Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases

Sala, Valentina; Sala, Angela Della; Ghigo, Alessandra; Hirsch, Emilio

doi:10.15698/cst2021.04.246

Cited by 16 publications

(11 citation statements)

References 117 publications

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“…1 ). Such a biphasic relationship between cardiac health and IIS-PI3K signaling activity reconciles previous opposing studies [ 6 ], [ 6 ], and suggests that partial inhibition of PI3K might be worth considering for the treatment of heart failure and other age-related chronic diseases – albeit at a much lower and safer dosage than that applied in cancer therapy [ 10 ], [ 11 ]. Alternatively, emerging autophagy inducers and caloric restriction mimetics, like spermidine and nicotinamide adenine dinucleotide (NAD + ) precursors [ 8 ], [ 12 ], [ 13 ], [ 14 ], might offer a readily-available, and perhaps safer, strategy for immediate testing in cardiac patients [ 15 ].…”

supporting

confidence: 78%

Cardiac PI3K p110α attenuation delays aging and extends lifespan

Abdellatif¹,

Eisenberg²,

Heberle³

et al. 2022

CST

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Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular metabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend healthspan in humans. We recently demonstrated that reduced PI3K activity in cardiomyocytes delays cardiac growth, causing subnormal contractility and cardiopulmonary functional capacity, as well as increased risk of mortality at young age. In stark contrast, in aged mice, experimental attenuation of PI3K signaling reduced the age-dependent decline in cardiac function and extended maximal lifespan, suggesting a biphasic effect of PI3K on cardiac health and survival. The cardiac anti-aging effects of reduced PI3K activity coincided with enhanced oxidative phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed increased PI3K signaling, as indicated by increased phosphorylation of the serine/threonine-protein kinase AKT. Hence, late-life cardiac-specific targeting of PI3K might have a therapeutic potential in cardiac aging and related diseases.

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supporting

confidence: 78%

Cardiac PI3K p110α attenuation delays aging and extends lifespan

Abdellatif¹,

Eisenberg²,

Heberle³

et al. 2022

CST

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“…The inhibition of PI3Kα/δ/β plays a key role in the inflammatory response to damage and infection (41,42). PI3K/Akt inhibition by compound 8C and PIK-75 has been shown to markedly decrease the production and biological activity of pro-inflammatory cytokines, such as TNF-α and IL-6 in a NF-κB-dependent manner (43,44), which is considered the central mediator of inflammatory process by inducing the expression of various pro-inflammatory genes (45,46). In the present study, it was found that LY294002 treatment inhibited the activation of the PI3K/Akt signal pathway, and decreased the upregulated expression of NF-κB, TNF-α and IL-1β in the spinal cords of rats with BCP.…”

Section: Discussionmentioning

confidence: 99%

LY294002 alleviates bone cancer pain by reducing mitochondrial dysfunction and the inflammatory response

et al. 2023

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Bone cancer pain (BCP) is mainly caused by bone metastasis and markedly impairs the functional capacity and daily functions of patients. Neuroinflammation plays a pivotal role in the pathogenesis and maintenance of chronic pain. Oxidative stress in the mitochondria is a key contributor to neuroinflammation and neuropathic pain. Herein, a rat model of BCP was established which was characterized by bone destruction, pain hypersensitivity and motor disability. In the spinal cord, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling was activated, and the inflammatory response and mitochondrial dysfunction were also observed. The intrathecal injection of LY294002, a selective inhibitor of PI3K/Akt signaling, decreased mechanical pain sensitivity, suppressed spontaneous pain and recovered the motor coordination of rats with BCP. Second, LY294002 treatment blocked spinal inflammation by reducing astrocytic activation and downregulating the expression levels of inflammatory factors, such as NF-κB, IL-1β and TNF-α. Moreover, LY294002 treatment recovered mitochondrial function by activating the manganese superoxide dismutase enzyme, increasing NADH:ubiquinone oxidoreductase subunit B11 expression, and decreasing BAX and dihydroorotate dehydrogenase expression. LY294002 treatment also increased the mitochondrial membrane potential and decreased the mitochondrial reactive oxygen species levels in C6 cells. On the whole, the results of the present study suggest that the inhibition of PI3K/Akt signaling by LY294002 restores mitochondrial function, suppresses spinal inflammation and alleviates BCP.

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“…Exploring more molecular mechanisms involved in the reparative phase of ALI and determining optimal treatments is required to ameliorate EMT and lung fibrogenesis. PI3K represents a crucial signaling pathway during oxidative stress and fibrogenesis [ 14 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Ventilation-Enhanced Epithelial–Mesenchymal Transition through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model

Huang

et al. 2023

IJMS

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Mechanical ventilation (MV) used in patients with acute lung injury (ALI) induces lung inflammation and causes fibroblast proliferation and excessive collagen deposition—a process termed epithelial–mesenchymal transition (EMT). Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating EMT during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, EMT, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase EMT through the PI3K-γ pathway. C57BL/6 mice, either wild-type or PI3K-γ-deficient, were exposed to 6 or 30 mL/kg MV for 5 h after receiving 5 mg/kg AS605240 intraperitoneally 5 days after bleomycin administration. We found that, after bleomycin exposure in wild-type mice, high-tidal-volume MV induced substantial increases in inflammatory cytokine production, oxidative loads, Masson’s trichrome staining level, positive staining of α-smooth muscle actin, PI3K-γ expression, and bronchial epithelial apoptosis (p < 0.05). Decreased respiratory function, antioxidants, and staining of the epithelial marker Zonula occludens-1 were also observed (p < 0.05). MV-augmented bleomycin-induced pulmonary fibrogenesis and epithelial apoptosis were attenuated in PI3K-γ-deficient mice, and we found pharmacological inhibition of PI3K-γ activity through AS605240 (p < 0.05). Our data suggest that MV augmented EMT after bleomycin-induced ALI, partially through the PI3K-γ pathway. Therapy targeting PI3K-γ may ameliorate MV-associated EMT.

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Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases

Cited by 16 publications

References 117 publications

Cardiac PI3K p110α attenuation delays aging and extends lifespan

Cardiac PI3K p110α attenuation delays aging and extends lifespan

LY294002 alleviates bone cancer pain by reducing mitochondrial dysfunction and the inflammatory response

Attenuation of Ventilation-Enhanced Epithelial–Mesenchymal Transition through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model

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