Vascular dementia (VaD), the second most prevalent type of dementia, lacks a well-defined cause and effective treatment. Our objective was to utilize bioinformatics analysis to discover the ...fundamental disease-causing genes and pathological mechanisms in individuals diagnosed with VaD.
To identify potential pathogenic genes associated with VaD, we conducted weighted gene co-expression network analysis (WGCNA), differential expression analysis, and protein–protein interaction (PPI) analysis. The exploration of potential biological mechanisms involved the utilization of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Moreover, a bilateral common carotid artery stenosis (BCAS) mouse model of VaD was established, and the expression of the hub gene, its relationship with cognitive function and its potential pathogenic mechanism were verified by cognitive behavior tests, cerebral blood flow measurement, Western blotting, and immunofluorescence experiments.
This study identified 293 DEGs from the brain cortex of VaD patients and healthy controls, among these genes, the Toll-like receptor 2 (TLR2) gene was identified as hub gene, and it was associated with the apoptosis-related pathway PI3K/AKT.The BCAS model demonstrated that the use of TLR2 inhibitors greatly enhanced the cognitive function of the mice (p < 0.05). Additionally, there was a notable decrease in the number of apoptotic cells in the brain cortex of the mice (p < 0.01). Moreover, significant alterations in the levels of proteins related to the PI3K/AKT pathway and cleaved-caspase3 proteins were detected (p < 0.05).
TLR2 plays a role in the pathophysiology of VaD by enhancing the neuronal apoptotic pathway, suggesting it could be a promising therapeutic target.
•Identified Toll-like receptor 2 (TLR2) as a hub gene in VaD pathology•TLR2 inhibition improved cognitive function in a VaD mouse model.•Decreased apoptotic cells in mouse brain cortex with TLR2 inhibition•TLR2's association with apoptosis via the PI3K/AKT pathway.
Rehmannioside A is derived from Rehmannia glutinosa Libosch, which is widely used as an important ingredient in diverse traditional Chinese medicines to treat diseases caused by “kidney deficiency” ...such as cerebral arteriosclerosis, aging-related stroke and dementia in China. Recent studies have proved that Rehmannia glutinosa Libosch and Rehmannioside A can improve memory capability and recover nerve damage.
To investigate the effect of Rehmannioside A on cognitive impairment after ischemia in rats and SH-SY5Y cells, and further evaluate the anti-oxidative and anti-ferroptosis mechanisms.
Differentially expressed proteins (DEPs) in patients after cerebral ischemic stroke were revealed by a RayBio protein array. Cognitive impairment model was established by middle cerebral artery occlusion and reperfusion (MCAO) 14 days in rats. Rehmannioside A was administered intraperitoneally injection at dose of 80 mg/kg. The SH-SY5Y cells were exposed to H2O2 for 24 h and treated with Rehmannioside A (80 μM) for 24 h. The neuroprotecion of Rehmannioside A were evaluated by infarct volume (TTC), neurological defects (Garcia score) and learning memory (Morris water maze test) in vivo, and cell viability (CCK-8 or LDH) in vitro. Superoxide dismutase (SOD), malondialdehyde (MDA) and myeloperoxidase (MPO) activity of rats, glutathione (GSH), oxidized glutathione (GSSG) and nicotinamide adenine dinucleotide phosphate (NADPH) of cells were detected by biochemical assay. Intracellular reactive oxygen species (ROS) were measured by DCFH-DA assay. Myeloperoxidase (MPO), PI3 kinase (PI3K), p-PI3K, Akt, p-Akt, heme oxygenase-1 (HO-1), nuclear factor-E2-related factor 2 (Nrf2), SLC7A11, glutathione peroxidase 4 (GPX4) of the cerebral cortex in rats or SH-SY5Y cells were examined by western blotting.
Compared with model group, the cognitive impairment and neurological deficits of Rehmannioside A group were significantly improved, and the cerebral infarction was reduced in MCAO rats. Moreover, the cell viability obviously increased and the H2O2-induced toxicity was reduced in Rehmannioside A group. Further research indicated that the expression of p-PI3K, p-Akt, nuclear Nrf2, HO-1 and SLC7A11 in Rehmannioside A group was significantly higher than model group.
Rehmannioside A has neuroprotection effect and improves cognitive impairment after cerebral ischemia by inhibiting ferroptosis and activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway. These findings provide valuable insight into the pathogenesis and therapeutic target of ischemic stroke.
Display omitted
PIK3CA mutations may have prognostic value for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer, representing an important potential ...target for systemic therapy. Prognostic and predictive values associated with PIK3CA mutations are not well understood.
A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and conference abstracts was performed for English-language articles published January 1993 through April 2019. Articles were categorized by treatment arms based on experimental and treatment drug classes. Information on progression-free survival (PFS), hazard ratios, overall survival, response rate, and clinical benefit rate was obtained. A total of 17 studies were included. Among those evaluating non-PI3Ki based therapies, 91% showed numerically shorter median PFS, ranging from 1.5 to 19.2 months and 1.8 to 29.6 months for the mutant versus non-mutant subgroups, respectively. Where reported (n = 13 studies), PFS was shorter between those arms offering endocrine monotherapy (range, 1.6-14.7 months) compared with a corresponding targeted therapy + endocrine monotherapy (range, 3.9-29.6 months). Of 5 PI3Ki-based arms comparing PFS, higher median PFS in PIK3CA mutant versus non-mutant cases was demonstrated. PFS was shorter for patients with PIK3CA mutant (range, 1.6-19.2 months) compared with PIK3CA wild-type (range, 1.8-29.6 months) in 10 (71%) of 14 treatment arms reporting PFS. Studies (n = 4) not reporting PFS reported response rate, but there were no clear directional trends.
The presence of PIK3CA mutations may be associated with worse clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Clinical outcomes such as PFS may be improved using a combination of PI3Ki-based therapies and endocrine therapies among this population. However, more research is warranted to fully elucidate this association.
•Repeated radon exposure reduced the cell adhesion, promoted the cell proliferation and invasion in 16HBE and BEAS-2B cells.•Repeated radon exposure induced epithelial–mesenchymal transition (EMT) in ...epithelial cells and mice.•Repeated radon exposure induced lung damage and pulmonary fibrosis in mice.•The lung injury and EMT induced by radon involved the PI3K/AKT/mTOR signaling pathway.
Radon exposure is the most frequent cause of lung cancer in non-smokers. The high linear energy transfer alpha-particles from radon decay cause the accumulation of multiple genetic changes and lead to cancer development. Epithelial–mesenchymal transition (EMT) plays an important role in oncogenesis. However, the mechanisms underlying chronic radon exposure-induced EMT attributed to carcinogenesis are not understood. This study aimed to explore the EMT and potential molecular mechanisms induced by repeated radon exposure. The EMT model of 16HBE and BEAS-2B cells was established with radon exposure (20000 Bq/m3, 20 min each time every 3 days). We found repeated radon exposure facilitated epithelial cell migration, proliferation, reduced cell adhesion and ability to undergo EMT through a decrease in epithelial markers and an increase in mesenchymal markers. Radon regulated the expression of matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 2 (TIMP2) to disrupt the balance of MMP2/TIMP2. In vivo, BALB/c mice were exposed to 105 Bq/m3 radon gas for cumulative doses of 60 and 120 Working Level Months (WLM). Radon inhalation caused lung damage and fibrosis in mice, which was aggravated with the increase of exposure dose. EMT-like transformation also occurred in lung tissues of radon-exposure mice. Moreover, radon radiation increased p-PI3K, p-AKT and p-mTOR in cells and mice. Radon reduced the GSK-3β level and elevated the active β-catenin in 16HBE cells. The m-TOR and AKT inhibitors attenuated radon exposure-induced EMT by regulation related biomarkers. These data demonstrated that radon exposure induced EMT through the PI3K/AKT/mTOR pathway in epithelial cells and lung tissue.
Hepatic fibrosis (HF) is a common disease, with currently no available treatment. Galangin, a natural flavonoid extracted from Alpinia officinaruim Hance, has multiple effects demonstrated in ...previous studies. The aim of the present study was to explore the anti-fibrogenic effect of galangin in vitro, and research its potential molecular mechanisms. LX-2 cells were chosen as an in vitro HF model, and were treated with galangin in different concentrations. Cell viability was analyzed using Cell Counting Kit-8 (CCK-8) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis was measured using flow cytometry, and the anti-fibrogenic effect of galangin was determined using RT-quantitative (q) PCR, immunofluorescence, and Western blotting. The results show that the proliferation of LX-2 cells was efficiently inhibited by galangin, and apoptosis was induced in a dose-dependent manner. Both the mRNA and protein expression of alpha-smooth muscle actin (α-SMA) and collagen I were markedly downregulated. Galangin also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt and Wnt/β-catenin signaling pathways and increased the Bax/Bcl-2 ratio. The results of this study suggest that galangin has an anti-fibrogenic effect and may represent a promising agent in the treatment of hepatic fibrosis.
Phosphoinositide-3-kinases (PI3Ks) are central to several cellular signaling pathways in human physiology and are potential pharmacological targets for many pathologies including cancer, thrombosis, ...and pulmonary diseases. Tremendous efforts to develop isoform-selective inhibitors have culminated in the approval of several drugs, validating PI3K as a tractable and therapeutically relevant target. Although successful therapeutic validation has focused on isoform-selective class I orthosteric inhibitors, recent clinical findings have indicated challenges regarding poor drug tolerance owing to sustained on-target inhibition. Hence, additional approaches are warranted to increase the clinical benefits of specific clinical treatment options, which may involve the employment of so far underexploited targeting modalities or the development of inhibitors for currently underexplored PI3K class II isoforms. We review recent key discoveries in the development of isoform-selective inhibitors, focusing particularly on PI3K class II isoforms, and highlight the emerging importance of developing a broader arsenal of pharmacological tools.
Increasing attentions have been paid to the role of circRNAs in the etiology of triple-negative breast cancer (TNBC), and we strived to figure out the association of circRNA AKT3/miRNA axis with TNBC ...chemo-resistance. Altogether 207 BC patients were divided into TNBC group (n=83) and non-TNBC group (n=124), and MCF-10A, MDA-MB-231, MDA-MB-468, SK-BR-3 and MCF-7 cell lines were prepared in advance. Expressions of AKT3-derived circRNAs and relevant miRNAs in the TNBC tissues and cell lines were determined by employing real-time polymerase chain reaction (PCR). It was indicated that hsa_circ_0000199 expression was higher in TNBC tissues than in non-TNBC tissues, and high hsa_circ_0000199 expression was predictive of large tumor size, advanced TNM grade, high Ki-67 level and poor 3-year survival of TNBC patients (all
<0.05). Furthermore, miR-613 and miR-206 were sponged and negatively regulated by hsa_circ_0000199 (
<0.001), and PI3K/Akt/mTOR signaling was depressed by si-hsa_circ_0000199 in TNBC cell lines (
<0.01). Ultimately, miR-206/miR-613 inhibitor reversed impacts of si-hsa_circ_0000199 on PI3K/Akt/mTOR signaling, proliferation, migration, invasion, chemo-sensitivity and autophagy of TNBC cells (all
<0.01). Conclusively, silencing of hsa_circ_0000199 enhanced TNBC chemo-sensitivity by promoting miR-206/miR-613 expression and deactivating PI3K/Akt/mTOR signaling, which was conducive to improving chemotherapeutic efficacy of TNBC patients.
The class I phosphoinositide 3-kinases (PI3Ks) are key signaling enzymes composed of a heterodimer of a p110 catalytic subunit and a p85 regulatory subunit, with PI3K mutations being causative of ...multiple human diseases including cancer, primary immunodeficiencies, and developmental disorders. Mutations in the p85α regulatory subunit encoded by PIK3R1 can both activate PI3K through oncogenic truncations in the iSH2 domain, or inhibit PI3K through developmental disorder mutations in the cSH2 domain. Using a combined biochemical and hydrogen deuterium exchange mass spectrometry approach we have defined the molecular basis for how these mutations alter the activity of p110α/p110δ catalytic subunits. We find that the oncogenic Q572∗ truncation of PIK3R1 disrupts all p85-inhibitory inputs, with p110α being hyper-activated compared with p110δ. In addition, we find that the R649W mutation in the cSH2 of PIK3R1 decreases sensitivity to activation by receptor tyrosine kinases. This work reveals unique insight into isoform-specific regulation of p110s by p85α.
Display omitted
•Oncogenic Q572∗ variant of p85α leads to hyper-activation of p110α compared with p110δ•HDX-MS revealed that Q572∗ leads to disruption of all inhibitory interfaces in p110α•An SHORT syndrome mutation in p85α leads to decreased sensitivity to RTKs for p110α/δ
Dornan et al. use HDX-MS and activity assays to describe the molecular mechanisms of activating and loss-of-function mutations in the regulatory subunit p85α of the class IA PI3K complexes. These data further expand our understanding of how PI3Ks are inhibited and activated downstream of phosphorylated receptors, and how clinical mutations lead to PI3K misregulation leading to cancer and developmental disorders.
Cerebral cavernous malformations (CCMs) are low-flow, hemorrhagic vascular lesions of the central nervous system of genetic origin, which can cause stroke-like symptoms and seizures. From the ...identification of CCM1, CCM2 and CCM3 as genes related to disease progression, molecular and cellular mechanisms for CCM pathogenesis have been established and the search for potential drugs to target CCM has begun. Broadly speaking, kinases are the major group signaling in CCM pathogenesis. These include the MEKK3/MEK5/ERK5 cascade, Rho/Rock signaling, CCM3/GCKIII signaling, PI3K/mTOR signaling, and others. Since the discovery of Rho/Rock in CCM pathogenesis, inhibitors for Rho signaling and subsequently other components in CCM signaling were discovered and applied in preclinical and clinical trials to ameliorate CCM progression. This review discusses the general aspects of CCM disease, kinase-mediated signaling in CCM pathogenesis and the current state of potential treatment options for CCM. It is suggested that kinase target drug development in the context of CCM might facilitate and meet the unmet requirement – a non-surgical option for CCM disease.
Various studies demonstrated that bone morphogenetic proteins (BMPs) and their antagonists contribute to the development of cancers. Chordin‐like 2 (CHRDL2) is a member of BMP antagonists. However, ...the role and its relative mechanism of CHRDL2 in osteosarcoma remains unclear. In the present study, we demonstrated that the expression of CHRDL2 was significantly upregulated in osteosarcoma tissues and cell lines compared with adjacent tissues and human normal osteoblast. Inhibition of CHRDL2 decreased the proliferation and colony formation of osteosarcoma cells in vitro, as well as the migration and invasion. CHRDL2 overexpression induced the opposite effects. CHRDL2 can bind with BMP‐9, thus decreasing BMP‐9 expression and the combination to its receptor protein kinase ALK1. It was predicted that BMP‐9 regulates PI3K/AKT pathways using gene set enrichment analysis. Inhibition of CHRDL2 decreased the activation of PI3K/AKT pathway, while overexpression of CHRDL2 upregulated the activation. Increasing the expression of BMP‐9 reversed the effects of CHRDL2 overexpression on the activation of PI3K/AKT pathway, as well as the proliferation and metastasis of osteosarcoma cells. Take together, our present study revealed that CHRDL2 upregulated in osteosarcoma tissues and cell lines, and promoted osteosarcoma cell proliferation and metastasis through the BMP‐9/PI3K/AKT pathway. CHRDL2 maybe an oncogene in osteosarcoma, as well as novel biomarker for the diagnosis of osteosarcoma.
PDF
