Molecular Mechanisms Triggered by Bile Acids on Intestinal Ca2+ Absorption

2018 ◽  
Vol 25 (18) ◽  
pp. 2122-2132 ◽  
Author(s):  
Ana Marchionatti ◽  
Maria Rivoira ◽  
Valeria Rodriguez ◽  
Adriana Perez ◽  
Nori Tolosa de Talamoni
Keyword(s):  
Bile Acids ◽  
Redox State ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Metabolic Diseases ◽  
Sodium Deoxycholate ◽  
Inhibitory Effect ◽  
Single Administration ◽  
Pubmed Database ◽  
Main Components

Background: Bile acids (BAs) are among the main components of bile. Lately, they are also considered important signaling molecules, not only by regulating their own synthesis, but also having a role in several metabolic diseases. Objective: In this review we focus on the effect of sodium deoxycholate (NaDOC), ursodeoxycholic (UDCA) and litocholic (LCA) acids and their combination upon the intestinal Ca2+ absorption. To make clear the actions of those BAs on this physiological process, an overview of current information about the mechanisms by which the intestinal Ca2+ occurs is described. Methods: The PubMed database was searched until 2017, using the keywords bile acids, NaDOC, UDCA and LCA and redox state, apoptosis, autophagy and intestinal Ca2+ absorption. Results: The modulation of redox state, apoptosis and autophagy are mechanisms that are involved in the action of BAs on intestinal Ca2+ absorption. Although the mechanisms are still not completely understood, we provide the latest knowledge regarding the effect of BAs on intestinal Ca2+ absorption. Conclusion: The response of the intestine to absorb Ca2+ is affected by BAs, but it is different according to the type and dose of BA. When there is a single administration, NaDOC has an inhibitory effect, UDCA is an stimulator whereas LCA does not have any influence. However, the combination of BAs modifies the response. Either UDCA or LCA protects the intestine against the oxidative injury caused by NaDOC by blocking the oxidative/nitrosative stress, apoptosis and autophagy.

Abstract 90: Akt Mediated Mitochondrial Dysfunction Involves Mitochondrial Endothelial Nitric Oxide Synthase Translocation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ruslan Rafikov ◽  
Olga Rafikova ◽  
Xutong Sun ◽  
Saurabh Aggarwal ◽  
Stephen M Black
Keyword(s):  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Mitochondrial Respiratory Chain ◽  
Inhibitory Effect ◽  
Resistant Cell ◽  
Akt Signaling ◽  
Cell Phenotype ◽  
Mtor Phosphorylation ◽  
Pre Treatment

Pulmonary arterial hypertension (PH) is a fatal disease characterized by uncontrolled pulmonary vascular cell proliferation. Mitochondrial dysfunction (MD) of pulmonary endothelial cells (EC) was shown to be one of the primary events implicated into proliferative, apoptosis resistant cell phenotype. However, the particular molecular mechanisms responsible for MD remain unclear. The development of PH in patients is associated with severe nitrosative stress, leading to post-translational protein modifications. Thus, we have recently found that Akt is susceptible to nitration of tyrosine Y350 residue. We hypothesize that nitration of Akt induces activation of Akt signaling and contributes to the development of MD. Nitrosative stress in EC was initiated by eNOS uncoupler ADMA or peroxynitrite donor SIN-1 and resulted in significant Akt nitration and activation (1.5±0.1 fold control; p=0.007; N=3-4), as well as activation of anti-apoptotic (BAD phosphorylation), and proliferative (mTOR phosphorylation) signaling cascades. Increased Akt signaling induced phosphorylation of eNOS at serine S615 (1.47±0.08 fold control, p=0.005, N=3) and S1177 (0.22±0.04 vs. 0.47±0.07, p=0.029, N=3). Phosphorylation of eNOS resulted in its translocation to mitochondria (3± 0.3 fold control; p=0.003; N=3) which, in turn, significantly decreased basal mitochondrial respiration (oxygen consumption rate, pmol/min: untransfected cells 1022±96 vs. mitochondrial targeted phospho-mimetic eNOS mutants S615D 102±9 and S1177D 117±7, p<0.001, N=4-6), perhaps due to previously reported inhibitory effect of NO on mitochondrial respiratory chain. Finally, we have created an anti-oxidant conjugated “shielding” peptide that, by shielding the Akt nitration site, is capable to prevent Akt activation. Indeed, pre-treatment with shielding peptide (100μg/ml, 30min) completely abolished SIN-1 induced nitration of Akt in EC. We conclude that Akt nitration may contribute to proliferative/apoptosis resistant EC phenotype through pathological activation of Akt signaling and Akt mediated mitochondrial eNOS translocation. Besides, our novel shielding peptide based therapeutic strategy opens new avenues in MD prevention.

Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

2019 ◽  
Vol 25 (28) ◽  
pp. 3057-3073 ◽  
Author(s):  
Kobra B. Juybari ◽  
Azam Hosseinzadeh ◽  
Habib Ghaznavi ◽  
Mahboobeh Kamali ◽  
Ahad Sedaghat ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathways ◽  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Ganglion Cells ◽  
Axon Growth ◽  
Nerve Fibers ◽  
Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

Periodontal Pathogens and Neuropsychiatric Health

2020 ◽  
Vol 20 (15) ◽  
pp. 1353-1397 ◽  
Author(s):  
Abhishek Wadhawan ◽  
Mark A. Reynolds ◽  
Hina Makkar ◽  
Alison J. Scott ◽  
Eileen Potocki ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Low Grade ◽  
Periodontal Pathogens ◽  
Synergistic Interactions ◽  
Brain Vasculature ◽  
Micro Rnas ◽  
Clinical Conditions ◽  
Low Grade Inflammation ◽  
Neuropsychiatric Illness

Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic diseases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the disease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vasculature has important pathophysiological consequences. Distant effects via translocation rely on virulence factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its capability to manipulate the immune system via several mechanisms, including its capacity to induce production of immune-downregulating micro-RNAs. Possible targets for intervention and drug development to manage distal consequences of infection with P. gingivalis are also reviewed.

Molecular Mechanisms of the Inhibitory Effects of Bupivacaine, Levobupivacaine, and Ropivacaine on Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channels in the Cardiovascular System

2004 ◽  
Vol 101 (2) ◽  
pp. 390-398 ◽  
Author(s):  
Takashi Kawano ◽  
Shuzo Oshita ◽  
Akira Takahashi ◽  
Yasuo Tsutsumi ◽  
Yoshinobu Tomiyama ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Adenosine Triphosphate ◽  
Local Anesthetics ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Katp Channels ◽  
Inhibitory Effect ◽  
Amino Acid Residues ◽  
Sulfonylurea Receptor ◽  
Inhibitory Effects

Background Sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted KATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits. Methods The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted KATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs. Results Bupivacaine inhibited the activities of cardiac KATP channels (IC50 = 52 microm) stereoselectively (levobupivacaine, IC50 = 168 microm; ropivacaine, IC50 = 249 microm). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2 delta C36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac KATP channels with approximately eightfold higher potency than vascular KATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit. Conclusions Inhibitory effects of local anesthetics on KATP channels in the cardiovascular system are (1) stereoselective: bupivacaine was more potent than levobupivacaine and ropivacaine; and (2) tissue specific: local anesthetics blocked cardiac KATP channels more potently than vascular KATP channels, via the intracellular pore mouth of the Kir6.0 subunit and the 42 amino acids at the C-terminal tail of the SUR2A subunit, respectively.

scholarly journals Proanthocyanidins against Oxidative Stress: From Molecular Mechanisms to Clinical Applications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Lingyu Yang ◽  
Dehai Xian ◽  
Xia Xiong ◽  
Rui Lai ◽  
Jing Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Low Cost ◽  
Natural Agents ◽  
Molecular Damage ◽  
And Control

Proanthocyanidins (PCs) are naturally occurring polyphenolic compounds abundant in many vegetables, plant skins (rind/bark), seeds, flowers, fruits, and nuts. Numerousin vitroandin vivostudies have demonstrated myriad effects potentially beneficial to human health, such as antioxidation, anti-inflammation, immunomodulation, DNA repair, and antitumor activity. Accumulation of prooxidants such as reactive oxygen species (ROS) exceeding cellular antioxidant capacity results in oxidative stress (OS), which can damage macromolecules (DNA, lipids, and proteins), organelles (membranes and mitochondria), and whole tissues. OS is implicated in the pathogenesis and exacerbation of many cardiovascular, neurodegenerative, dermatological, and metabolic diseases, both through direct molecular damage and secondary activation of stress-associated signaling pathways. PCs are promising natural agents to safely prevent acute damage and control chronic diseases at relatively low cost. In this review, we summarize the molecules and signaling pathways involved in OS and the corresponding therapeutic mechanisms of PCs.

scholarly journals The Inhibitory Effect of a Novel Polypeptide Fraction fromArca subcrenataon Cancer-Related Inflammation in Human Cervical Cancer HeLa Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Yu Wu ◽  
Xianjing Hu ◽  
Liyan Song ◽  
Jianhua Zhu ◽  
Rongmin Yu
Keyword(s):  
Cervical Cancer ◽  
Hela Cells ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Basic Research ◽  
Inhibitory Effect ◽  
Fishery Resource ◽  
Proinflammatory Mediators ◽  
Raw264.7 Macrophage ◽  
Human Cervical Cancer

Inflammation is known to be closely associated with the development of cancer. The study was launched in human cervical cancer HeLa cells to investigate the antitumor and anti-inflammatory effects of P2, a marine polypeptide fraction from an important fishery resourceArca subcrenata. The basic research showed that P2 could suppress the production of nitric oxide in LPS-induced RAW264.7 macrophage cells as well as the secretion of inflammatory cytokines IL-6 and TNF-αin human cervical cancer HeLa cells. For the molecular mechanisms, P2 was shown to downregulate the gene expression of proinflammatory cytokines IL-6 and IL-8 and to inhibit the COX-2 and iNOS-related pathways in HeLa cells. In consequence, P2 might inhibit tumor development by blocking the interaction between tumor microenvironment and proinflammatory mediators. All findings indicate that P2 possesses the potential to be developed as a novel agent for cancer therapy.

Molecular mechanisms of the inhibitory effect of lipopolysaccharide (LPS) on osteoblast differentiation

2010 ◽  
Vol 402 (4) ◽  
pp. 755-761 ◽  
Author(s):  
Kenjiro Bandow ◽  
Aya Maeda ◽  
Kyoko Kakimoto ◽  
Joji Kusuyama ◽  
Mitsuo Shamoto ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Molecular Mechanisms ◽  
Inhibitory Effect

scholarly journals Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

2001 ◽  
pp. 59-64 ◽  
Author(s):  
F Bogazzi ◽  
L Bartalena ◽  
S Brogioni ◽  
A Burelli ◽  
F Raggi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Molecular Level ◽  
Inhibitory Effect ◽  
Mobility Shift ◽  
Down Regulation ◽  
Nih3t3 Cells ◽  
Peripheral Tissues

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

Inhibitory effect of bile acids on renin angiotensinogen reaction system

1972 ◽  
Vol 28 (2) ◽  
pp. 165-166 ◽  
Author(s):  
T. Kokubu ◽  
K. Hiwada ◽  
E. Ueda ◽  
Y. Yamamura
Keyword(s):  
Bile Acids ◽  
Reaction System ◽  
Inhibitory Effect

scholarly journals Cellular Redox State Acts as Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 967
Author(s):  
Maria Favia ◽  
Anna Atlante
Keyword(s):  
Cystic Fibrosis ◽  
Redox State ◽  
Molecular Mechanisms ◽  
Activity Level ◽  
Cellular Redox ◽  
Redox States ◽  
Mitochondrial Ros ◽  
New Information ◽  
Cellular Dysfunction ◽  
Cellular Redox State

The redox states of NAD and NADP are linked to each other in the mitochondria thanks to the enzyme nicotinamide nucleotide transhydrogenase (NNT) which, by utilizing the mitochondrial membrane potential (mΔΨ), catalyzes the transfer of redox potential between these two coenzymes, reducing one at the expense of the oxidation of the other. In order to define NNT reaction direction in CF cells, NNT activity under different redox states of cell has been investigated. Using spectrophotometric and western blotting techniques, the presence, abundance and activity level of NNT were determined. In parallel, the levels of NADPH and NADH as well as of mitochondrial and cellular ROS were also quantified. CF cells showed a 70% increase in protein expression compared to the Wt sample; however, regarding NNT activity, it was surprisingly lower in CF cells than healthy cells (about 30%). The cellular redox state, together with the low mΔΨ, pushes to drive NNT reverse reaction, at the expense of its antioxidant potential, thus consuming NADPH to support NADH production. At the same time, the reduced NNT activity prevents the NADH, produced by the reaction, from causing an explosion of ROS by the damaged respiratory chain, in accordance with the reduced level of mitochondrial ROS in NNT-loss cells. This new information on cellular bioenergetics represents an important building block for further understanding the molecular mechanisms responsible for cellular dysfunction in cystic fibrosis.

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