chondrocyte nodule formation stage, an event that correlated with increased mRNA levels of Sox9, a potent high-mobility-group (HMG) box-containing transcription factor required for cartilage formation. Inhibition of furin activity led to a diminution in maturation of PTHrP, suggesting a relationship between Sox9-induced regulation of furin and chondrogenesis events. Transient transfection of Sox9 in nonchondrogenic cells resulted in a marked increase in furin mRNA and in the transactivation of the furin P1A promoter. Direct Sox9 action on the P1A promoter was narrowed down to a critical paired site with Sox9 binding capability in vitro and in vivo. Sox9 transactivation effect was inhibited by L-Sox5 and Sox-6, two Sox9 homologs also expressed in ATDC5 cells. Sox6 inhibitory effect was reduced when using Sox6-HMG-box mutants, indicating a repressive effect through direct HMG-box/DNA binding. Our work suggests a mechanism by which furin is regulated during chondrogenesis. It also adds to the complexity of Sox molecule interaction during gene regulation.

A Multicenter Phase II Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2564-2564 ◽  
Author(s):  
James Berenson ◽  
Ralph Boccia ◽  
David Siegel ◽  
Marek Bozdech ◽  
Alberto Bessudo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Vitamin C ◽  
Arsenic Trioxide ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response ◽  
In Vivo Studies

Abstract Background: Despite the recent increase in treatment options for patients with multiple myeloma (MM), the disease remains largely incurable. Both arsenic trioxide (ATO) and melphalan have shown clinical activity in MM. Recent in vitro and in vivo studies in our laboratory have shown that arsenic trioxide sensitizes chemoresistant MM cells to melphalan-induced cytotoxicity; the addition of ascorbic acid (AA) further improves this effect. We conducted a multi-center clinical trial to evaluate the safety and efficacy of this steroid-free combination, melphalan, ATO and vitamin C (MAC), for patients with relapsed/refractory MM. Methods: MM pts who relapsed after responding to 1st-line therapy and/or were refractory to prior treatment were enrolled. During week 1 of each 6-week cycle, pts received ATO, 0.25 mg/kg IV, followed by ascorbic acid (AA), 1 g IV, days 1–4. ATO followed by AA was given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) was administered orally for the first 4 days of each cycle. Pts received a maximum of 6 cycles followed by weekly maintenance treatment with ATO and AA. The primary objectives of this study were to determine response rate and safety and tolerability of MAC therapy. Results: 65 patients have been enrolled and 51 are currently evaluable for response. 26 (1 CR, 10 PR, 15 MR) of the 51 evaluable patients (51%) had an objective response and an additional 14 patients achieved stable disease, resulting in a total of 40 patients (78%) with disease control. Among patients with elevated serum creatinine levels at baseline, renal function improved for those with responsive or stable disease. 20 of the 26 responding patients had failed ≥ 2 prior therapies: 19 pts had received prior thalidomide or lenalidomide therapy and 8 pts had received prior bortezomib. The regimen was well-tolerated with few significant side effects reported. Mild cytopenias occurred infrequently and were reversible. Conclusions: The results from this large multi-center phase II trial show that the MAC regimen is active in a group of MM patients who had either relapsed or were refractory to standard and/or investigational MM treatments. The regimen was well-tolerated even in this heavily pre-treated patient population. These findings are consistent with preclinical studies that showed the efficacy of this combination from both in vitro and in vivo studies.

On the role and fate of LPS-dephosphorylating activity in the rat liver

2006 ◽  
Vol 290 (2) ◽  
pp. G377-G385 ◽  
Author(s):  
Annemarie Tuin ◽  
Ali Huizinga-Van der Vlag ◽  
Anne-Miek M. A. van Loenen-Weemaes ◽  
Dirk K. F. Meijer ◽  
Klaas Poelstra
Keyword(s):  
Bacterial Species ◽  
Intestinal Wall ◽  
In Vivo Studies ◽  
Protective Mechanism ◽  
Mrna Levels ◽  
Factor Α ◽  
Necrosis Factor ◽  
Enzyme Alkaline Phosphatase

Gut-derived lipopolysaccharide (LPS) plays a role in the pathogenesis of liver diseases like fibrosis. The enzyme alkaline phosphatase (AP) is present in, among others, the intestinal wall and liver and has been previously shown to dephosphorylate LPS. Therefore, we investigated the effect of LPS on hepatic AP expression and the effect of AP on LPS-induced hepatocyte responses. LPS-dephosphorylating activity was expressed at the hepatocyte canalicular membrane in normal and fibrotic animals. In addition to this, fibrotic animals also displayed high LPS-dephosphorylating activity around bile ducts. The enzyme was shown to dephosphorylate LPS from several bacterial species. LPS itself rapidly enhanced the intrahepatic mRNA levels for this enzyme within 2 h by a factor of seven. Furthermore, in vitro and in vivo studies showed that exogenous intestinal AP quickly bound to the asialoglycoprotein receptor on hepatocytes. This intestinal isoform significantly attenuated LPS-induced hepatic tumor necrosis factor-α and nitric oxide (nitrite and nitrate) responses in vitro. The enzyme also reduced LPS-induced hepatic glycogenolysis in vivo. This study shows that LPS enhances AP expression in hepatocytes and that intestinal AP is rapidly taken up by these same cells, leading to an attenuation of LPS-induced responses in vivo. Gut-derived LPS-dephosphorylating activity or enzyme upregulation within hepatocytes by LPS may therefore be a protective mechanism within the liver.

scholarly journals Delayed Puberty in Spontaneously Hypertensive Rats Involves a Primary Ovarian Failure Independent of the Hypothalamic KiSS-1/GPR54/GnRH System

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2889-2897 ◽  
Author(s):  
L. Pinilla ◽  
J. M. Castellano ◽  
M. Romero ◽  
M. Tena-Sempere ◽  
F. Gaytán ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Follicular Development ◽  
Experimental Models ◽  
Gnrh Receptor ◽  
Delayed Puberty ◽  
Mrna Levels ◽  
Spontaneously Hypertensive ◽  
And Function

Spontaneously hypertensive (SH) rats, extensively used as experimental models of essential human hypertension, display important alterations in the neuroendocrine reproductive axis, which manifest as markedly delayed puberty onset in females but whose basis remains largely unknown. We analyze herein in female SH rats: 1) possible alterations in the expression and function of KiSS-1/GPR54 and GnRH/GnRH-receptor systems, 2) the integrity of feedback mechanisms governing the hypothalamic-pituitary-ovarian axis, and 3) the control of ovarian function by gonadotropins. Our data demonstrate that, despite overtly delayed puberty, no significant decrease in hypothalamic KiSS-1, GPR54, or GnRH mRNA levels was detected in this strain. Likewise, in vivo gonadotropin responses to ovariectomy and systemic kisspeptin-10 or GnRH administration, as well as in vitro gonadotropin responses to GnRH, were fully preserved in SH rats. Moreover, circulating LH levels were grossly conserved during prepubertal maturation, whereas FSH levels were even enhanced from d 20 postpartum onwards. In striking contrast, ovarian weight and hormone (progesterone and testosterone) responses to human chorionic gonadotropin (CG) in vitro were profoundly decreased in SH rats, with impaired follicular development and delayed ovulation at puberty. Such reduced hormonal responses to human CG could not be attributed to changes in LH/CG or FSH-receptor mRNA expression but might be linked to blunted P450scc, 3β-hydroxy steroid dehydrogenase, and aromatase mRNA levels in ovaries from SH rats. In conclusion, our results indicate that the expression and function of KiSS-1/GPR54 and GnRH/GnRH-receptor systems is normal in SH rats, whereas ovarian development, steroidogenesis, and responsiveness to gonadotropins are strongly compromised.

scholarly journals Obestatin Plays an Opposite Role in the Regulation of Pituitary Somatotrope and Corticotrope Function in Female Primates and Male/Female Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (4) ◽  
pp. 1407-1417 ◽  
Author(s):  
Raúl M. Luque ◽  
José Córdoba-Chacón ◽  
Alejandro Ibáñez-Costa ◽  
Iacopo Gesmundo ◽  
Cristina Grande ◽  
...  
Keyword(s):  
Hormone Secretion ◽  
Somatostatin Receptors ◽  
Inhibitory Effect ◽  
Pituitary Function ◽  
Pituitary Hormone ◽  
Mrna Levels ◽  
Ghrh Receptor ◽  
Acth Release

Obestatin is a 23-amino-acid amidated peptide that is encoded by the ghrelin gene. Previous studies have shown obestatin can modulate the hypothalamic neuronal circuitry that regulates pituitary function, perhaps by modulating the actions of ghrelin. However, the direct actions of obestatin on pituitary function remain controversial. Here, primary pituitary cell cultures from a nonhuman primate (baboon) and mice were used to test the effects of obestatin on pituitary hormone expression and secretion. In pituitary cultures from both species, obestatin had no effect on prolactin, LH, FSH, or TSH expression/release. Conversely, obestatin stimulated proopiomelanocortin expression and ACTH release and inhibited GH expression/release in vitro, actions that were also observed in vivo in mice treated with obestatin. In vitro, obestatin inhibited the stimulatory actions of ghrelin on GH but not ACTH release. The inhibitory effect of obestatin on somatotrope function was associated with an overall reduction in pituitary transcription factor-1 and GHRH receptor mRNA levels in vitro and in vivo as well as a reduction in hypothalamic GHRH and ghrelin expression in vivo. The stimulatory effect of obestatin on ACTH was associated with an increase in pituitary CRF receptors. Obestatin also reduced the expression of pituitary somatostatin receptors (sst1/sst2), which could serve to modify its impact on hormone secretion. The in vitro actions of obestatin on both GH and ACTH release required the adenylyl cyclase and MAPK routes. Taken together, our results provide evidence that obestatin can act directly at the pituitary to control somatotrope and corticotrope function, and these effects are conserved across species.

Inhibitory effect of nicotinamide on in vitro and in vivo production of tumor necrosis factor-α

1997 ◽  
Vol 59 (1) ◽  
pp. 7-11 ◽  
Author(s):  
Masamitsu Fukuzawa ◽  
Jo Satoh ◽  
Gen Muto ◽  
Yoshiko Muto ◽  
Sachiko Nishimura ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Inhibitory Effect ◽  
Factor Α ◽  
Necrosis Factor

Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-α

2003 ◽  
Vol 284 (3) ◽  
pp. H960-H969 ◽  
Author(s):  
Andrzej M. Janczewski ◽  
Toshiaki Kadokami ◽  
Bonnie Lemster ◽  
Carole S. Frye ◽  
Charles F. McTiernan ◽  
...  
Keyword(s):  
Contractile Function ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Functional Changes ◽  
Tnf Α ◽  
Intracellular Ca ◽  
And Gender ◽  
Factor Α ◽  
And Function

Transgenic (TG) TNF1.6 mice, which cardiac specifically overexpress tumor necrosis factor-α (TNF-α), exhibit heart failure (HF) and increased mortality, which is markedly higher in young (<20 wk) males (TG-M) than females (TG-F). HF in this model may be partly caused by remodeling of the extracellular matrix and/or structure/function alterations at the single myocyte level. We studied left ventricular (LV) structure and function using echocardiography and LV myocyte morphometry, contractile function, and intracellular Ca2+ (Ca[Formula: see text]) handling using cell edge detection and fura 2 fluorescence, respectively, in 12-wk-old TG-M and TG-F mice and their wild-type (WT) littermates. TG-F mice showed LV hypertrophy without dilatation and only a small reduction of basal fractional shortening (FS) and response to isoproterenol (Iso). TG-M mice showed a large LV dilatation, higher mRNA levels of β-myosin heavy chain and atrial natriuretic factor versus TG-F mice, reduced FS relative to both WT and TG-F mice, and minimal response to Iso. TG-F and TG-M myocytes were similarly elongated (by ≈20%). The amplitude of Ca[Formula: see text] transients and contractions and the response to Iso were comparable in WT and TG-F myocytes, whereas the time to 50% decline (TD50%) of the Ca[Formula: see text]transient, an index of the rate of sarcoplasmic reticulum Ca2+ uptake, was prolonged in TG-F myocytes. In TG-M myocytes, the amplitudes of Ca[Formula: see text] transients and contractions were reduced, TD50% of the Ca[Formula: see text] transient was prolonged, and the inotropic effect of Iso on Ca[Formula: see text] transients was reduced approximately twofold versus WT myocytes. Protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase 2 and phospholamban was unaltered in TG versus WT hearts, suggesting functional origins of impaired Ca2+ handling in the former. These results indicate that cardiac-specific overexpression of TNF-α induces myocyte hypertrophy and gender-dependent alterations in Ca[Formula: see text] handling and contractile function, which may at least partly account for changes in LV geometry and in vivo cardiac function in this model.

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