Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis.

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis.

Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells.

Auranofin (AF), a gold (I)-containing phosphine compound, is being investigated for oncological application as a repurposed drug. We show here that 4~5 µM AF induces paraptosis, a non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells. Although the covalent inhibition of thioredoxin reductase (TrxR), an enzyme that critically controls intracellular redox homeostasis, is considered the primary mechanism of AF's anticancer activity, knockdown of TrxR1 did not induce paraptosis.

PSMD14 Targeting Triggers Paraptosis in Breast Cancer Cells by Inducing Proteasome Inhibition and Ca Imbalance.

PSMD14, a subunit of the 19S regulatory particles of the 26S proteasome, was recently identified as a potential prognostic marker and therapeutic target in diverse human cancers. Here, we show that the silencing and pharmacological blockade of PSMD14 in MDA-MB 435S breast cancer cells induce paraptosis, a non-apoptotic cell death mode characterized by extensive vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. The PSMD14 inhibitor, capzimin (CZM), inhibits proteasome activity but differs from the 20S proteasome subunit-inhibiting bortezomib (Bz) in that it does not induce aggresome formation or Nrf1 upregulation, which underlie Bz resistance in cancer cells.

ISRIB plus bortezomib triggers paraptosis in breast cancer cells via enhanced translation and subsequent proteotoxic stress.

Despite the success of proteasome inhibitors (PIs) in treating hematopoietic malignancies, including multiple myeloma (MM), their clinical efficacy is limited in solid tumors. In this study, we investigated the involvement of the integrated stress response (ISR), a central cellular adaptive program that responds to proteostatic defects by tuning protein synthesis rates, in determining the fates of cells treated with PI, bortezomib (Bz). We found that Bz induces ISR, and this can be reversed by ISRIB, a small molecule that restores eIF2B-mediated translation during ISR, in both Bz-sensitive MM cells and Bz-insensitive breast cancer cells.

Tacky-Free Polyurethanes Pressure-Sensitive Adhesives by Molecular-Weight and HDI Trimer Design.

Polyurethane pressure-sensitive adhesives (PU-PSAs) with satisfactory tack, cohesion, and removability were newly developed through the synthetic process by reacting methylene diisocyanate, poly(ethylene glycol) (PEG), and a 1,4-butanediol chain extender based on the different HDI/HDI trimer ratios. The sticking properties of PU-PSAs depended on both the HDI/HDI trimer ratio and crosslinking-agent composition in the formulation. The molecular weight (MW) dependence of adhesion in PU-PSA was observed in the range of 1000 < Mn < 3000, suggesting that the increase in MW limits the pressure-sensitive adhesion of these samples.

A Segmentation of Melanocytic Skin Lesions in Dermoscopic and Standard Images Using a Hybrid Two-Stage Approach.

The segmentation of a skin lesion is regarded as very challenging because of the low contrast between the lesion and the surrounding skin, the existence of various artifacts, and different imaging acquisition conditions. The purpose of this study is to segment melanocytic skin lesions in dermoscopic and standard images by using a hybrid model combining a new hierarchical -means and level set approach, called HK-LS. Although the level set method is usually sensitive to initial estimation, it is widely used in biomedical image segmentation because it can segment more complex images and does not require a large number of manually labelled images.

Intracellular Ca Imbalance Critically Contributes to Paraptosis.

Paraptosis is a type of programmed cell death that is characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria. Since paraptosis is morphologically and biochemically different from apoptosis, understanding its regulatory mechanisms may provide a novel therapeutic strategy in malignant cancer cells that have proven resistant to conventional pro-apoptotic treatments. Relatively little is known about the molecular basis of paraptosis, but perturbations of cellular proteostasis and ion homeostasis appear to critically contribute to the process.

Screening of Drug-Induced Steatosis and Phospholipidosis Using Lipid Droplet-Selective Two-Photon Probes.

Lipid droplets (LDs) are organelles that play a major role in regulating the storage of neutral lipids. Dysregulation of LDs is associated with metabolic disorders, such as fatty liver diseases, obesity, diabetes, and atherosclerosis. We have developed LD-selective small-molecule fluorescence probes (probes and ) that are available for both one- and two-photon microscopy, employing live or fixed cells.

Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial Ca Overload.

The proteasome inhibitor (PI), bortezomib (Btz), is effective in treating multiple myeloma and mantle cell lymphoma, but not solid tumors. In this study, we show for the first time that lercanidipine (Ler), an antihypertensive drug, enhances the cytotoxicity of various PIs, including Btz, carfilzomib, and ixazomib, in many solid tumor cell lines by inducing paraptosis, which is accompanied by severe vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. We found that Ler potentiates Btz-mediated ER stress and ER dilation, possibly due to misfolded protein accumulation, in MDA-MB 435S cells.

Growth Kinetics of Individual Co Particles Ex-solved on SrTiCoO Polycrystalline Perovskite Thin Films.

A precise control of the size, density, and distribution of metal nanoparticles dispersed on functional oxide supports is critical for promoting catalytic activity and stability in renewable energy and catalysis devices. Here, we measure the growth kinetics of individual Co particles ex-solved on SrTiCoO polycrystalline thin films under a high vacuum, and at various temperatures and grain sizes using in situ transmission electron microscopy. The ex-solution preferentially occurs at grain boundaries and corners which appear essential for controlling particle density and distribution, and enabling low temperature ex-solution.

Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis.

Gambogic acid (GA), a xanthonoid extracted from the resin of the tree, Garcinia hanburyi, was recently shown to exert anticancer activity in multiple studies, but the underlying action mechanism remains unclear. Here, we show that GA induces cancer cell death accompanied by vacuolation in vitro and in vivo. This GA-induced vacuolation in various cancer cells was derived from dilation of the endoplasmic reticulum (ER) and mitochondria, and was blocked by cycloheximide.

Loperamide overcomes the resistance of colon cancer cells to bortezomib by inducing CHOP-mediated paraptosis-like cell death.

Although the proteasome inhibitor (PI) bortezomib (Btz) is in current clinical use as a front-line treatment for multiple myeloma, its clinical efficacy in solid tumors has not been satisfactory. Here, we show that loperamide (Lop), an antidiarrheal drug, effectively sensitizes various colon cancer cells, but not normal epithelial cells, to PI-mediated cell death. We report that combined treatment with Btz and Lop induces paraptosis-like cell death accompanied by severe endoplasmic reticulum (ER)-derived vacuolation.

Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis.

Ophiobolin A (OP-A), a fungal sesterterpene from , was recently shown to have anti-glioma activity. We show here that OP-A induces paraptosis-like cell death accompanied by dilation of the endoplasmic reticulum (ER) in glioma cells, and that CHOP-mediated ER stress plays a critical role in this process. OP-A-induced ER-derived dilation and cell death were found to be independent of reactive oxygen species, but were effectively blocked by various thiol antioxidants.

Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis.

The proteasome inhibitor, bortezomib, is ineffective against many solid tumors. Nutlin-3 is a potent antagonist of human homolog of murine double minute 2/p53 interaction exhibiting promising therapeutic anti-cancer activity. In this study, we show that treatment of various p53-defective bortezomib-resistant solid tumor cells with bortezomib plus nutlin-3 induces paraptosis, which is a cell death mode accompanied by dilation of the endoplasmic reticulum (ER) and mitochondria.

Robot-assisted gait training improves brachial-ankle pulse wave velocity and peak aerobic capacity in subacute stroke patients with totally dependent ambulation: Randomized controlled trial.

Objective: Brachial-ankle pulse wave velocity (baPWV) evaluates arterial stiffness and also predicts early outcome in stroke patients. The objectives of this study were to investigate arterial stiffness of subacute nonfunctional ambulatory stroke patients and to compare the effects of robot-assisted gait therapy (RAGT) combined with rehabilitation therapy (RT) on arterial stiffness and functional recovery with those of RT alone.

Method: The RAGT group (N = 30) received 30 minutes of robot-assisted gait therapy and 30 minutes of conventional RT, and the control group (N = 26) received 60 minutes of RT, 5 times a week for 4 weeks.

A case of reversible very low voltage electrocardiogram in fulminant myocarditis.

Clinical features of acute myocarditis range from a subclinical state to a fulminant state. Fulminant myocarditis with ventricular arrhythmia or atrioventricular block is associated with a high mortality rate. In cases in which aggressive medical therapy for fulminant myocarditis is not likely to be successful, intensive and emergency mechanical circulatory support, such as extracorporeal membrane oxygenation (ECMO) or intra-aortic balloon pump, should be considered.

[A case of pneumatosis intestinalis associated with sunitinib treatment for renal cell carcinoma].

Sunitinib as a multitarget tyrosine kinase inhibitor is one of the anti-tumor agents, approved by the United States Food and Drug Administration to use treat gastrointestinal stromal tumor and metastatic renal cell carcinoma. The agent is known to commonly induce adverse reactions such as fatigue, nausea, diarrhea, stomatitis, esophagitis, hypertension, skin toxicity, reduciton in cardiac output of left ventricle, and hypothyroidism. However, it has been reported to rarely induce adverse reactions such as nephrotic syndrome and irreversible reduction in renal functions, and cases of intestinal perforation or pneumatosis interstinalis as such reactions have been consistently reported.

Curcumin inhibits CD4(+) T cell activation, but augments CD69 expression and TGF-β1-mediated generation of regulatory T cells at late phase.

Background: Curcumin is a promising candidate for a natural medicinal agent to treat chronic inflammatory diseases. Although CD4(+) T cells have been implicated in the pathogenesis of chronic inflammation, whether curcumin directly regulates CD4(+) T cells has not been definitively established. Here, we showed curcumin-mediated regulation of CD2/CD3/CD28-initiated CD4(+) T cell activation in vitro.

Mxi1 influences cyst formation in three-dimensional cell culture.

Cyst formation is a major characteristic of ADPKD and is caused by the abnormal proliferation of epithelial cells. Renal cyst formation disrupts renal function and induces diverse complications. The mechanism of cyst formation is unclear.

GATA-binding protein 1 is a novel transcription regulator of peroxiredoxin 5 in human breast cancer cells.

Peroxiredoxin 5 (Prx5) is a member of a family consisting of six antioxidant enzymes. Prx5 is ubiquitously expressed in various tissues including mitochondria and peroxisomes, implying that Prx5 functions as a regulator of the cellular oxidation state. Prx5 plays a critical role in protecting cells from oxidative stress by inhibiting the accumulation of reactive oxygen species and cell death.

Interactions of dendritic cells with cancer cells and modulation of surface molecules affect functional properties of CD8+ T cells.

To understand the interaction of dendritic cells (DCs) with cancer cells, we investigated molecular changes in DCs following co-culture with cancer cells. DCs co-cultured with Jurkat cancer cells showed remarkable down-regulation of MHC class I molecules, while DCs co-cultured with MCF-7 cancer cells showed minimal changes. Interestingly, down-regulation of MHC class I on DCs was not observed upon treatment with Jurkat cell lysate or culture supernatant, suggesting the importance of direct cell-cell interactions.

Effects of specific genes activating RAGE on polycystic kidney disease.

Background: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation and secretion of fluid and is associated with interstitial inflammation and fibrosis, resulting in the loss of renal function. We previously generated mice overexpressing PKD2, causing progressive cyst development with an inflammatory and fibrotic phenotype in the kidneys.

Methods: To profile the gene expression related to inflammation and cystogenesis, microarray analysis was performed with kidney tissue from 6-, 12- and 18-month-old mice.

Up-regulation of Idh3alpha causes reduction of neuronal differentiation in PC12 cells.

The PC12 is the widely used cell line to study neuronal differentiation. We had extensively investigated the details of protein expression in differentiated PC12 cells by proteomic analysis. The cells were incubated at the presence of nerve growth factor.

Proteomic analysis of time-dependent difference of protein expression profile changes during neuronal differentiation of mouse embryonic stem cells.

The study of ES cell-mediated neuronal differentiation allows elucidating the mechanism of neuronal development in spite of the complexity and the difficult accessibility. During the differentiation of embryonic stem cells into neuronal cell, the expression profiles in the level of protein were extensively investigated by proteomic analysis. These cells were analyzed for charges in proteome during the differentiation of ES cells by 2-dimensional electrophoresis (2-DE) and MALDI-TOF MS.

Alpha-eleostearic acid induces autophagy-dependent cell death through targeting AKT/mTOR and ERK1/2 signal together with the generation of reactive oxygen species.

Alpha-eleostearic acid (alpha-ESA, 9Z11E13E-18:3), a linolenic acid isomer with a conjugated triene system, is a natural and biologically-active compound that has been shown to possess potent anti-tumor properties. Herein, we demonstrate alpha-ESA induced apoptosis and autophagy with reactive oxygen species (ROS) generation in HeLa cells. Treatment with alpha-ESA caused inhibition of phosphorylated (p)AKT and elongated the sub G1 phase in the cell cycle, indicating induction of apoptosis.