Cell Signaling Defects and Human Disease

Mora-Garcia, Patricia; Sakamoto, Kathleen M.

doi:10.1006/mgme.1998.2798

Cited by 4 publications

(3 citation statements)

References 206 publications

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“…TGF-b1, because of its properties in the regulation of production, degradation, and accumulation of proteins of the extracellular matrix, is described as having an important role in the formation of fibrosis. 18 Studies done in patients with CP and normal controls showed an increased expression of TGF-b1 in pancreatic tissue of ill individuals in relation to tissue from the normal pancreas. 19,20 In the same way, a higher expression of this cytokine was obtained in pancreatic tissue of transgenic hamsters after CP induction.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of Cytokine Genes (TGF-??1, IFN-??, IL-6, IL-10, and TNF-??) in Patients With Chronic Pancreatitis

Bendicho¹,

Guedes²,

Silva³

et al. 2005

Pancreas

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Section: Discussionmentioning

confidence: 99%

Polymorphism of Cytokine Genes (TGF-??1, IFN-??, IL-6, IL-10, and TNF-??) in Patients With Chronic Pancreatitis

Bendicho¹,

Guedes²,

Silva³

et al. 2005

Pancreas

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show abstract

“…Negative feedback also ensures that signalling pathways are resistant to external perturbations ( Stelling et al, 2004 ) and may optimise the energetic cost of signal transduction ( Anders et al, 2020 ). Identifying and characterising feedback mechanisms in signal transduction pathways is pivotal since dysfunctional cell signalling frequently underlies complex diseases ( Fazakerley et al, 2019 ; Mora-Garcia and Sakamoto, 1999 ; Nguyen and Kholodenko, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis

Kearney

Norris

Ghomlaghi

et al. 2021

eLife

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The phosphoinositide 3-kinase (PI3K)-Akt network is tightly controlled by feedback mechanisms that regulate signal flow and ensure signal fidelity. A rapid overshoot in insulin-stimulated recruitment of Akt to the plasma membrane has previously been reported, which is indicative of negative feedback operating on acute timescales. Here, we show that Akt itself engages this negative feedback by phosphorylating insulin receptor substrate (IRS) 1 and 2 on a number of residues. Phosphorylation results in the depletion of plasma membrane-localised IRS1/2, reducing the pool available for interaction with the insulin receptor. Together these events limit plasma membrane-associated PI3K and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) synthesis. We identified two Akt-dependent phosphorylation sites in IRS2 at S306 (S303 in mouse) and S577 (S573 in mouse) that are key drivers of this negative feedback. These findings establish a novel mechanism by which the kinase Akt acutely controls PIP3 abundance, through post-translational modification of the IRS scaffold.

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“…As all these signaling pathways are very complex, they occasionally fail, causing a disruption in the normal cellular function and ultimately leads to the establishment of a pathological state in the body. Defects in the signaling pathways are the basis of many diseases and are thus the target for drug therapies (Mora-Garcia and Sakamoto, 1999;Berg et al, 2002a;Halazy, 2003). Nanomedicine presents a novel, safe and effective approach to target these aberrant pathways.…”

Section: Nanomedicine: Targeting Signaling Pathwaysmentioning

confidence: 99%

Nanotechnology to the Rescue: Treatment Perspective for the Immune Dysregulation Observed in COVID-19

Peter

Sandeep

Rao

et al. 2021

Front. Nanotechnol.

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The study of the use of nanotechnology for drug delivery has been extensive. Nanomedical approaches for therapeutics; drug delivery in particular is superior to conventional methods in that it allows for controlled targeted delivery and release, higher stability, extended circulation time, minimal side-effects, and improved pharmacokinetic clearance (of the drug) form the body, to name a few. The magnitude of COVID-19, the current ongoing pandemic has been severe; it has caused widespread the loss of human life. In individuals with severe COVID-19, immune dysregulation and a rampant state of hyperinflammation is observed. This kind of an immunopathological response is detrimental and results in rapid disease progression, development of secondary infections, sepsis and can be fatal. Several studies have pin-pointed the reason for this immune dysregulation; deviations in the signaling pathways involved in the mediation and control of immune responses. In severe COVID-19 patients, many signaling cascades including JAK/STAT, NF-κB, MAPK/ERK, TGF beta, VEGF, and Notch signaling were found to be either upregulated or inactivated. Targeting these aberrant signaling pathways in conjunction with antiviral therapy will effectuate mitigation of the hyperinflammation, hypercytokinemia, and promote faster recovery. The science of the use of nanocarriers as delivery agents to modulate these signaling pathways is not new; it has already been explored for other inflammatory diseases and in particular, cancer therapy. Numerous studies have evaluated the efficacy and potential of nanomedical approaches to modulate these signaling pathways and have been met with positive results. A treatment regime, that includes nanotherapeutics and antiviral therapies will prove effective and holds great promise for the successful treatment of COVID-19. In this article, we review different nanomedical approaches already studied for targeting aberrant signaling pathways, the host immune response to SARS-CoV-2, immunopathology and the dysregulated signaling pathways observed in severe COVID-19 and the current treatment methods in use for targeting signaling cascades in COVID-19. We then conclude by suggesting that the use of nanomedical drug delivery systems for targeting signaling pathways can be extended to effectively target the aberrant signaling pathways in COVID-19 for best treatment results.

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Cell Signaling Defects and Human Disease

Cited by 4 publications

References 206 publications

Polymorphism of Cytokine Genes (TGF-??1, IFN-??, IL-6, IL-10, and TNF-??) in Patients With Chronic Pancreatitis

Polymorphism of Cytokine Genes (TGF-??1, IFN-??, IL-6, IL-10, and TNF-??) in Patients With Chronic Pancreatitis

Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis

Nanotechnology to the Rescue: Treatment Perspective for the Immune Dysregulation Observed in COVID-19

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