scholarly journals Investigation of Antifungal Mechanisms of Thymol in the Human Fungal Pathogen, Cryptococcus neoformans

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3476
Author(s):  
Kwang-Woo Jung ◽  
Moon-Soo Chung ◽  
Hyoung-Woo Bai ◽  
Byung Yeoup Chung ◽  
Sungbeom Lee
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogens ◽  
Reverse Genetics ◽  
Mapk Pathway ◽  
Global Climate ◽  
Mitogen Activated Protein Kinase ◽  
Ergosterol Biosynthesis ◽  
Thymus Vulgaris ◽  
Dependent Manner ◽  
Expression Levels

Due to lifespan extension and changes in global climate, the increase in mycoses caused by primary and opportunistic fungal pathogens is now a global concern. Despite increasing attention, limited options are available for the treatment of systematic and invasive mycoses, owing to the evolutionary similarity between humans and fungi. Although plants produce a diversity of chemicals to protect themselves from pathogens, the molecular targets and modes of action of these plant-derived chemicals have not been well characterized. Using a reverse genetics approach, the present study revealed that thymol, a monoterpene alcohol from Thymus vulgaris L., (Lamiaceae), exhibits antifungal activity against Cryptococcus neoformans by regulating multiple signaling pathways including calcineurin, unfolded protein response, and HOG (high-osmolarity glycerol) MAPK (mitogen-activated protein kinase) pathways. Thymol treatment reduced the intracellular concentration of Ca2+ by controlling the expression levels of calcium transporter genes in a calcineurin-dependent manner. We demonstrated that thymol decreased N-glycosylation by regulating the expression levels of genes involved in glycan-mediated post-translational modifications. Furthermore, thymol treatment reduced endogenous ergosterol content by decreasing the expression of ergosterol biosynthesis genes in a HOG MAPK pathway-dependent manner. Collectively, this study sheds light on the antifungal mechanisms of thymol against C. neoformans.

scholarly journals Chlorpyrifos Suppresses Neutrophil Extracellular Traps in Carp by Promoting Necroptosis and Inhibiting Respiratory Burst Caused by the PKC/MAPK Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Qiaojian Zhang ◽  
Shengchen Wang ◽  
Shufang Zheng ◽  
Ziwei Zhang ◽  
Shiwen Xu
Keyword(s):  
Protein Kinase ◽  
Respiratory Burst ◽  
Mapk Pathway ◽  
Organophosphorus Pesticide ◽  
Neutrophil Extracellular Traps ◽  
Mitogen Activated Protein Kinase ◽  
Serine Threonine Kinase ◽  
Expression Levels ◽  
Threonine Kinase ◽  
Extracellular Traps

Neutrophil extracellular traps (NETs) are reticular structures formed by myeloperoxidase (MPO), histones, and neutrophil elastase (NE) that are released from neutrophils in response to pathogenic stimuli. Chlorpyrifos (CPF) is wildly used as an organophosphorus pesticide that causes a range of toxicological and environmental problems. Exposure to CPF can increase the production of neutrophils in carps, and this increase can be considered a biomarker of water pollution. To explore a relationship between NETs and CPF and its mechanism of influence, we treated neutrophils from the blood of carp with 1 μg/mL phorbol 12-myristate 13-acetate (PMA), 0.325 mg/L CPF, or 20 μM necrostatin-1 (Nec-1). The production of MPO and NETs was reduced in the CPF+PMA group compared with that in the PMA group. CPF can cause an increase in reactive oxygen species (ROS), while inhibiting respiratory burst caused by PMA stimulation. We found that the expression levels of protein-coupled receptor 84 (gpr84), dystroglycan (DAG), proto-oncogene serine/threonine kinase (RAF), protein kinase C (PKC), and mitogen-activated protein kinase 3 (MAPK3) in the CPF+PMA group were lower than those in the PMA group, indicating that the PKC-MAPK pathway was suppressed. The expression levels of cylindromatosis (CYLD), mixed lineage kinase domain-like pseudokinase (MLKL), receptor-interacting serine-threonine kinase 1 (RIP1), and receptor-interacting serine-threonine kinase 3 (RIP3) were increased, and the expression levels of caspase 8 were reduced by CPF, indicating that CPF may cause necroptosis. The addition of Nec-1 restored the number of NETs in the CPF+PMA group. The results indicate that CPF reduced the production of NETs by inhibiting respiratory burst and increasing necroptosis. The results contribute to the understanding of the immunotoxicological mechanism of CPF and provide a reference for comparative medical studies.

scholarly journals Phosphorylation of High-Mobility Group Protein A2 by Nek2 Kinase during the First Meiotic Division in Mouse Spermatocytes

2004 ◽  
Vol 15 (3) ◽  
pp. 1224-1232 ◽  
Author(s):  
Silvia Di Agostino ◽  
Monica Fedele ◽  
Paolo Chieffi ◽  
Alfredo Fusco ◽  
Pellegrino Rossi ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Chromatin Condensation ◽  
High Mobility ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Correct Process ◽  
High Mobility Group Protein ◽  
Mitogen Activated Protein ◽  
Pachytene Spermatocytes

The mitogen-activated protein kinase (MAPK) pathway is required for maintaining the chromatin condensed during the two meiotic divisions and to avoid a second round of DNA duplication. However, molecular targets of the MAPK pathway on chromatin have not yet been identified. Here, we show that the architectural chromatin protein HMGA2 is highly expressed in male meiotic cells. Furthermore, Nek2, a serine-threonine kinase activated by the MAPK pathway in mouse pachytene spermatocytes, directly interacts with HMGA2 in vitro and in mouse spermatocytes. The interaction does not depend on the activity of Nek2 and seems constitutive. On progression from pachytene to metaphase, Nek2 is activated and HMGA2 is phosphorylated in an MAPK-dependent manner. We also show that Nek2 phosphorylates in vitro HMGA2 and that this phosphorylation decreases the affinity of HMGA2 for DNA and might favor its release from the chromatin. Indeed, we find that most HMGA2 associates with chromatin in mouse pachytene spermatocytes, whereas it is excluded from the chromatin upon the G2/M progression. Because hmga2-/- mice are sterile and show a dramatic impairment of spermatogenesis, it is possible that the functional interaction between HMGA2 and Nek2 plays a crucial role in the correct process of chromatin condensation in meiosis.

scholarly journals Collagen/β1 integrin signaling up-regulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner

2012 ◽  
Vol 23 (17) ◽  
pp. 3473-3484 ◽  
Author(s):  
Mohammed-Amine El Azreq ◽  
Dalila Naci ◽  
Fawzi Aoudjit
Keyword(s):  
Actin Polymerization ◽  
Mitogen Activated Protein Kinase ◽  
Integrin Signaling ◽  
Β1 Integrin ◽  
Dependent Manner ◽  
Expression Levels ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
And Function

The mechanisms by which β1 integrins regulate chemoresistance of cancer cells are still poorly understood. In this study, we report that collagen/β1 integrin signaling inhibits doxorubicin-induced apoptosis of Jurkat and HSB2 leukemic T-cells by up-regulating the expression and function of the ATP-binding cassette C 1 (ABCC1) transporter, also known as multidrug resistance–associated protein 1. We find that collagen but not fibronectin reduces intracellular doxorubicin content and up-regulates the expression levels of ABCC1. Inhibition and knockdown studies show that up-regulation of ABCC1 is necessary for collagen-mediated reduction of intracellular doxorubicin content and collagen-mediated inhibition of doxorubicin-induced apoptosis. We also demonstrate that activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase signaling pathway is involved in collagen-induced reduction of intracellular doxorubicin accumulation, collagen-induced up-regulation of ABCC1 expression levels, and collagen-mediated cell survival. Finally, collagen-mediated up-regulation of ABCC1 expression and function also requires actin polymerization. Taken together, our results indicate for the first time that collagen/β1 integrin/ERK signaling up-regulates the expression and function of ABCC1 and suggest that its activation could represent an important pathway in cancer chemoresistance. Thus simultaneous targeting of collagen/β1 integrin and ABCC1 may be more efficient in preventing drug resistance than targeting each pathway alone.

scholarly journals Cryptococcus neoformans Phosphoinositide-Dependent Kinase 1 (PDK1) Ortholog Is Required for Stress Tolerance and Survival in Murine Phagocytes

2012 ◽  
Vol 12 (1) ◽  
pp. 12-22 ◽  
Author(s):  
Yeissa Chabrier-Roselló ◽  
Kimberly J. Gerik ◽  
Kristy Koselny ◽  
Louis DiDone ◽  
Jennifer K. Lodge ◽  
...  
Keyword(s):  
Cell Wall ◽  
Stress Tolerance ◽  
Cryptococcus Neoformans ◽  
Nitrosative Stress ◽  
Galleria Mellonella ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Oxidative And Nitrosative Stress ◽  
Independent Manner ◽  
Content Type

ABSTRACTCryptococcus neoformansPKH2-01andPKH2-02are orthologous to mammalian PDK1 kinase genes. Although orthologs of these kinases have been extensively studied inS. cerevisiae, little is known about their function in pathogenic fungi. In this study, we show thatPKH2-02but notPKH2-01is required forC. neoformansto tolerate cell wall, oxidative, nitrosative, and antifungal drug stress. Deletion ofPKH2-02leads to decreased basal levels of Pkc1 activity and, consequently, reduced activation of the cell wall integrity mitogen-activated protein kinase (MAPK) pathway in response to cell wall, oxidative, and nitrosative stress.PKH2-02function also is required for tolerance of fluconazole and amphotericin B, two important drugs for the treatment of cryptococcosis. Furthermore, OSU-03012, an inhibitor of human PDK1, is synergistic and fungicidal in combination with fluconazole. Using aGalleria mellonellamodel of low-temperature cryptococcosis, we found thatPKH2-02is also required for virulence in a temperature-independent manner. Consistent with the hypersensitivity of thepkh2-02Δ mutant to oxidative and nitrosative stress, this mutant shows decreased survival in murine phagocytes compared to that of wild-type (WT) cells. In addition, we show that deletion ofPKH2-02affects the interaction betweenC. neoformansand phagocytes by decreasing its ability to suppress production of tumor necrosis factor alpha (TNF-α) and reactive oxygen species. Taken together, our studies demonstrate that Pkh2-02-mediated signaling inC. neoformansis crucial for stress tolerance, host-pathogen interactions, and both temperature-dependent and -independent virulence.

scholarly journals Angiotensin II-Induced Mitogen-Activated Protein Kinase Phosphatase-1 Expression in Bovine Adrenal Glomerulosa Cells: Implications in Mineralocorticoid Biosynthesis

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5573-5581 ◽  
Author(s):  
Andrés J. Casal ◽  
Stéphane Ryser ◽  
Alessandro M. Capponi ◽  
Carine F. Wang-Buholzer
Keyword(s):  
Angiotensin Ii ◽  
Mapk Pathway ◽  
Fold Increase ◽  
Zona Glomerulosa ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Aldosterone Production ◽  
Glomerulosa Cells

Angiotensin II (AngII) stimulates aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex. AngII also triggers the MAPK pathways (ERK1/2 and p38). Because ERK1/2 phosphorylation is a transient process, phosphatases could play a crucial role in the acute steroidogenic response. Here we show that the dual specificity (threonine/tyrosine) MAPK phosphatase-1 (MKP-1) is present in bovine adrenal glomerulosa cells in primary culture and that AngII markedly increases its expression in a time- and concentration-dependent manner (IC50 = 1 nm), a maximum of 548 ± 10% of controls being reached with 10 nm AngII after 3 h (n = 3, P < 0.01). This effect is completely abolished by losartan, a blocker of the AT1 receptor subtype. Moreover, this AngII-induced MKP-1 expression is reduced to 250 ± 35% of controls (n = 3, P < 0.01) in the presence of U0126, an inhibitor of ERK1/2 phosphorylation, suggesting an involvement of the ERK1/2 MAPK pathway in MKP-1 induction. Indeed, shortly after AngII-induced phosphorylation of ERK1/2 (220% of controls at 30 min), MKP-1 protein expression starts to increase. This increase is associated with a reduction in ERK1/2 phosphorylation, which returns to control values after 3 h of AngII challenge. Enhanced MKP-1 expression is essentially due to a stabilization of MKP-1 mRNA. AngII treatment leads to a 53-fold increase in phosphorylated MKP-1 levels and a doubling of MKP-1 phosphatase activity. Overexpression of MKP-1 results in decreased phosphorylation of ERK1/2 and aldosterone production in response to AngII stimulation. These results strongly suggest that MKP-1 is the specific phosphatase induced by AngII and involved in the negative feedback mechanism ensuring adequate ERK1/2-mediated aldosterone production in response to the hormone.

scholarly journals Flavonoid Naringenin: A Potential Immunomodulator forChlamydia trachomatisInflammation

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Abebayehu N. Yilma ◽  
Shree R. Singh ◽  
Lisa Morici ◽  
Vida A. Dennis
Keyword(s):  
Inflammatory Mediators ◽  
Mapk Pathway ◽  
Costimulatory Molecule ◽  
Asymptomatic Infection ◽  
Mitogen Activated Protein Kinase ◽  
Gene Transcript ◽  
Dependent Manner ◽  
Sexually Transmitted ◽  
Gm Csf ◽  
Mitogen Activated Protein

Chlamydia trachomatis, the agent of bacterial sexually transmitted infections, can manifest itself as either acute cervicitis, pelvic inflammatory disease, or a chronic asymptomatic infection. Inflammation induced byC. trachomatiscontributes greatly to the pathogenesis of disease. Here we evaluated the anti-inflammatory capacity of naringenin, a polyphenolic compound, to modulate inflammatory mediators produced by mouse J774 macrophages infected with liveC. trachomatis. Infected macrophages produced a broad spectrum of inflammatory cytokines (GM-CSF, TNF, IL-1β, IL-1α, IL-6, IL-12p70, and IL-10) and chemokines (CCL4, CCL5, CXCL1, CXCL5, and CXCL10) which were downregulated by naringenin in a dose-dependent manner. Enhanced protein and mRNA gene transcript expressions of TLR2 and TLR4 in addition to the CD86 costimulatory molecule on infected macrophages were modulated by naringenin. Pathway-specific inhibition studies disclosed that p38 mitogen-activated-protein kinase (MAPK) is involved in the production of inflammatory mediators by infected macrophages. Notably, naringenin inhibited the ability ofC. trachomatisto phosphorylate p38 in macrophages, suggesting a potential mechanism of its attenuation of concomitantly produced inflammatory mediators. Our data demonstrates that naringenin is an immunomodulator of inflammation triggered byC. trachomatis, which possibly may be mediated upstream by modulation of TLR2, TLR4, and CD86 receptors on infected macrophages and downstream via the p38 MAPK pathway.

Signal transduction events involved in TPA downregulation of SP-A gene expression

2004 ◽  
Vol 286 (6) ◽  
pp. L1210-L1219 ◽  
Author(s):  
Olga L. Miakotina ◽  
Jeanne M. Snyder
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Surfactant Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Novel Isoforms

Surfactant protein A (SP-A), the most abundant pulmonary surfactant protein, plays a role in innate host defense and blocks the inhibitory effects of serum proteins on surfactant surface tension-lowering properties. SP-A mRNA and protein are downregulated by phorbol esters (TPA) via inhibition of gene transcription. We evaluated the TPA signaling pathways involved in SP-A inhibition in a lung cell line, H441 cells. TPA caused sustained phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK, and c-Jun-NH2-terminal kinase. An inhibitor of conventional and novel isoforms of protein kinase C (PKC) and two inhibitors of p44/42 MAPK kinase partially or completely blocked the inhibitory effects of TPA on SP-A mRNA levels. In contrast, inhibitors of conventional PKC-α and -β, stress-activated protein kinases, protein phosphatases, protein kinase A, and the phosphatidylinositol 3-kinase pathway had no effect on the TPA-mediated inhibition of SP-A mRNA. TPA also stimulated the synthesis of c-Jun mRNA and protein in a time-dependent manner. Inhibitors of the p44/42 MAPK signaling pathway and PKC blocked the TPA-mediated phosphorylation of p44/42 MAPK and the increase in c-Jun mRNA. We conclude that TPA inhibits SP-A gene expression via novel isoforms of PKC, the p44/42 MAPK pathway, and the activator protein-1 complex.

scholarly journals Sex-dependent expression of brain medullary MAP and PI3 kinases in adult sheep with antenatal betamethasone exposure

2018 ◽  
Vol 132 (17) ◽  
pp. 1953-1962 ◽  
Author(s):  
Alexa S. Hendricks ◽  
Hossam A. Shaltout ◽  
Brain M. Westwood ◽  
Mark C. Chappell ◽  
Debra I. Diz
Keyword(s):  
Fetal Programming ◽  
Intracellular Signaling ◽  
Mapk Pathway ◽  
Pi3k Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Premature Delivery ◽  
Dependent Manner ◽  
Sheep Model ◽  
The Status ◽  
The Brain

Antenatal betamethasone (BM) therapy for women in jeopardy of premature delivery accelerates the lung development in preterm infants and reduces infant mortality rates, but may induce early programming events with chronic cardiovascular consequences. In a sheep model of fetal programming, in utero BM-exposed (BMX) offspring as adults exhibit elevated mean arterial pressure (MAP), decreased baroreflex sensitivity (BRS) for the control of heart rate and insulin resistance accompanied by dysregulation of the brain renin–angiotensin (Ang) system (RAS). However, the status of signaling mechanisms in the brain dorsomedial medulla (DMM) of the BMX sheep that comprise both the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) cellular pathways is unknown. Given the importance of these signaling pathways in the actions of Ang peptides as well as baroreflex function and autonomic integration, we applied both a kinase signaling array and associated individual immunoblots of the dorsomedial brain medulla from adult female and male sheep with antenatal BMX. MAPK and PI3K pathways were altered significantly in the BMX sheep in a sex-dependent manner. A protein array for kinases (PathScan® Intracellular Signaling Array Kit, Cell Signaling) and subsequent verification by immunoblot revealed that within the DMM, female BMX sheep exhibit lower expression of proteins in the PI3K pathway, while male BMX sheep show greater expression of p-MAPK pathway proteins extracellular signal regulated kinase (ERK) 1/2. We conclude that maladaptive changes in these two kinase pathways in the DMM may contribute to the chronic dysregulation of blood pressure in this model of fetal programming.

scholarly journals Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaochen Chen ◽  
Haofeng Lin ◽  
Jinyang Chen ◽  
Lisheng Wu ◽  
Junqing Zhu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Mediator ◽  
Mapk Pathway ◽  
Bone Destruction ◽  
New Drugs ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Inflammatory Mediator Production ◽  
Tnf Α ◽  
Mitogen Activated Protein

Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). It is urgent to develop new drugs that can effectively inhibit the abnormal activation of RA-FLS. In our study, the RA-FLS cell line, MH7A, and mice with collagen-induced arthritis (CIA) were used to evaluate the effect of paclitaxel (PTX). Based on the results, PTX inhibited the migration of RA-FLS in a dose-dependent manner and significantly reduced the spontaneous expression of IL-6, IL-8, and RANKL mRNA and TNF-α-induced transcription of the IL-1β, IL-8, MMP-8, and MMP-9 genes. However, PTX had no significant effect on apoptosis in RA-FLS. Mechanistic studies revealed that PTX significantly inhibited the TNF-α-induced phosphorylation of ERK1/2 and JNK in the mitogen-activated protein kinase (MAPK) pathway and suppressed the TNF-α-induced activation of AKT, p70S6K, 4EBP1, and HIF-1α in the AKT/mTOR pathway. Moreover, PTX alleviated synovitis and bone destruction in CIA mice. In conclusion, PTX inhibits the migration and inflammatory mediator production of RA-FLS by targeting the MAPK and AKT/mTOR signaling pathways, which provides an experimental basis for the potential application in the treatment of RA.

scholarly journals Calcium-binding protein S100A6 interaction with VEGF receptors integrates signaling and trafficking pathways

2021 ◽  
Author(s):  
Sreenivasan Ponnambalam ◽  
Leyuan Bao ◽  
Gareth W Fearnley ◽  
Chi-Chuan Lin ◽  
Adam F Odell ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Trafficking ◽  
Calcium Binding ◽  
Mapk Pathway ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Mitogen Activated Protein Kinase ◽  
Tyrosine Kinase Domain ◽  
Dependent Manner ◽  
Endothelial Cell Function

The mammalian endothelium which lines all blood vessels responds to soluble factors which control vascular development and sprouting. Endothelial cells bind to vascular endothelial growth factor A via two different receptor tyrosine kinases (VEGFR1, VEGFR2) which regulate such cellular responses. The integration of VEGFR signal transduction and membrane trafficking is not well understood. Here, we used a yeast-based membrane protein screen to identify VEGFR-interacting factor(s) which modulate endothelial cell function. By screening a human endothelial cDNA library, we identified a calcium-binding protein, S100A6, which can interact with either VEGFR. We found that S100A6 binds in a calcium-dependent manner to either VEGFR1 or VEGFR2. S100A6 binding was mapped to the VEGFR2 tyrosine kinase domain. Depletion of S100A6 impacts on VEGF-A-regulated signaling through the canonical mitogen-activated protein kinase (MAPK) pathway. Furthermore, S100A6 depletion caused contrasting effects on biosynthetic VEGFR delivery to the plasma membrane. Co-distribution of S100A6 and VEGFRs on tubular profiles suggest the presence of transport carriers that facilitate VEGFR trafficking. We propose a mechanism whereby S100A6 acts as a calcium regulated switch which facilitates biosynthetic VEGFR trafficking from the TGN-to-plasma membrane. VEGFR-S100A6 interactions thus enable integration of signaling and trafficking pathways in controlling the endothelial response to VEGF-A.

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