Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

Liu, Xunxian; Yao, Zemin

doi:10.7555/jbr.31.20160096

Cited by 4 publications

(2 citation statements)

References 24 publications

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“…In the present study, we also detected an increase of AKT and phosphorylation of GSK3α in RGC-5 cells containing c.977C>T mutation. Impairment of AKT/GSK3 signaling pathway in some eye disorders such as glaucoma, diabetic retinopathy, and retinitis pigmentosa have been reported during the past few years [ 26 – 27 ]. The function of AKT is to phosphorylate GSK3, which is a crucial regulator of differentiation, metabolism, and apoptosis [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in PCK2 gene causes primary angle-closure glaucoma

Yang

Sun

et al. 2021

Aging

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Primary angle-closure glaucoma (PACG) is an ophthalmic genetic disease characterized by direct contact between the iris and trabecular meshwork, resulting in an obstructed outflow of aqueous humor from the eye. However, it is unclear as to what role genetics plays in the development of PACG. The present study investigated the disease-causing mutation in a five-generation Chinese PACG family using whole-genome sequencing. A novel heterozygous missense mutation c.977C>T in PCK2 gene was identified in five affected family members, but not in any unaffected and 86 unrelated healthy individuals. This nucleotide substitute is predicted to result in a proline to leucine substitution p.Pro326Leu. Furthermore, the function of this mutation was analyzed through various in vitro assays using the RGC-5 cell line. Our results demonstrate that the p.Pro326Leu mutation induces RGC-5 cell cycle arrest and apoptosis with a decreased BcL-XL. The increasing P53, P27, P21, AKT, and P-GSK3α were also detected in the cells transfected with c.977C>T mutation, suggesting that this mutation within PCK2 gene cause PACG through impairment of AKT/GSK3α signaling pathway.

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Section: Discussionmentioning

confidence: 99%

A novel mutation in PCK2 gene causes primary angle-closure glaucoma

Yang

Sun

et al. 2021

Aging

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“…The PI3K-Akt-GSK-3 pathway was reported to be insensitive in peripheral blood mononuclear cells of AMD patients and in cultured RPE cells (Busch et al, 2017; Liu and Yao, 2017; Zheng et al, 2018). In our previous study, we found that P021 inhibited the tau and Aβ pathologies by increasing BDNF-mediated activation of TrkB-PI3K-Akt-GSK-3β signaling (Kazim and Iqbal, 2016).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of AMD-Like Pathology With a Neurotrophic Compound in Aged Rats and 3xTg-AD Mice

Liu

Wei

Baazaoui

et al. 2019

Front. Aging Neurosci.

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Age-associated macular degeneration (AMD), which leads to loss of vision at its end stage, is one of the most common neurodegenerative diseases among the elderly. However, to date, no effective drug therapy is available for the prevention of AMD. Here, we report the occurrence of AMD pathology and its prevention by chronic treatment with the neurotrophic peptidergic compound P021, in aged rats and 3xTg-AD mice. We found photoreceptor degeneration, lipofuscin granules, vacuoles, and atrophy in retinal pigment epithelium (RPE) as well as Bruch’s membrane (BM) thickening; in aged rats, we even found rosette-like structure formation. Microgliosis and astrogliosis were observed in different retinal layers. In addition, we also found that total tau, phosphorylated tau, Aβ/APP, and VEGF were widely distributed in the sub-retina of aged rats and 3xTg mice. Importantly, chronic treatment with P021 for 3 months in rats and for 18 months in 3xTg mice ameliorated the pathological changes above. These findings indicate the therapeutic potential of P021 for prevention and treatment of AMD and retinal changes associated with aging and Alzheimer’s disease.

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A Phase Ib Study of Single-Agent Idelalisib Followed by Idelalisib in Combination with Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

et al. 2020

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Lessons Learned Although this study of idelalisib in patients with PDAC was limited in size and duration because of early termination, idelalisib exposure resulted in an overall safety profile consistent with studies in hematological malignancies, except that the incidences of diarrhea and colitis were reduced in patients with PDAC. Preclinical studies of the PI3K pathway in PDAC and positive clinical results of PI3K inhibition in other cancers support the continued development of PI3K inhibitors in PDAC. Background Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal solid tumors and is often refractory to treatment. Phosphatidylinositol‐3 kinase (PI3K) δ inhibition influences regulatory immune cell function and improves survival in preclinical PDAC models. Here, idelalisib, an inhibitor of PI3Kδ, was investigated as treatment for metastatic PDAC. Methods This was an open‐label, multicenter, phase Ib, nonrandomized, dose‐escalation study. Study aims were to investigate the maximum tolerated dose, safety, pharmacokinetics/pharmacodynamics, and efficacy of idelalisib alone and in combination with chemotherapeutics—nab‐paclitaxel and modified (m)FOLFOX6. Results Because of early termination, only 16 patients were enrolled in the single‐agent idelalisib arm, 12 of whom received at least one dose of idelalisib. The most common treatment‐emergent adverse events (≥25%) related to idelalisib (n = 12) were increased aspartate aminotransferase, pyrexia, and maculopapular rash. One patient presented with diarrhea; no cases of colitis were reported. One patient discontinued treatment because of pyrexia and maculopapular rash; two patients died because of disease progression. Conclusion This study was terminated because factors contributing to safety concerns in phase III studies of idelalisib for hematological malignancies were not fully understood. In this small sample of patients with metastatic PDAC, exposure to idelalisib resulted in safety findings consistent with previous studies, with reduced diarrhea/colitis.

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Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

Cited by 4 publications

References 24 publications

A novel mutation in PCK2 gene causes primary angle-closure glaucoma

A novel mutation in PCK2 gene causes primary angle-closure glaucoma

Inhibition of AMD-Like Pathology With a Neurotrophic Compound in Aged Rats and 3xTg-AD Mice

A Phase Ib Study of Single-Agent Idelalisib Followed by Idelalisib in Combination with Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

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