Stress is a critical player in CYP3A, CYP2C, and CYP2D regulation: role of adrenergic receptor signaling pathways

2012 ◽  
Vol 303 (1) ◽  
pp. E40-E54 ◽  
Author(s):  
Evangelos P. Daskalopoulos ◽  
Foteini Malliou ◽  
Georgia Rentesi ◽  
Marios Marselos ◽  
Matti A. Lang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Adrenergic Receptor ◽  
Drug Efficacy ◽  
Stress System ◽  
Wide Range ◽  
Repeated Restraint Stress ◽  
Pharmacological Manipulations

Stress is a critical player in the regulation of the major cytochrome P-450s ( CYPs) that metabolize the majority of the prescribed drugs. Early in life, maternal deprivation (MD) stress and repeated restraint stress (RS) modified CYP expression in a stress-specific manner. In particular, the expression of CYP3A1 and CYP2C11 was increased in the liver of MD rats, whereas RS had no significant effect. In contrast, hepatic CYP2D1/2 activity was increased by RS, whereas MD did not affect it. The primary effectors of the stress system, glucocorticoids and epinephrine, highly induced CYP3A1/2. Epinephrine also induced the expression of CYP2C11 and CYP2D1/2. Further investigation indicated that AR-agonists may modify CYP regulation. In vitro experiments using primary hepatocyte cultures treated with the AR-agonists phenylephrine, dexmedetomidine, and isoprenaline indicated an AR-induced upregulating effect on the above-mentioned CYPs mediated by the cAMP/protein kinase A and c-Jun NH2-terminal kinase signaling pathways. Interestingly though, in vivo pharmacological manipulations of ARs using the same AR-agonists led to a suppressed hepatic CYP expression profile, indicating that the effect of the complex network of central and peripheral AR-linked pathways overrides that of the hepatic ARs. The AR-mediated alterations in CYP3A1/2, CYP2C11, and CYP2D1/2 expressions are potentially connected with those observed in the activation of signal transducer and activator of transcription 5b. In conclusion, stress and AR-agonists may modify the expression of the major CYP genes involved in the metabolism of drugs used in a wide range of diseases, thus affecting drug efficacy and toxicity.

scholarly journals Subinhibitory Antimicrobial Concentrations: A Review of In Vitro and In Vivo Data

1992 ◽  
Vol 3 (4) ◽  
pp. 193-201 ◽  
Author(s):  
George G Zhanel ◽  
Daryl J Hoban ◽  
Godfrey KM Harding
Keyword(s):  
Antimicrobial Activity ◽  
Animal Studies ◽  
Molecular Level ◽  
Bacterial Virulence ◽  
Antibacterial Effects ◽  
Wide Range ◽  
Immune Defences

Antimicrobial activity is not an ‘all or none’ effect. An increase in the rate and extent of antimicrobial action is usually observed over a wide range of antimicrobial concentrations. Subinhibitory antimicrobial concentrations are well known to produce significant antibacterial effects, and various antimicrobials at subinhibitory concentrations have been reported to inhibit the rate of bacterial growth. Bacterial virulence may be increased or decreased by subinhibitory antimicrobial concentrations by changes in the ability of bacteria to adhere to epithelial cells or by alterations in bacterial susceptibility to host immune defences. Animal studies performed in rats, hamsters and rabbits demonstrate decreased bacterial adherence, reduced infectivity and increased survival of animals treated with subinhibitory antimicrobial concentrations compared to untreated controls. The major future role of investigation of subinhibitory antimicrobial concentrations will be to define more fully, at a molecular level, how antimicrobials exert their antibacterial effects.

Correlation between magnesium and potassium contents in muscle: role of Na(+)-K+ pump

1993 ◽  
Vol 264 (2) ◽  
pp. C457-C463 ◽  
Author(s):  
I. Dorup ◽  
T. Clausen
Keyword(s):  
Extensor Digitorum Longus ◽  
Extensor Digitorum ◽  
Deficient Diet ◽  
Young Rats ◽  
Wide Range ◽  
86Rb Influx

In young rats fed a Mg(2+)-deficient diet for 3 wk, Mg2+ and K+ contents in soleus and extensor digitorum longus muscles were significantly reduced and closely correlated. In isolated soleus muscles, Mg2+ depletion induced an even more pronounced loss of K+, and Mg2+ and K+ contents were correlated over a wide range (r = 0.95, P < 0.001). Extracellular Mg2+ (0-1.2 mM) caused no change in total or ouabain-suppressible 86Rb influx. After long-term incubation in Ca(2+)-Mg(2+)-free buffer with EDTA and EGTA, cellular Mg2+ and K+ contents were reduced by 35 and 15%, respectively, without any reduction in ATP and total or ouabain-suppressible 86Rb influx. In Mg(2+)-depleted muscles 42K efflux was increased by up to 42%, and repletion with Mg2+ produced a graded decrease. We conclude that Mg2+ and K+ contents are closely correlated in muscles Mg2+ depleted in vivo or in vitro and that neither extracellular nor moderate intracellular Mg2+ depletion affects total or Na(+)-K+ pump-mediated K+ influx. The reduced K+ content may rather be related to increased K+ efflux from the muscles.

scholarly journals A Possible Role of Allatostatin C in Inhibiting Ecdysone Biosynthesis Revealed in the Mud Crab Scylla paramamosain

2021 ◽  
Vol 8 ◽  
Author(s):  
An Liu ◽  
Wenyuan Shi ◽  
Dongdong Lin ◽  
Haihui Ye
Keyword(s):  
Scylla Paramamosain ◽  
Dependent Manner ◽  
Mud Crab ◽  
Methyl Farnesoate ◽  
Independent Manner ◽  
Wide Range ◽  
Negative Effect

C-type allatostatins (C-type ASTs) are a family of structurally related neuropeptides found in a wide range of insects and crustaceans. To date, the C-type allatostatin receptor in crustaceans has not been deorphaned, and little is known about its physiological functions. In this study, we aimed to functionally define a C-type ASTs receptor in the mud crab, Scylla paramamosian. We showed that C-type ASTs receptor can be activated by ScypaAST-C peptide in a dose-independent manner and by ScypaAST-CCC peptide in a dose-dependent manner with an IC50 value of 6.683 nM. Subsequently, in vivo and in vitro experiments were performed to investigate the potential roles of ScypaAST-C and ScypaAST-CCC peptides in the regulation of ecdysone (20E) and methyl farnesoate (MF) biosynthesis. The results indicated that ScypaAST-C inhibited biosynthesis of 20E in the Y-organ, whereas ScypaAST-CCC had no effect on the production of 20E. In addition, qRT-PCR showed that both ScypaAST-C and ScypaAST-CCC significantly decreased the level of expression of the MF biosynthetic enzyme gene in the mandibular organ, suggesting that the two neuropeptides have a negative effect on the MF biosynthesis in mandibular organs. In conclusion, this study provided new insight into the physiological roles of AST-C in inhibiting ecdysone biosynthesis. Furthermore, it was revealed that AST-C family peptides might inhibit MF biosynthesis in crustaceans.

scholarly journals Nutraceutical Activity in Osteoarthritis Biology: A Focus on the Nutrigenomic Role

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1232
Author(s):  
Stefania D’Adamo ◽  
Silvia Cetrullo ◽  
Veronica Panichi ◽  
Erminia Mariani ◽  
Flavio Flamigni ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Antioxidant Activities ◽  
Synergistic Effects ◽  
National Health System ◽  
Bioactive Molecules ◽  
Joint Disease ◽  
In Vivo Studies ◽  
Wide Range

Osteoarthritis (OA) is a disease associated to age or conditions that precipitate aging of articular cartilage, a post-mitotic tissue that remains functional until the failure of major homeostatic mechanisms. OA severely impacts the national health system costs and patients’ quality of life because of pain and disability. It is a whole-joint disease sustained by inflammatory and oxidative signaling pathways and marked epigenetic changes responsible for catabolism of the cartilage extracellular matrix. OA usually progresses until its severity requires joint arthroplasty. To delay this progression and to improve symptoms, a wide range of naturally derived compounds have been proposed and are summarized in this review. Preclinical in vitro and in vivo studies have provided proof of principle that many of these nutraceuticals are able to exert pleiotropic and synergistic effects and effectively counteract OA pathogenesis by exerting both anti-inflammatory and antioxidant activities and by tuning major OA-related signaling pathways. The latter are the basis for the nutrigenomic role played by some of these compounds, given the marked changes in the transcriptome, miRNome, and methylome. Ongoing and future clinical trials will hopefully confirm the disease-modifying ability of these bioactive molecules in OA patients.

scholarly journals Role of Exosomes in Islet Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jordan Mattke ◽  
Srividya Vasu ◽  
Carly M. Darden ◽  
Kenjiro Kumano ◽  
Michael C. Lawrence ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Graft Function ◽  
Pancreatic Islet Transplantation ◽  
Complex Molecules ◽  
Wide Range ◽  
And Function ◽  
Antigen Presenting

Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

scholarly journals Role of long non-coding RNA TP73-AS1 in cancer

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Caizhi Chen ◽  
Long Shu ◽  
Wen Zou
Keyword(s):  
Cell Carcinoma ◽  
Signaling Pathways ◽  
Cell Renal Cell Carcinoma ◽  
Aberrant Expression ◽  
Diagnosis And Prognosis ◽  
Early Diagnosis Of Cancer ◽  
Cause Of Deaths

Abstract Cancer incidence rate has increased so much that it is the second leading cause of deaths worldwide after cardiovascular diseases. Sensitive and specific biomarkers are needed for an early diagnosis of cancer and in-time treatment. Recent studies have found that long non-coding RNAs (lncRNAs) participate in cancer tumorigenesis. LncRNA P73 antisense RNA 1T (TP73-AS1), also known as KIAA0495 and p53-dependent apoptosis modulator (PDAM), is located in human chromosomal band 1p36.32 and plays a crucial role in many different carcinomas. This review summarizes current findings on the role of TP73-AS1 and its signaling pathways in various cancers, including glioma, esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), osteosarcoma, gastric cancer (GC), clear cell renal cell carcinoma (ccRCC), breast cancer (BC), bladder cancer, ovarian cancer, cholangiocarcinoma (CCA), lung cancer, and pancreatic cancer. Its aberrant expression generally correlates with clinicopathological characterization of patients. Moreover, TP73-AS1 regulates proliferation, migration, invasion, apoptosis, and chemoresistance cancer mechanisms, both in vivo and in vitro, through different signaling pathways. Therefore, TP73-AS1 may be considered as a marker for diagnosis and prognosis, also as a target for cancer treatment.

scholarly journals IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration

2019 ◽  
Vol 316 (1) ◽  
pp. H24-H34 ◽  
Author(s):  
Dylan J. Wodsedalek ◽  
Samantha J. Paddock ◽  
Tina C. Wan ◽  
John A. Auchampach ◽  
Aria Kenarsary ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Rna Sequencing ◽  
Akt Signaling ◽  
Heart Regeneration ◽  
Newborn Mice ◽  
Neonatal Cardiomyocyte

There is great interest in identifying signaling mechanisms by which cardiomyocytes (CMs) can enter the cell cycle and promote endogenous cardiac repair. We have previously demonstrated that IL-13 stimulated cell cycle activity of neonatal CMs in vitro. However, the signaling events that occur downstream of IL-13 in CMs and the role of IL-13 in CM proliferation and regeneration in vivo have not been explored. Here, we tested the role of IL-13 in promoting neonatal CM cell cycle activity and heart regeneration in vivo and investigated the signaling pathway(s) downstream of IL-13 specifically in CMs. Compared with control, CMs from neonatal IL-13 knockout (IL-13−/−) mice showed decreased proliferative markers and coincident upregulation of the hypertrophic marker brain natriuretic peptide ( Nppb) and increased CM nuclear size. After apical resection in anesthetized newborn mice, heart regeneration was significantly impaired in IL-13−/− mice compared with wild-type mice. Administration of recombinant IL-13 reversed these phenotypes by increasing CM proliferation markers and decreasing Nppb expression. RNA sequencing on primary neonatal CMs treated with IL-13 revealed activation of gene networks regulated by ERK1/2 and Akt. Western blot confirmed strong phosphorylation of ERK1/2 and Akt in both neonatal and adult cultured CMs in response to IL-13. Our data demonstrated a role for endogenous IL-13 in neonatal CM cell cycle and heart regeneration. ERK1/2 and Akt signaling are important pathways known to promote CM proliferation and protect against apoptosis, respectively; thus, targeting IL-13 transmembrane receptor signaling or administering recombinant IL-13 may be therapeutic approaches for activating proregenerative and survival pathways in the heart. NEW & NOTEWORTHY Here, we demonstrate, for the first time, that IL-13 is involved in neonatal cardiomyocyte cell cycle activity and heart regeneration in vivo. Prior work has shown that IL-13 promotes cardiomyocyte cell cycle activity in vitro; however, the signaling pathways were unknown. We used RNA sequencing to identify the signaling pathways activated downstream of IL-13 in cardiomyocytes and found that ERK1/2 and Akt signaling was activated in response to IL-13.

scholarly journals Role of Spore Coat Proteins in the Resistance of Bacillus subtilis Spores to Caenorhabditis elegans Predation

2008 ◽  
Vol 190 (18) ◽  
pp. 6197-6203 ◽  
Author(s):  
Maria-Halima Laaberki ◽  
Jonathan Dworkin
Keyword(s):  
Bacillus Subtilis ◽  
Caenorhabditis Elegans ◽  
Spore Coat ◽  
Coat Proteins ◽  
Host Interaction ◽  
Wide Range ◽  
In The Wild

ABSTRACT Bacterial spores are resistant to a wide range of chemical and physical insults that are normally lethal for the vegetative form of the bacterium. While the integrity of the protein coat of the spore is crucial for spore survival in vitro, far less is known about how the coat provides protection in vivo against predation by ecologically relevant hosts. In particular, assays had characterized the in vitro resistance of spores to peptidoglycan-hydrolyzing enzymes like lysozyme that are also important effectors of innate immunity in a wide variety of hosts. Here, we use the bacteriovorous nematode Caenorhabditis elegans, a likely predator of Bacillus spores in the wild, to characterize the role of the spore coat in an ecologically relevant spore-host interaction. We found that ingested wild-type Bacillus subtilis spores were resistant to worm digestion, whereas vegetative forms of the bacterium were efficiently digested by the nematode. Using B. subtilis strains carrying mutations in spore coat genes, we observed a correlation between the degree of alteration of the spore coat assembly and the susceptibility to the worm degradation. Surprisingly, we found that the spores that were resistant to lysozyme in vitro can be sensitive to C. elegans digestion depending on the extent of the spore coat structure modifications.

scholarly journals The Role of Small Molecules and Their Effect on the Molecular Mechanisms of Early Retinal Organoid Development

2021 ◽  
Vol 22 (13) ◽  
pp. 7081
Author(s):  
Philip E. Wagstaff ◽  
Andrea Heredero Berzal ◽  
Camiel J. F. Boon ◽  
Peter M. J. Quinn ◽  
Anneloor L. M. A. ten Asbroek ◽  
...  
Keyword(s):  
Small Molecules ◽  
Signaling Pathways ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Retinal Development ◽  
Comprehensive Overview ◽  
Or Efficiency

Early in vivo embryonic retinal development is a well-documented and evolutionary conserved process. The specification towards eye development is temporally controlled by consecutive activation or inhibition of multiple key signaling pathways, such as the Wnt and hedgehog signaling pathways. Recently, with the use of retinal organoids, researchers aim to manipulate these pathways to achieve better human representative models for retinal development and disease. To achieve this, a plethora of different small molecules and signaling factors have been used at various time points and concentrations in retinal organoid differentiations, with varying success. Additions differ from protocol to protocol, but their usefulness or efficiency has not yet been systematically reviewed. Interestingly, many of these small molecules affect the same and/or multiple pathways, leading to reduced reproducibility and high variability between studies. In this review, we make an inventory of the key signaling pathways involved in early retinogenesis and their effect on the development of the early retina in vitro. Further, we provide a comprehensive overview of the small molecules and signaling factors that are added to retinal organoid differentiation protocols, documenting the molecular and functional effects of these additions. Lastly, we comparatively evaluate several of these factors using our established retinal organoid methodology.

scholarly journals In VitroAntifungal Susceptibility of Candida glabrata to Caspofungin and the Presence ofFKSMutations Correlate with Treatment Response in an Immunocompromised Murine Model of Invasive Infection

2014 ◽  
Vol 58 (7) ◽  
pp. 3646-3649 ◽  
Author(s):  
Fabiola Fernández-Silva ◽  
Michaela Lackner ◽  
Javier Capilla ◽  
Emilio Mayayo ◽  
Deanna Sutton ◽  
...  
Keyword(s):  
Murine Model ◽  
Hot Spot ◽  
Drug Efficacy ◽  
Invasive Infection ◽  
Content Type ◽  
Wide Range ◽  
Systemic Infections ◽  
First Time

ABSTRACTIt has been argued that thein vitroactivity of caspofungin (CSP) is not a good predictor of the outcome of echinocandin treatmentin vivo. We evaluated thein vitroactivity of CSP and the presence ofFKSmutations in the hot spot 1 (HS1) region of theFKS1andFKS2genes in 17 Candida glabratastrains with a wide range of MICs. The efficacy of CSP against systemic infections from each of the 17 strains was evaluated in a murine model. No HS1 mutations were found in the eight strains showing MICs for CSP of ≤0.5 μg/ml, but they were present in eight of the nine strains with MICs of ≥1 μg/ml, i.e., three in theFKS1gene and five in theFKS2gene. CSP was effective for treating mice infected with strains with MICs of ≤0.5 μg/ml, showed variable efficacy in animals challenged with strains with MICs of 1 μg/ml, and did not work in those with strains with MICs of >1 μg/ml. In addition, mutations, including one reported for the first time, were found outside the HS1 region in theFKS2gene of six strains with different MICs, but their presence did not influence drug efficacy. Thein vitroactivity of CSP was compared with that of another echinocandin, anidulafungin, suggesting that the MICs of both drugs, as well as mutations in the HS1 regions of theFKS1andFKS2genes, are predictive of outcome.

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