scholarly journals Usnic acid deteriorates acidogenicity, acidurance and glucose metabolism of Streptococcus mutans through downregulation of two-component signal transduction systems

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arumugam Priya ◽  
Chandra Bose Manish Kumar ◽  
Alaguvel Valliammai ◽  
Anthonymuthu Selvaraj ◽  
Shunmugiah Karutha Pandian
Keyword(s):  
Streptococcus Mutans ◽  
Therapeutic Potential ◽  
Usnic Acid ◽  
Low Frequency ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Resistance Development ◽  
Buccal Epithelial Cells ◽  
Two Component Signal Transduction ◽  
Signal Transduction Systems

AbstractThe principal etiological agent of human dental caries, Streptococcus mutans is a multi-virulent pathogen that can transform commensal oral microbial community to plaque biofilms. Major virulence factors that are associated with the cariogenicity of S. mutans include adhesion, acidogenicity and acidurity. All these pathogenic traits coordinate and alter the dental plaque ecology which provide room for interaction with other similar acidogenic and aciduric bacteria. This cariogenic flora increases the possibility of enamel demineralization which headway to caries development. The present study was aimed at evaluating the antimicrobial and antiinfective potential of a lichen secondary metabolite usnic acid (UA) against S. mutans. Minimum inhibitory concentration (MIC), Minimum bactericidal concentration (MBC) and growth kinetics were evaluated to determine the antimicrobial potential of UA against S. mutans. UA at 5 µg mL−1 and 10 µg mL−1 concentration were considered as MIC and MBC respectively. Effect on biofilm formation was microscopically assessed and found to be reduced in a concentration dependent manner. Gene expression of gtfB, gtfC, gtfD, vicR, ComDE and smu0630 was found to be downregulated upon treatment with sub-MIC of UA. Acidogenicity, acidurity, eDNA synthesis and response to oxidative stress were found to be attenuated by the influence of UA. It was also demonstrated to act on preformed mature biofilm of S. mutans. Moreover, UA was shown to possess very low frequency to acquire spontaneous resistance development in S. mutans. Besides, no morphological aberrations or toxic effect was instigated by UA in the human buccal epithelial cells as well as to the oral commensals. Altogether, these results demonstrate the therapeutic potential of usnic acid in the treatment of S. mutans infection.

scholarly journals Exposure to the natural alkaloid Berberine affects cardiovascular system morphogenesis and functionality during zebrafish development

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Davide Martini ◽  
Cecilia Pucci ◽  
Chiara Gabellini ◽  
Mario Pellegrino ◽  
Massimiliano Andreazzoli
Keyword(s):  
Cardiovascular System ◽  
Therapeutic Potential ◽  
System Development ◽  
Developmental Toxicity ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Pericardial Edema ◽  
Pregnancy And Lactation ◽  
Cardiovascular Defects ◽  
Natural Alkaloid

Abstract The plant-derived natural alkaloid berberine displays therapeutic potential to treat several pathological conditions, including dyslipidemias, diabetes and cardiovascular disorders. However, data on berberine effects during embryonic development are scarce and in part controversial. In this study, using zebrafish embryos as vertebrate experimental model, we address the effects of berberine treatment on cardiovascular system development and functionality. Starting from the observation that berberine induces developmental toxicity and pericardial edema in a time- and concentration-dependent manner, we found that treated embryos display cardiac looping defects and, at later stages, present an abnormal heart characterized by a stretched morphology and atrial endocardial/myocardial detachment. Furthermore, berberine affected cardiac functionality of the embryos, promoting bradycardia and reducing the cardiac output, the atrial shortening fraction percentage and the atrial stroke volume. We also found that, during development, berberine interferes with the angiogenic process, without altering vascular permeability. These alterations are associated with increased levels of vascular endothelial growth factor aa (vegfaa) mRNA, suggesting an important role for Vegfaa as mediator of berberine-induced cardiovascular defects. Altogether, these data indicate that berberine treatment during vertebrate development leads to an impairment of cardiovascular system morphogenesis and functionality, suggesting a note of caution in its use during pregnancy and lactation.

scholarly journals Methanol Extract ofArtemisia apiaceaHance Attenuates the Expression of Inflammatory Mediators via NF-κB Inactivation

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Ji Choul Ryu ◽  
Sang Mi Park ◽  
Min Hwangbo ◽  
Sung Hui Byun ◽  
Sae Kwang Ku ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Potential ◽  
Interleukin 1 ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Paw Edema ◽  
Concentration Dependent Manner ◽  
Proinflammatory Mediators ◽  
Inducible Nitric Oxide

Artemisia apiaceaHance is one of the most widely used herbs for the treatment of malaria, jaundice, and dyspeptic complaint in oriental medicine. This study investigated the effects of methanol extracts ofA. apiaceaHance (MEAH) on the induction of inducible nitric oxide synthase (iNOS) and proinflammatory mediators by lipopolysaccharide (LPS) in Raw264.7 macrophage cells and also evaluated thein vivoeffect of MEAH on carrageenan-induced paw edema in rats. MEAH treatment in Raw264.7 cells significantly decreased LPS-inducible nitric oxide production and the expression of iNOS in a concentration-dependent manner, while MEAH (up to 100 μg/mL) had no cytotoxic activity. Results from immunoblot analyses and ELISA revealed that MEAH significantly inhibited the expression of cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in LPS-activated cells. As a plausible molecular mechanism, increased degradation and phosphorylation of inhibitory-κBαand nuclear factor-κB accumulation in the nucleus by LPS were partly blocked by MEAH treatment. Finally, MEAH treatment decreased the carrageenan-induced formation of paw edema and infiltration of inflammatory cells in rats. These results demonstrate that MEAH has an anti-inflammatory therapeutic potential that may result from the inhibition of nuclear factor-κB activation, subsequently decreasing the expression of proinflammatory mediators.

scholarly journals Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exhibit single agent therapeutic activity and sensitize glioblastoma cells to ionizing radiation

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv12-iv12
Author(s):  
Mark Jackson ◽  
Natividad Gomez-Roman ◽  
Anthony Chalmers
Keyword(s):  
Ionizing Radiation ◽  
Therapeutic Potential ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Unmet Need ◽  
Clonogenic Survival ◽  
Dependent Manner ◽  
Therapeutic Activity ◽  
Intrinsic Resistance ◽  
Concentration Dependent Manner

Abstract Objective The lack of an effective therapy for glioblastoma (GBM) largely results from the intrinsic resistance of GBM cells. The radiosensitizing activity of inhibitors of poly(ADP-ribose) polymerases (PARPs) highlights the important role of poly(ADP-ribose) (PAR) in the DNA damage response. In contrast to PARPs, inhibition of poly(ADP-ribose) glycohydrolase (PARG), the enzyme responsible for degrading PAR chains, has shown single agent therapeutic activity in non-glioma cancer cells. This work aims to validate the therapeutic potential of PARG inhibitors (PARGi) in GBM. Results Baseline PAR levels were found to vary between different primary and commercial GBM cells, with PARylation increasing upon exposure of cells to ionizing radiation (IR), as expected. Target engagement of a novel PARGi, PDD00017273, was confirmed by the accumulation of nuclear PAR in treated cells. Inhibitor specificity was demonstrated using an inactive control compound and by combining PARGi with the PARP inhibitor olaparib, which blocked the effect. Single agent treatment with PARGi reduced the clonogenic survival of GBM cells in a concentration-dependent manner. Importantly, PARGi also sensitized GBM cells to IR (sensitizer enhancement ratios, SER, ≥ 1.40) Conclusion In contrast to PARP inhibitors, novel PARGi exhibit single agent activity against a panel of GBM cell lines, and also show robust radiosensitizing activity. PARGi therefore have therapeutic potential in this cancer of unmet need.

Recovery of Acid Production in Streptococcus mutans Biofilms after Short-Term Fluoride Treatment

2016 ◽  
Vol 50 (4) ◽  
pp. 363-371 ◽  
Author(s):  
Minh-Huy Dang ◽  
Ji-Eun Jung ◽  
Dae-Woo Lee ◽  
Kwang-Yeob Song ◽  
Jae-Gyu Jeon
Keyword(s):  
Treatment Period ◽  
Streptococcus Mutans ◽  
Acid Production ◽  
Fluoride Concentration ◽  
Dependent Manner ◽  
Short Term ◽  
Concentration Dependent Manner ◽  
Fluoride Treatment ◽  
Linear Pattern ◽  
Hygiene Measures

Fluoride is commonly used as an ingredient of topical oral hygiene measures. Despite the anti-acidogenic activities of fluoride against cariogenic biofilms, the recovery of the biofilms from fluoride damage is unclear. Herein, we investigated the recovery of acid production in Streptococcus mutans biofilms after short-term or during periodic 1-min fluoride treatments. For this study, 46-hour-old S. mutans biofilms were treated with fluoride (0-2,000 ppm F-) for 1-8 min and then incubated in saliva for 0-100 min. The 74-hour-old biofilms were also periodically treated with the fluoride concentration during biofilm formation (1 min/treatment). Changes in acidogenicity and viability were determined via pH drop and colony-forming unit assays, respectively. In this study, acid production after a 1-min fluoride treatment was recovered as saliva incubation time increased, which followed a linear pattern of concentration dependence (R = 0.99, R2 = 0.98). The recovery pattern was in a biphasic pattern, with an initial rapid rate followed by a second slow recovery. Furthermore, recovery from fluoride damage was retarded in a concentration-dependent manner as treatment time increased. In periodic 1-min fluoride treatments, acid production in the biofilms was not diminished during the non-fluoride treatment period; however, it was reduced in a concentration-dependent manner during the fluoride treatment period. The viability of the biofilm cells did not change, even at high fluoride concentrations. Collectively, our results suggest that brief fluoride treatment does not sustain anti-acidogenic activity against S. mutans in biofilms since the damage is recoverable with time.

scholarly journals Anti-Inflammatory and Neuroprotective Effects of Constituents Isolated fromRhodiola rosea

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Yeonju Lee ◽  
Jae-Chul Jung ◽  
Soyong Jang ◽  
Jieun Kim ◽  
Zulfiqar Ali ◽  
...  
Keyword(s):  
Biological Activity ◽  
Crude Extract ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Rhodiola Rosea ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Concentration Dependent Manner ◽  
Bv2 Cells ◽  
Proinflammatory Factors

To determine the biological activity ofRhodiola rosea, the protein expression of iNOS and proinflammatory cytokines was measured after the activation of murine microglial BV2 cells by LPS under the exposure of constituents ofRhodiola rosea: crude extract, rosin, rosarin, and salidroside (each 1–50 μg/mL). The LPS-induced expression of iNOS and cytokines in BV2 cells was suppressed by the constituents ofRhodiola roseain a concentration-dependent manner. Also the expression of the proinflammatory factors iNOS, IL-1β, and TNF-αin the kidney and prefrontal cortex of brain in mice was suppressed by the oral administration ofRhodiola roseacrude extract (500 mg/kg). To determine the neuroprotective effect of constituents ofRhodiola rosea, neuronal cells were activated by L-glutamate, and neurotoxicity was analyzed. The L-glutamate-induced neurotoxicity was suppressed by the treatment with rosin but not by rosarin. The level of phosphorylated MAPK, pJNK, and pp38 was increased by L-glutamate treatment but decreased by the treatment with rosin and salidroside. These results indicate thatRhodiola roseamay have therapeutic potential for the treatment of inflammation and neurodegenerative disease.

scholarly journals Antiadipogenic Effects ofAster glehniExtract: In Vivo and In Vitro Effects

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Heon-Myung Lee ◽  
Gabsik Yang ◽  
Tae-Gue Ahn ◽  
Myung-Dong Kim ◽  
Agung Nugroho ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Control Diet ◽  
Epididymal Adipose Tissue ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Master Regulators ◽  
In Vitro Effects

Aster glehni(AG) is a Korean traditional herb that grows in Ulleungdo Island, Republic of Korea. None of the several reports on AG include a determination of the effect of AG on adipogenesis. The primary aim of this study was to determine whether AG attenuates adipogenesis in mouse 3T3-L1 cells and epididymal fat tissue. AG blocked the differentiation of 3T3-L1 preadipocytes in a concentration-dependent manner and suppressed the expression of adipogenesis-related genes such asPPARγ,C/EBPα, andSREBP1c, the master regulators of adipogenesis. Male C57BL/6J mice were divided randomly and equally into 4 diet groups: control diet (CON), high-fat diet (HFD), HFD with 1% AG extract added (AG1), and HFD with 5% AG extract added (AG5). The experimental animals were fed HFD and the 2 combinations for 10 weeks. Mice fed HFD with AG gained less body weight and visceral fat-pad weight than did the mice fed HFD alone. Moreover, AG inhibited the expression of important adipogenic genes such asPPARγ,C/EBPα,SREBP1c,LXR, and leptin in the epididymal adipose tissue of the mice treated with AG1 and AG5. These findings indicate antiadipogenic and antiobesity effects of AG and suggest its therapeutic potential in obesity and obesity-related diseases.

scholarly journals GHB confers neuroprotection by stabilizing the CaMKIIα hub domain

2020 ◽  
Author(s):  
Ulrike Leurs ◽  
Anders B. Klein ◽  
Ethan D. McSpadden ◽  
Nane Griem-Krey ◽  
Sara M. Ø. Solbak ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Concentration Dependent Manner ◽  
Chemical Proteomics ◽  
Differential Scanning Fluorimetry ◽  
Selective Ligands ◽  
Dependent Protein ◽  
Thermal Stability Of

ABSTRACTCa2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is an abundant neuronal signaling protein involved in synaptic plasticity and memory formation1,2. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers3-6. Recent findings have suggested that the hub is also an allosteric determinant of kinase activity7, and is thus an emerging target for therapies to correct CaMKIIα dysregulation8,9. However, pharmacological modulation of the hub domain has never been demonstrated. Here we show that stabilization of the CaMKIIα hub domain confers neuroprotection. By combining photoaffinity labeling and chemical proteomics using small molecule analogs of the natural metabolite γ-hydroxybutyrate (GHB)10 we reveal that CaMKIIα is the selective target for GHB. We further find that these GHB analogs bind to the hub interior by solving a 2.2 Å crystal structure of CaMKIIα with bound ligand. Using differential scanning fluorimetry, we show that binding of ligands to the hub interior increases the thermal stability of hub oligomers in a concentration-dependent manner. Moreover, we demonstrate the functional significance of this hub stabilization by showing substantial neuroprotective effects in cellular excitotoxicity assays and in a mouse model of cerebral ischemia. Together, our results reveal that CaMKIIα hub stabilization is the mechanism by which GHB provides endogenous neuroprotection and that small-molecule CaMKIIα-selective ligands have therapeutic potential.

scholarly journals Purinergic signaling in the pancreas and the therapeutic potential of ecto-nucleotidases in diabetes.

2014 ◽  
Vol 61 (4) ◽  
Author(s):  
Marek Cieślak ◽  
Katarzyna Roszek
Keyword(s):  
Therapeutic Potential ◽  
Current Knowledge ◽  
Purinergic Signaling ◽  
Receptor Activation ◽  
Extracellular Nucleotides ◽  
P2x Receptor ◽  
Nucleotide Receptors ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Adenosine Concentration

It is widely accepted that purinergic signaling is involved in the regulation of functions of all known tissues and organs. Extracellular purines activate two classes of receptors, P1-adenosine receptors and P2-nucleotide receptors, in a concentration-dependent manner. Ecto-enzymes metabolizing nucleotides outside the cell are involved in the termination of the nucleotide signaling pathway through the release of ligands from their receptors. The pancreas is a central organ in nutrient and energy homeostasis with endocrine, exocrine and immunoreactive functions. The disturbances in cellular metabolism in diabetes mellitus lead also to changes in concentrations of intra- and extracellular nucleotides. Purinergic receptors P1 and P2 are present on the pancreatic islet cells as well as on hepatocytes, adipocytes, pancreatic blood vessels and nerves. The ATP-dependent P2X receptor activation on pancreatic β-cells results in a positive autocrine signal and subsequent insulin secretion. Ecto-NTPDases play the key role in regulation of extracellular ATP concentration. These enzymes, in cooperation with 5'-nucleotidase can significantly increase ecto-adenosine concentration. It has been demonstrated that adenosine, through activation of P1 receptors present on adipocytes and pancreatic islets cells, inhibits the release of insulin. Even though we know for 50 years about the regulatory role of nucleotides in the secretion of insulin, an integrated understanding of the involvement of purinergic signaling in pancreas function is still required. This comprehensive review presents our current knowledge about purinergic signaling in physiology and pathology of the pancreas as well as its potential therapeutic relevance in diabetes.

scholarly journals MRSA emerges through natural transformation

2020 ◽  
Author(s):  
Mais Maree ◽  
Le Thuy Thi Nguyen ◽  
Ryosuke L. Ohniwa ◽  
Shenghe Huang ◽  
Masato Higashide ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Transformation Efficiency ◽  
Natural Transformation ◽  
Transmission Mechanism ◽  
Dependent Manner ◽  
Coagulase Negative Staphylococci ◽  
Methicillin Resistant ◽  
Two Component Signal Transduction ◽  
The Stability ◽  
Signal Transduction Systems

AbstractMethicillin-resistant Staphylococcus aureus (MRSA) carries the resistance gene mecA in the staphylococcal cassette chromosome (SCC) that disseminates among staphylococci but the cell-to-cell transmission mechanism of SCC has not been clarified for half a century1. Here, we present evidence for efficient natural transformation in Staphylococcus aureus and its relevance in SCCmec transmission. We found that growth in biofilm conditions increased the transformation efficiency in a dependent manner on two component signal transduction systems, TCS13 (AgrCA) and TCS17 (BraSR). Strikingly, we demonstrate that natural transformation mediates the transfer of SCCmec from MRSA or methicillin-resistant coagulase negative staphylococci to methicillin-sensitive S. aureus. The site-specific insertion/excision system mediated by cassette chromosome recombinases was essential for SCCmec transformation while the stability of SCCmec varied depending on SCC types and recipients. We propose that natural transformation is the key process in the emergence of MRSA.

Abstract 3218: Pharmacokinetics, Pharmacodynamics, and Safety of an Anti-von Willebrand Factor Therapeutic Aptamer, ARC1779, in Healthy Volunteers

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
James C Gilbert ◽  
Tia DeFeo-Fraulini ◽  
Renta M Hutabarat ◽  
Christopher J Horvath ◽  
Patricia G Merlino ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Platelet Function ◽  
Therapeutic Potential ◽  
Controlled Study ◽  
Terminal Phase ◽  
Dependent Manner ◽  
Double Blind ◽  
Concentration Dependent Manner ◽  
Platelet Receptor ◽  
The Mean

Background: The prominent role played by vWF in arterial thrombogenesis suggests that vWF inhibition may offer an effective adjunct therapy to PCI in ACS patients. ARC1779 is a PEG-conjugated aptamer that blocks platelet activation through inhibition of vWF A1 domain binding to platelet receptor GPIb. Design: This was an ascending-dose, double-blind, placebo-controlled study in 47 healthy volunteers at doses of 0 (placebo, n = 6) or 0.05 to 1.0 mg/kg ARC1779 (n = 41) given via IV push, “slow bolus” IV infusion over 15 minutes, or “slow bolus” followed by 4-hour IV infusion. PK parameters were estimated from plasma ARC1779 concentrations determined with a validated assay. PD effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer, the PFA-100 ® . PK: The concentration-time profiles for ARC1779 after IV push or slow bolus appeared monophasic, though the terminal phase may not have been fully captured. The C max and AUC values were dose-proportional. The highest exposure was observed after 1.0 mg/kg slow bolus, with mean C max of 21.15 μg/mL and AUC (0-∞) of 80.92 μ g·hr/mL. The mean apparent elimination half-life (t 1/2β ) was ~2 hours and mean residence time (MRT) was ~3 hours. The mean apparent volumes of distribution (V z and V ss ) were ~1/2 of the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance (CL) values ranged from ~10% to 21% of GRF, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. PD: Inhibition of vWF A1 binding was achieved in a dose- and concentration-dependent manner, with respective EC 50 and EC 90 values of 0.22 μ g/mL (17 nM) and 1.98 μg/mL (151 nM). Platelet function inhibition (PFA-100 ® closure time) was achieved, with respective EC 50 and EC 90 values of 0.75 μ g/mL (57 nM) and 2.57 μg/mL (196 nM). vWF activity returned in a dose- and concentration-dependent manner. Safety: ARC1779 was generally well tolerated and no bleeding was observed. Adverse events tended to be minor and not dose related. One volunteer had a hypersensitivity reaction to IV push administration, but no such reactions occurred at higher doses given by slow bolus or infusion. Conclusion: The PK, PD and safety profile of ARC1779 supports its therapeutic potential for use in ACS.

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