Mapk Pathways

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of
psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers
promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity
of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine (DOI), and 3,4-methylenedioxy-methamphetamine (MDMA) will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAFV600-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2C125S, but not the
synonymous MEK1C121S protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.

Pathogens hide immunogenic epitopes from the host to evade immunity, persist and cause infection. The opportunistic human fungal pathogen Candida albicans, which can cause fatal disease in immunocompromised patient populations, offers a good example as it masks the inflammatory epitope β-glucan in its cell wall from host recognition. It has been demonstrated previously that β-glucan becomes exposed during infection in vivo but the mechanism behind this exposure was unknown. Here, we show that this unmasking involves neutrophil extracellular trap (NET) mediated attack, which triggers changes in fungal cell wall architecture that enhance immune recognition by the Dectin-1 β-glucan receptor in vitro. Furthermore, using a mouse model of disseminated candidiasis, we demonstrate the requirement for neutrophils in triggering these fungal cell wall changes in vivo. Importantly, we found that fungal epitope unmasking requires an active fungal response in addition to the stimulus provided by neutrophil attack. NET-mediated damage initiates fungal MAP kinase-driven responses, particularly by Hog1, that dynamically relocalize cell wall remodeling machinery including Chs3, Phr1 and Sur7. Neutrophil-initiated cell wall disruptions augment some macrophage cytokine responses to attacked fungi. This work provides insight into host-pathogen interactions during disseminated candidiasis, including valuable information about how the C. albicans cell wall responds to the biotic stress of immune attack. Our results highlight the important but underappreciated concept that pattern recognition during infection is dynamic and depends on the host-pathogen dialog. Opportunistic fungal infections, including those caused by C. albicans, have emerged as a significant global health burden and the disseminated form of these infections still have unacceptably high mortality rates despite modern antifungal treatments. The fungal cell wall controls its interaction with the host environment and immune recognition, although

Prolactinoma is the most Pituitary adenomas that affect young women at fertile age. Visual impairment is a common presentation of this condition. Visual pathway mainly optic nerve maybe affected in these patients. Visual evoked potential is one of the techniques to screen the visual pathway. The aim of present work is to search for probable adverse effect of Prolactinoma on visual pathway using visual evoked Potentials.
Patients and Method
Fifteen female patients with age range of 20-40 years were selected. The patients had healthy visual system as far as visual acuity, field of vision & magnetic resonance of imaging of brain were concerned. The latency and amplitude of visual evoked potential, P100 peak was recorded for this patients & 15 age and sex matched controls with healthy visual system.
Results
The mean age was 29.4±6.68 and 29.13±6.82 is case and control group respectively. The mean visual acuity in case was 0.00±0.00 (Log MAR) and 0.00±0.00 (Log MAR) in control group. The difference in values were not statistically significant as for as age (P=0.967) and visual acuity (P=1) were concerned. The values obtained for latencies were 101.13 ±5.95 and 98.06 ±4.01 for case and control groups respectively. In case of amplitude the values were 8 ±1.96 and 7.93 ±2.06 in case and control groups. The values for visual evoked potential were statistically significant for latency between case and control groups ( P=0.036) , where as in case of amplitude the difference between two groups i.e., case and control groups were not significant (P=0.756)
Conclusion
Prolactinoma might have adverse effect on visual pathway mainly optic nerve despite normal visual acuity, field of vision and brain magnetic resonance imaging which can be diagnosed by latency of pattern visual evoked potential VEP, P100 peak.

During the development of the vertebrate feeding apparatus, a variety of complicated cellular and molecular processes participate in the formation and integration of individual skeletal elements. The molecular mechanisms regulating the formation of skeletal primordia and their development into specific morphological structures are tightly controlled by a set of interconnected signalling pathways. Some of these pathways, such as Bmp, Hedgehog, Notch and Wnt, are long known for their pivotal roles in craniofacial skeletogenesis. Studies addressing the functional details of their components and downstream targets, the mechanisms of their interactions with other signals as well as their potential roles in adaptive morphological divergence, are currently attracting considerable attention. An increasing number of signalling pathways that had previously been described in different biological contexts have been shown to be important in the regulation of jaw skeletal development and morphogenesis. In this review, I provide an overview of signalling pathways involved in trophic skeletogenesis emphasizing studies of the most species-rich group of vertebrates, the teleost fish, which through their evolutionary history have undergone repeated episodes of spectacular trophic diversification.

Drought is a ubiquitous abiotic factor that severely impedes growth and development of horticulture crops. The challenge postured by global climate change is the evolution of drought-tolerant cultivars that could cope with concurrent stress. Hence, in this study, biochemical, physiological and transcriptome analysis were investigated in drought-treated grapevine leaves. The results revealed that photosynthetic activity and reducing sugars were significantly diminished which were positively correlated with low stomatal conductance and CO 2 exchange in drought-stressed leaves. Further, the activities of superoxide dismutase, peroxidase, and catalase were significantly actuated in the drought-responsive grapevine leaves. Similarly, the levels of abscisic acid and jasmonic acid were also significantly increased in the drought-stressed leaves. In transcriptome analysis, 12,451 differentially expressed genes (DEGs) were annotated, out of which 8021 DEGs were up-regulated and 4430 DEGs were down-regulated in response to drought stress. In addition, the genes encoding pathogen-associated molecular pattern (PAMP) triggered immunity (PTI), including calcium signals, protein phosphatase 2C, calcineurin B-like proteins, MAPKs, and phosphorylation (FLS2 and MEKK1) cascades were up-regulated in response to drought stress. Several genes related to plant-pathogen interaction pathway (RPM1, PBS1, RPS5, RIN4, MIN7, PR1, and WRKYs) were also found up-regulated in response to drought stress. Overall the results of present study showed the dynamic interaction of DEG in grapevine physiology which provides the premise for selection of defense-related genes against drought stress for subsequent grapevine breeding programs.

G-protein-coupled receptors (GPCRs) are known to activate both G protein- and β-arrestin-dependent signalling cascades. The initiation of mitogen-activated protein kinase (MAPK) pathways is a key downstream event in the control of cellular functions including proliferation, differentiation, migration and apoptosis. Both G proteins and β-arrestins have been reported to mediate context-specific activation of ERK1/2, p38 and JNK MAPKs. Recently, the activation of ERK5 MAPK by Gq-coupled receptors has been described to involve a direct interaction between Gαq and two novel effectors, PKCζ and MEK5. However, the possible contribution of β-arrestin towards this pathway has not yet been addressed. In the present work we sought to investigate the role of receptor internalization processes and β-arrestin recruitment in the activation of ERK5 by Gq-coupled GPCRs. Our results show that ERK5 activation is independent of M1 or M3 muscarinic receptor internalization. Furthermore, we demonstrate that phosphorylation-deficient muscarinic M1 and M3 receptors are still able to fully activate the ERK5 pathway, despite their reported inability to recruit β-arrestins. Indeed, the overexpression of Gαq, but not that of β-arrestin1 or β-arrestin2, was found to potently enhance ERK5 activation by GPCRs, whereas silencing of β-arrestin2 expression did not affect the activation of this pathway. Finally, we show that a β-arrestin-biased mutant form of angiotensin II (SII; Sar1-Ile4-Ile8 AngII) failed to promote ERK5 phosphorylation in primary cardiac fibroblasts, as compared to the natural ligand. Overall, this study shows that the activation of ERK5 MAPK by model Gq-coupled GPCRs does not depend on receptor internalization, β-arrestin recruitment or receptor phosphorylation but rather is dependent on Gαq-signalling.

Background and Objectives Previous studies with p38MAPK inhibitors at room temperature demonstrated that they improve a large number of platelet storage parameters, but cannot substantially inhibit p38MAPK activation nor protect
against widespread decrements in platelet quality parameters during 4 °C storage. In this study, platelet quality parameters and inhibition of p38MAPK by VX-702 were studied after incubation of platelets at 16 °C without agitation, suboptimal
storage conditions which produce moderate platelet decrements. Materials and Methods Trima apheresis units were collected and aliquoted into three 60-ml CLX storage bags: (i) a control aliquot which was held at 20–24 °C with constant agitation; (ii) a test aliquot which was held at 20–24 °C with agitation until Day 2, when it was reincubated at 16 – 1 °C for 24 – 0
5 h without agitation and then returned 20–24 °C with agitation; (iii) a test aliquot containing 1 lm VX-702 stored in an identical fashion as aliquot 2. Aliquots were tested
for an array of platelet storage parameters and p38MAPK activation on Days 1, 4 and 7. Results Many platelet storage parameters and p38MAPK activation were adversely affected by 24-h incubation at 16 °C without agitation. With the
exception of ESC, addition of VX-702 prevented p38MAPK activation and the decrements in most observed parameters.
Conclusion Unlike 4 °C storage, VX-702 prevents activation of p38MAPK and decrements in many platelet storage parameters after exposure to 16 °C without agitation for 24 h.

The heterotrimeric G proteins and mitogen-activated protein kinases (MAPKs) conserved signaling pathways are involved in the development, reproduction and pathogenicity in filamentous fungi. The two-component histidine kinase, known also as the HOG MAPK pathway, regulates a similar complex set of responses and is known to mediate the phenylpyrrole fludioxonil fungicide response in fungi. We used Cochliobolus heterostrophus mutant strains deficient in G-protein α (cga1) and/or β (cgb1) subunits or MAPK (chk1, mps1 and hog1) to uncover their role in the mediation of this fungicide’s activity and resistance. The results revealed complex interactions between the G-protein subunits and the MAPK in response to osmotic/ionic and fludioxonil stresses. Under normal conditions, the Hog1 pathway restricts glycerol accumulation since its disruption leads to hyperosmosensitivity and very high cellular glycerol accumulation. The hog1 mutants were also relatively resistance to fludioxonil. Moreover, our results suggest that cgb1, chk1 and mps1 are also weak repressors of this response since mutation in these genes caused relatively high elevation in glycerol levels in the cells. Supporting this is the finding that these three strains exhibit resistance to KCl stress. In contrast, the cga1 strain has only moderate levels of cellular glycerol (higher than those of the wild type, but lower than those of the other mutants) that are little affected by KCl or fludioxonil stress. Indeed, these mutants are highly sensitive to KCl stress. This suggests that Cga1 is a moderate repressor of cellular glycerol under normal conditions and an enhancer of glycerol accumulation under osmotic/ionic stress conditions. Together these findings reveals that the sensitivity to fludioxonil is not only positively controlled by the Hog1 pathway, but also mediated by the Chk1, Mps1, Cga1 and Cgb1 pathways. This study provides insight into the roles of G-protein in mediating the anti-fungal fludioxonil response. A model is proposed for the interactions between the G-protein and MAPK signaling pathways.

Pathogenicity mitogen-activated protein kinases (MAPKs), related to yeast FUS3/KSS1, are essential for virulence in fungi, including Cochliobolus heterostrophus, a necrotrophic pathogen causing Southern corn leaf blight. We compared the phenotypes of mutants in three MAPK genes: HOG1, MPS1, and CHK1. The chk1 and mps1 mutants show autolytic appearance, light pigmentation, and dramatic reduction in virulence and conidiation. Similarity of mps1 and chk1 mutants is reflected by coregulation by these two MAPKs of several genes. Unlike chk1, mps1 mutants are female-fertile and form normal-looking appressoria. HOG1 mediates resistance to hyperosmotic and, to a lesser extent, oxidative stress, and is required for stress upregulation of glycerol-3-phosphate phosphatase, transaldolase, and a monosaccharide transporter. Hog1, but not Mps1 or Chk1, was rapidly phosphorylated in response to increased osmolarity. The hog1 mutants have smaller appressoria and cause decreased disease symptoms on maize leaves. Surprisingly, loss of MPS1 in a wild-type or hog1 background improved resistance to some stresses. All three MAPKs contribute to the regulation of central developmental functions under normal and stress conditions, and full virulence cannot be achieved without appropriate input from all three pathways.

The signal transduction pathways have an important role in cell growth, as they are the primary means of communication of cells with their environment, which determines the activity of cells promoting responses such as proliferation, differentiation, migration, development, apop-tosis, etc., there have been models representing these pathways using different techniques, such as ODE, stochas-tic methods, Petri nets, pi calculation, Boolean networks, Bayesian networks, cellular automaton and agent-based systems , among others. In this research, an agent-based mod-eling and simulation of subsequent events after activation of the Ras molecule in the intracellular MAPK pathway section is presented, using a multi-agent programmable modeling environment called NetLogo.

In the last few years the interactome of Gαq has expanded considerably, contributing to improve our understanding of the cellular and physiological events controlled by this G alpha subunit. The availability of high-resolution crystal structures has led the identification of an effector-binding region within the surface of Gαq that is able to recognise a variety of effector proteins. Consequently, it has been possible to ascribe different Gαq functions to specific cellular players and to identify important processes that are triggered independently of the canonical activation of phospholipase Cβ (PLCβ), the first identified Gαq effector. Novel effectors include p63RhoGEF, that provides a link between G protein-coupled receptors and RhoA activation, phosphatidylinositol 3-kinase (PI3K), implicated in the regulation of the Akt pathway, or the cold-activated TRPM8 channel, which is directly inhibited upon Gαq binding. Recently, the activation of ERK5 MAPK by Gq-coupled receptors has also been described as a novel PLCβ-independent signalling axis that relies upon the interaction between this G protein and two novel effectors (PKCζ and MEK5). Additionally, the association of Gαq with different regulatory proteins can modulate its effector coupling ability and, therefore, its signalling potential. Regulators include accessory proteins that facilitate effector activation or, alternatively, inhibitory proteins that downregulate effector binding or promote signal termination. Moreover, Gαq is known to interact with several components of the cytoskeleton as well as with important organisers of membrane microdomains, which suggests that efficient signalling complexes might be confined to specific subcellular environments. Overall, the complex interaction network of Gαq underlies an ever-expanding functional diversity that puts forward this G alpha subunit as a major player in the control of physiological functions and in the development of different pathological situations.

Prolactinoma is the most Pituitary adenomas that affect young women at fertile age. Visual impairment is a common presentation of this condition. Visual pathway mainly optic nerve maybe affected in these patients. Visual evoked potential is one of the techniques to screen the visual pathway. The aim of present work is to search for probable adverse effect of Prolactinoma on visual pathway using visual evoked Potentials. Patients and Method Fifteen female patients with age range of 20-40 years were selected. The patients had healthy visual system as far as visual acuity, field of vision & magnetic resonance of imaging of brain were concerned. The latency and amplitude of visual evoked potential, P100 peak was recorded for this patients & 15 age and sex matched controls with healthy visual system. Results The mean age was 29.4±6.68 and 29.13±6.82 is case and control group respectively. The mean visual acuity in case was 0.00±0.00 (Log MAR) and 0.00±0.00 (Log MAR) in control group. The difference in values were not statistically significant as for as age (P=0.967) and visual acuity (P=1) were concerned. The values obtained for latencies were 101.13 ±5.95 and 98.06 ±4.01 for case and control groups respectively. In case of amplitude the values were 8 ±1.96 and 7.93 ±2.06 in case and control groups. The values for visual evoked potential were statistically significant for latency between case and control groups ( P=0.036) , where as in case of amplitude the difference between two groups i.e., case and control groups were not significant (P=0.756) Conclusion Prolactinoma might have adverse effect on visual pathway mainly optic nerve despite normal visual acuity, field of vision and brain magnetic resonance imaging which can be diagnosed by latency of pattern visual evoked potential VEP, P100 peak.

The role of G-protein and mitogen-activated protein kinase (MAPK) in filamentous fungi has been studied for over a decade, but downstream elements are less known. Here, we used microarray and Northern blot analysis to examine the involvement of these signaling pathways in controlling the known Cochliobolus heterostrophus T-toxin biosynthetic gene, DEC1, whose control is important in epidemic prevention. Comparison of the expression profile in wild-type strains and in G-protein and MAPK signaling mutants revealed a unique, environmental-dependent control mechanism for the DEC1 gene. The results suggest, for the first time, a possible role in pathogenicity for the G-protein α2 subunit in this organism, and hint to a common role of G-protein α1 and β1 subunits and MAPK in maintaining accurate levels of this toxin during pathogenesis.

The effect of ApoE on NMDAR-dependent ERK/CREB signaling is isoform-dependent, and ApoE4 accelerates memory decline in ageing. However, this isoform-dependent function on neuronal signaling during ageing is unclear. In this study, we have examined NMDAR-associated ERK/CREB signal transduction in young and aged huApoE3 and huApoE4 targeted replacement (TR) mice. At 12 weeks
huApoE4 mouse brain, increased NR1-S896 phosphorylation was linked to higher protein kinase C (PKC) activation. This up-regulation was accompanied by higher phosphorylation of AMPA GluR1-S831,
CaMKII, ERK1/2 and CREB. But at 32 weeks, there was no significant difference between huApoE3 and huApoE4 TR mice on NMDAR-associated ERK/CREB signaling. Interestingly, in 72-week-old huApoE4 TR mice, protein phosphorylation that were increased in younger mice were significantly reduced. Lower NR1-S896 phosphorylation was linked to reduced PKC, GluR1-S831, CaMKII, ERK1/2 and CREB phosphorylation in huApoE4 TR mice as compared to huApoE3 TR mice. Furthermore, we have consistently detected lower ApoE levels in young and aged huApoE4 TR mouse brain, and this was associated with reduced expression of the ApoE receptor, LRP1 and NR2A-Y1246 phosphorylation. These results suggest age-specific, isoform-dependent effects of ApoE on neuronal signaling.