Poly Adenylate Binding Protein Interacting protein 1 (PAIP1) plays a critical role in translation initiation and is associated with the several cancer types. However, its function and clinical significance have not yet been described in oral squamous cell carcinoma (OSCC) and its associated features like lymph node metastasis (LNM). Here, we used the data available from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) to analyze PAIP1 expression in oral cancer. The publicly available data suggests that PAIP1 mRNA and protein levels were increased in OSCC. The high PAIP1 expression was more evident in samples with advanced stage, LNM, and worse pattern of invasion. Moreover, the in vitro experiments revealed that PAIP1 knockdown attenuated colony forming, the aggressiveness of OSCC cell lines, decreasing MMP9 activity and SRC phosphorylation. Importantly, we found a correlation between PAIP1 and pSRC through the analysis of the IHC scores and CPTAC data in patient samples. Our findings suggest that PAIP1 could be an independent prognostic factor in OSCC with LNM and a suitable therapeutic target to improve OSCC patient outcomes.
Carcinoma, Squamous Cell/genetics* ; Head and Neck Neoplasms ; Humans ; Lymphatic Metastasis ; Mouth Neoplasms/pathology* ; Peptide Initiation Factors/metabolism* ; Prognosis ; Proteomics ; RNA-Binding Proteins/metabolism* ; Squamous Cell Carcinoma of Head and Neck

Sarcopenia (loss of muscle mass and/or strength) frequently complicates liver cirrhosis and adversely affects the quality of life; cirrhosis related liver decompensation and significantly decreases wait-list and post-liver transplantation survival. The main therapeutic strategies to improve or reverse sarcopenia include dietary interventions (supplemental calorie and protein intake), increased physical activity (supervised resistance and endurance exercises), hormonal therapy (testosterone), and ammonia lowering agents (L-ornithine L-aspartate, branch chain amino acids) as well as mechanistic approaches that target underlying molecular and metabolic abnormalities. Besides other factors, hyperammonemia has recently gained attention and increase sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Sarcopenia contributes to frailty and increases the risk of minimal and overt hepatic encephalopathy.
Ammonia ; Aspartic Acid ; Fibrosis ; Hepatic Encephalopathy ; Hyperammonemia ; Liver ; Liver Cirrhosis ; Metabolism ; Motor Activity ; Myostatin ; Peptide Initiation Factors ; Phosphorylation ; Proteolysis ; Quality of Life ; Reactive Oxygen Species ; Sarcopenia ; Testosterone

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor (P-elF2α) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.
2-Aminopurine ; Animals ; Cardiomyopathies ; Chagas Disease ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress ; Heart ; Humans ; Lipid Droplets ; Lipid Metabolism ; Mice ; Mortality ; Pathology ; Peptide Initiation Factors ; Trypanosoma cruzi ; Ultrasonography

BACKGROUND: Development of chemotherapeutics for the treatment of advanced hepatocellular carcinoma (HCC) has been lagging. Screening of candidate therapeutic agents by using patient-derived preclinical models may facilitate drug discovery for HCC patients. METHODS: Four primary cultured HCC cells from surgically resected tumor tissues and six HCC cell lines were used for high-throughput screening of 252 drugs from the Prestwick Chemical Library. The efficacy and mechanisms of action of the candidate anti-cancer drug were analyzed via cell viability, cell cycle assays, and western blotting. RESULTS: Guanabenz acetate, which has been used as an antihypertensive drug, was screened as a candidate anti-cancer agent for HCC through a drug sensitivity assay by using the primary cultured HCC cells and HCC cell lines. Guanabenz acetate reduced HCC cell viability through apoptosis and autophagy. This occurred via inhibition of growth arrest and DNA damage-inducible protein 34, increased phosphorylation of eukaryotic initiation factor 2α, increased activating transcription factor 4, and cell cycle arrest. CONCLUSIONS: Guanabenz acetate induces endoplasmic reticulum stress–related cell death in HCC and may be repositioned as an anti-cancer therapeutic agent for HCC patients.
Activating Transcription Factor 4 ; Apoptosis ; Autophagy ; Blotting, Western ; Carcinoma, Hepatocellular ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Death ; Cell Line ; Cell Survival ; DNA ; Drug Discovery ; Drug Repositioning ; Endoplasmic Reticulum ; Guanabenz ; Humans ; Mass Screening ; Peptide Initiation Factors ; Phosphorylation ; Primary Cell Culture

BACKGROUND: The nuclear receptor peroxisome proliferator-activator gamma (PPARγ) is a useful therapeutic target for obesity and diabetes, but its role in protecting β-cell function and viability is unclear. METHODS: To identify the potential functions of PPARγ in β-cells, we treated mouse insulinoma 6 (MIN6) cells with the PPARγ agonist pioglitazone in conditions of lipotoxicity, endoplasmic reticulum (ER) stress, and inflammation. RESULTS: Palmitate-treated cells incubated with pioglitazone exhibited significant improvements in glucose-stimulated insulin secretion and the repression of apoptosis, as shown by decreased caspase-3 cleavage and poly (adenosine diphosphate [ADP]-ribose) polymerase activity. Pioglitazone also reversed the palmitate-induced expression of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], and IL-1β) and ER stress markers (phosphor-eukaryotic translation initiation factor 2α, glucose-regulated protein 78 [GRP78], cleaved-activating transcription factor 6 [ATF6], and C/EBP homologous protein [CHOP]), and pioglitazone significantly attenuated inflammation and ER stress in lipopolysaccharide- or tunicamycin-treated MIN6 cells. The protective effect of pioglitazone was also tested in pancreatic islets from high-fat-fed KK-Ay mice administered 0.02% (wt/wt) pioglitazone or vehicle for 6 weeks. Pioglitazone remarkably reduced the expression of ATF6α, GRP78, and monocyte chemoattractant protein-1, prevented α-cell infiltration into the pancreatic islets, and upregulated glucose transporter 2 (Glut2) expression in β-cells. Moreover, the preservation of β-cells by pioglitazone was accompanied by a significant reduction of blood glucose levels. CONCLUSION: Altogether, these results support the proposal that PPARγ agonists not only suppress insulin resistance, but also prevent β-cell impairment via protection against ER stress and inflammation. The activation of PPARγ might be a new therapeutic approach for improving β-cell survival and insulin secretion in patients with diabetes mellitus
Animals ; Apoptosis ; Blood Glucose ; Caspase 3 ; Chemokine CCL2 ; Cytokines ; Diabetes Mellitus ; Endoplasmic Reticulum Stress* ; Endoplasmic Reticulum* ; Glucose Transport Proteins, Facilitative ; Humans ; Inflammation* ; Insulin ; Insulin Resistance ; Insulin-Secreting Cells ; Insulinoma ; Interleukin-6 ; Islets of Langerhans ; Mice ; Necrosis ; Obesity ; Peptide Initiation Factors ; Peroxisomes ; Repression, Psychology ; Transcription Factors

Mast cells integrate innate and adaptive immunity and are implicated in pathophysiological conditions, including allergy, asthma, and anaphylaxis. Cross-linking of the high-affinity IgE receptor (FcεRI) initiates diverse signal transduction pathways and induces release of proinflammatory mediators by mast cells. In this study, we demonstrated that hyperactivation of mechanistic target of rapamycin (mTOR) signaling using the mTOR activator MHY1485 suppresses FcεRI-mediated mast cell degranulation and cytokine secretion. MHY1485 treatment increased ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation, which are downstream targets of mTOR complex 1 (mTORC1), but decreased phosphorylation of Akt on mTOR complex 2 (mTORC2) target site serine 473. In addition, this activator decreased β-hexosaminidase, IL-6, and tumor necrosis factor α (TNF-α) release in murine bone marrow-derived mast cells (BMMCs) after FcεRI stimulation. Furthermore, MHY1485-treated BMMCs showed significantly decreased proliferation when cultured with IL-3. These findings suggested hyperactivation of mTORC1 as a therapeutic strategy for mast cell-related diseases.
Adaptive Immunity ; Anaphylaxis ; Asthma ; Cell Degranulation ; Cell Proliferation ; Hypersensitivity ; Immunoglobulin E ; Interleukin-3 ; Interleukin-6 ; Mast Cells* ; Peptide Initiation Factors ; Phosphorylation ; Ribosomal Protein S6 Kinases ; Serine ; Signal Transduction ; Sirolimus ; Tumor Necrosis Factor-alpha

The lipid droplet (LD) is a unique multi-functional organelle that contains a neutral lipid core covered with a phospholipid monolayer membrane. The LDs have been found in almost all organisms from bacteria to humans with similar shape. Several conserved functions of LDs have been revealed by recent studies, including lipid metabolism and trafficking, as well as nucleic acid binding and protection. We summarized these findings and proposed a hypothesis that the LD is a conserved organelle.
Animals ; Bacteria ; metabolism ; ultrastructure ; Biological Evolution ; Cholesterol Esters ; metabolism ; Humans ; Lipid Droplets ; chemistry ; metabolism ; ultrastructure ; Lipid Metabolism ; genetics ; Nucleic Acids ; metabolism ; Peptide Initiation Factors ; chemistry ; metabolism ; Protein Binding ; RNA-Binding Proteins ; chemistry ; metabolism ; Ribosome Subunits ; chemistry ; metabolism ; Triglycerides ; metabolism

Due to advances in omics technologies, numerous genome-wide studies on human samples have been published, and most of the omics data with the associated clinical information are available in public repositories, such as Gene Expression Omnibus and ArrayExpress. While analyzing several public datasets, we observed that errors in gender information occur quite often in public datasets. When we analyzed the gender description and the methylation patterns of gender-specific probes (glucose-6-phosphate dehydrogenase [G6PD], ephrin-B1 [EFNB1], and testis specific protein, Y-linked 2 [TSPY2]) in 5,611 samples produced using Infinium 450K HumanMethylation arrays, we found that 19 samples from 7 datasets were erroneously described. We also analyzed 1,819 samples produced using the Affymetrix U133Plus2 array using several gender-specific genes (X (inactive)-specific transcript [XIST], eukaryotic translation initiation factor 1A, Y-linked [EIF1AY], and DEAD [Asp-Glu-Ala-Asp] box polypeptide 3, Y-linked [DDDX3Y]) and found that 40 samples from 3 datasets were erroneously described. We suggest that the users of public datasets should not expect that the data are error-free and, whenever possible, that they should check the consistency of the data.
Dataset* ; DNA Methylation ; Ephrin-B1 ; Gender Identity ; Gene Expression ; Humans ; Methylation ; Microarray Analysis ; Oxidoreductases ; Peptide Initiation Factors ; Testis

Identifying a target molecule that is crucially involved in pancreatic tumor growth and metastasis is necessary in developing an effective treatment. The study aimed to investigate the role of the eukaryotic translation initiation factor 3a (eIF3a) in the cell proliferation and motility in pancreatic cancer. Our data showed that the expression of eIF3a was upregulated in pancreatic ductal adenocarcinoma as compared with its expression in normal pancreatic tissues. Knockdown of eIF3a by a specific shRNA caused significant decreases in cell proliferation and clonogenic abilities in pancreatic cancer SW1990 and Capan-1 cells. Consistently, the pancreatic cancer cell growth rates were also impaired in xenotransplanted mice. Moreover, wound-healing assay showed that depletion of eIF3a significantly slowed down the wound recovery processes in SW1990 and Capan-1 cells. Transwell migration and invasion assays further showed that cell migration and invasion abilities were significantly inhibited by knockdown of eIF3a in SW1990 and Capan-1 cells. Statistical analysis of eIF3a expression in 140 cases of pancreatic ductal adenocarcinoma samples revealed that eIF3a expression was significantly associated with tumor metastasis and TNM staging. These analyses suggest that eIF3a contributes to cell proliferation and motility in pancreatic ductal adenocarcinoma.
Adenocarcinoma ; Animals ; Cell Movement ; Cell Proliferation* ; Mice ; Neoplasm Metastasis ; Neoplasm Staging ; Pancreatic Ducts ; Pancreatic Neoplasms* ; Peptide Initiation Factors* ; RNA, Small Interfering ; Wounds and Injuries

BACKGROUNDHypertrophic scar is one of the most common complications and often causes the disfigurement or deformity in burn or trauma patients. Therapeutic methods on hypertrophic scar treatment have limitations due to the poor understanding of mechanisms of hypertrophic scar formation. To throw light on the molecular mechanism of hypertrophic scar formation will definitely improve the outcome of the treatment. This study aimed to illustrate the negative role of eukaryotic initiation factor 6 (eIF6) in the process of human hypertrophic scar formation, and provide a possible indicator of hypertrophic scar treatment and a potential target molecule for hypertrophic scar.

METHODSIn the present study, we investigated the protein expression of eIF6 in the human hypertrophic scar of different periods by immunohistochemistry and Western blot analysis.

RESULTSIn the hypertrophic scar tissue, eIF6 expression was significantly decreased and absent in the basal layer of epidermis in the early period, and increased slowly and began to appear in the basal layer of epidermis by the scar formation time.

CONCLUSIONSThis study confirmed that eIF6 expression was significantly related to the development of hypertrophic scar, and the eIF6 may be a target molecule for hypertrophic scar control or could be an indicator of the outcomes for other treatment modalities.

Adult ; Blotting, Western ; Cicatrix, Hypertrophic ; metabolism ; Female ; Gene Expression Regulation ; genetics ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Peptide Initiation Factors ; metabolism ; Pregnancy ; Retrospective Studies ; Young Adult