Myc is a nuclear transcription factor that mainly regulates cell growth, cell cycle, metabolism, and survival. Myc family proteins contain c-Myc, n-Myc, and l-Myc. Among them, c-Myc can become a ...promising therapeutic target molecule in cancer. Cancer stem cells (CSCs) are known to be responsible for the therapeutic resistance. In the previous study, we demonstrated that c-Myc mediates drug resistance of colorectal CSCs using a patient-derived primary three-dimensional (3D) organoid culture. In this review, we mainly focus on the roles of c-Myc-related signaling in the regulation of CSCs, chemotherapy resistance, and colorectal cancer organoids. Finally, we introduce the various types of c-Myc inhibitors and propose the possibility of c-Myc as a therapeutic target against colorectal cancer.
Autophagy is an evolutionarily conserved intracellular degradation system that is involved in cell survival and activated in various diseases, including cancer. Beclin 1 is a central scaffold protein ...that assembles components for promoting or inhibiting autophagy. Association of Beclin 1 with its interacting proteins is regulated by the phosphorylation of Beclin 1 by various Ser/Thr kinases, but the Ser/Thr phosphatases that regulate these phosphorylation events remain unknown. Here we identify Ser-90 in Beclin 1 as a regulatory site whose phosphorylation is markedly enhanced in cells treated with okadaic acid, an inhibitor of protein phosphatase 2A (PP2A). Beclin 1 Ser-90 phosphorylation is induced in skeletal muscle tissues isolated from starved mice. The Beclin 1 S90A mutant blocked starvation-induced autophagy. We found association of PP2A B55α with Beclin 1, which dissociate by starvation. We also found that death-associated protein kinase 3 directly phosphorylates Beclin 1 Ser-90. We propose that physiological regulation of Beclin 1 Ser-90 phosphorylation by PP2A and death-associated protein kinase 3 controls autophagy.
Histone deacetylases (HDACs) are transcriptional coregulators. Recently, we demonstrated that HDAC4, one of class IIa family members, promotes reactive oxygen species–dependent vascular smooth muscle ...inflammation and mediates development of hypertension in spontaneously hypertensive rats. Pathogenesis of hypertension is, in part, modulated by vascular structural remodeling via proliferation and migration of vascular smooth muscle cells (SMCs). Thus, we examined whether HDAC4 controls SMC proliferation and migration. In rat mesenteric arterial SMCs, small interfering RNA against HDAC4 inhibited platelet-derived growth factor (PDGF)-BB–induced SMC proliferation as determined by a cell counting and bromodeoxyuridine incorporation assay as well as migration as determined by Boyden chamber assay. Expression and activity of HDAC4 were increased by PDGF-BB. HDAC4 small interfering RNA inhibited phosphorylation of p38 mitogen–activated protein kinase and heat shock protein 27 and expression of cyclin D1 as measured by Western blotting. HDAC4 small interfering RNA also inhibited PDGF-BB–induced reactive oxygen species production as measured fluorometrically using 2′, 7′-dichlorofluorescein diacetate and nicotinamide adenine dinucleotide phosphate oxidase activity as measured by lucigenin assay. A Ca/calmodulin-dependent protein kinase II inhibitor, KN93, inhibited PDGF-BB–induced SMC proliferation and migration as well as phosphorylation of HDAC4. In vivo, a class IIa HDACs inhibitor, MC1568 prevented neointimal hyperplasia in mice carotid ligation model. MC1568 also prevented increased activation of HDAC4 in the neointimal lesions. The present results for the first time demonstrate that HDAC4 controls PDGF-BB–induced SMC proliferation and migration through activation of p38 mitogen–activated protein kinase/heat shock protein 27 signals via reactive oxygen species generation in a Ca/calmodulin-dependent protein kinase-dependent manner, which may lead to the neointimal hyperplasia in vivo.
Death associated protein kinase (DAPK) is a calcium/calmodulin-regulated serine/threonine kinase; its main function is to regulate cell death. DAPK family proteins consist of DAPK1, DAPK2, DAPK3, ...DAPK-related apoptosis-inducing protein kinases (DRAK)-1 and DRAK-2. In this review, we discuss the roles and regulatory mechanisms of DAPK family members and their relevance to diseases. Furthermore, a special focus is given to several reports describing cross-talks between DAPKs and mitogen-activated protein kinases (MAPK) family members in various pathologies. We also discuss small molecule inhibitors of DAPKs and their potential as therapeutic targets against human diseases.
Abstract
Three-dimensional (3D) organoid culture holds great promises in cancer precision medicine. However, Matrigel and stem cell-stimulating supplements are necessary for culturing 3D organoid ...cells. It costs a lot of money and consumes more time and effort compared with 2D cultured cells. Therefore, the establishment of cheaper and Matrigel-free organoid culture that can maintain the characteristics of a part of 3D organoids is demanded. In the previous study, we established a dog bladder cancer (BC) 3D organoid culture system by using their urine samples. Here, we successfully isolated cells named “2.5D organoid” from multiple strains of dog BC 3D organoids using 2.5 organoid media. The cell proliferation speed of 2.5D organoids was faster than parental 3D organoid cells. The expression pattern of stem cell markers was close to 3D organoids. Injection of 2.5D organoid cells into immunodeficient mice formed tumors and showed the histopathological characteristics of urothelial carcinoma similar to the injection of dog BC 3D organoids. The 2.5D organoids had a similar sensitivity profile for anti-cancer drug treatment to their parental 3D organoids. These data suggest that our established 2.5D organoid culture method might become a reasonable and useful tool instead of 3D organoids in dog BC research and therapy.
Non-alcoholic steatohepatitis (NASH) is associated with liver fibrosis and cirrhosis, which eventually leads to hepatocellular carcinoma. Although several animal models were developed to understand ...the mechanisms of NASH pathogenesis and progression, it remains obscure. A 3D organoid culture system can recapitulate organ structures and maintain gene expression profiles of original tissues. We therefore tried to generate liver organoids from different degrees defined as mild (NASH A), moderate (NASH B) and severe (NASH C) of methionine- and choline-deficient diet-induced NASH model mice and analyzed the difference of their architecture, cell components, organoid-forming efficacy, and gene expression profiles. Organoids from each stage of NASH model mice were successfully generated. Interestingly, epithelial-mesenchymal transition was observed in NASH C organoids. Expression of Collagen I and an activated hepatic stellite cell marker, α-sma was upregulated in the liver organoids from NASH B and C mice. The analysis of RNA sequencing revealed that several novel genes were upregulated in all NASH liver organoids. These results suggest that our generated liver organoids from different stages of NASH diseased mice might become a useful tool for in vitro studies of the molecular mechanism of NASH development and also for identifying novel biomarkers for early diagnosis of NASH disease.
Aims/Introduction
Despite the emergence of new drugs with novel mechanisms of action, treatment options for older people and those with chronic kidney disease are still limited.
Materials and Methods
...Using a medical database compiled from Diagnostic Procedure Combination hospitals, we retrospectively analyzed treatment status, glycemic control and kidney function over 3 years after the first oral antidiabetic drugs in Japanese adults with type 2 diabetes who were aged ≥65 years.
Results
Among 5,434 study participants, 3,246 (59.7%) were men, the median age was 72.0 years, the baseline median hemoglobin A1c was 7.1% and the baseline median estimated glomerular filtration rate was 66.6 mL/min/1.73 m2. Treatment was intensified in 40.0% of people during the 3‐year observation period, and the median time to the first treatment intensification was 198 days. Insulin was the most commonly used agent for treatment intensification (36.9%, 802/2,175). Hemoglobin A1c of <7.0% was achieved in 3,571 (65.7%) at 360 ± 90 days. Multivariable logistic regression analysis found that baseline age, hemoglobin A1c and estimated glomerular filtration rate were negatively associated with achieving hemoglobin A1c of <7.0% at 360 ± 90 days.
Conclusions
In older Japanese adults with type 2 diabetes, those with a lower estimated glomerular filtration rate were more likely to achieve hemoglobin A1c of <7.0%. To safely manage blood glucose levels in older adults with chronic kidney disease, physicians should remain vigilant about the risk of iatrogenic hypoglycemia.
In older Japanese adults with type 2 diabetes, those with a lower estimated glomerular filtration rate were more likely to achieve hemoglobin A1c of <7.0%. To safely manage blood glucose levels in older adults with chronic kidney disease, physicians should remain vigilant about the risk of iatrogenic hypoglycemia.
•A soft capacitive tactile sensor using air–water interface that can measure press and pull forces is proposed.•The sensor consists of soft contact part and stiff detection part and, is fabricated ...soft lithography.•The applied force is detected as the change in capacitance of the sensor due to the displacement of the air-water interface.•The experimental results indicated that the sensor could detect the force in both press direction and pull direction.
Display omitted
We propose a soft capacitive tactile sensor using the displacement of an air–water interface. This soft tactile sensor is composed of a soft contact part with a chamber and channel filled with water and a clip-shaped sensing part to detect the position of the interface. This tactile sensor changes the displacement of the air–water interface in the channel when a contact force is applied. The change in displacement is detected as a change in the capacitance at the sensing part. This sensor structure does not require stiff electrical elements to be embedded in the soft silicone rubber body, which improves the flexibility and durability of the sensor. Therefore, the proposed tactile sensor exhibits high flexibility and durability against bending and external stresses. Additionally, the proposed tactile sensor can detect not only press force but also pull force. This results in the detection of a press or pinch in a robot skin. The experimental results show that the proposed sensor can successfully detect both press and pull static forces. The sensitivity of the proposed sensor was 0.169 pF/N for an applied force in the press direction and −0.152 pF/N for a force in the pull direction based on the results of an evaluation of the static sensor characteristics. Furthermore, an evaluation of the dynamic sensor characteristics revealed that the proposed tactile sensor has high repeatability and a quick response to an external force. Additionally, the hysteresis of the proposed tactile sensor is small, especially in the press direction.
Prostate cancer (PC) is the most prevalent cancer in men and the second main cause of cancer-related death in Western society. The lack of proper PC models that recapitulate the molecular and genomic ...landscape of clinical disease has hampered progress toward translational research to understand the disease initiation, progression, and therapeutic responses in each patient. Although several models have been developed, they hardly emulated the complicated PC microenvironment. Precision medicine is an emerging approach predicting appropriate therapies for individual cancer patients by means of various analyses of individual genomic profiling and targeting specific cancer pathways. In PC, precision medicine also has the potential to impose changes in clinical practices. Here, we describe the various PC models with special focus on PC organoids and their values in basic medicine, personalized therapy, and translational researches in vitro and in vivo, which could help to achieve the full transformative power of cancer precision medicine.
Death-associated protein kinase (DAPK) is a Ca/calmodulin-regulated serine/threonine kinase that mediates cell death. Our recent study demonstrated that DAPK3 protein increases in the mesenteric ...artery from spontaneously hypertensive rats compared with Wistar Kyoto rats. Pathogenesis of hypertension is modulated at least in part by vascular inflammation. We examined whether DAPK3 mediates vascular inflammatory responses and development of hypertension. In rat mesenteric arterial smooth muscle cells, small interfering RNA against DAPK3 inhibited vascular cell adhesion molecule 1 expression and monocyte adhesion induced by tumor necrosis factor-α. DAPK3 small interfering RNA inhibited phosphorylation of c-Jun amino-terminal kinase, p38, and Akt, as well as reactive oxygen species (ROS) production induced by tumor necrosis factor-α. In human umbilical vein endothelial cells, expressions of vascular cell adhesion molecule 1, endothelial selectin, and cyclooxygenase 2, as well as ROS production induced by tumor necrosis factor-α, were inhibited by DAPK inhibitor. In vivo, blood pressure, ROS production, inflammatory molecule expression (vascular cell adhesion molecule 1 and endothelial selectin), and hypertrophy in isolated mesenteric artery were elevated in spontaneously hypertensive rats (10 weeks old), which were prevented by long-term treatment with a DAPK inhibitor (500 µg/kg per day for 6 weeks). In isolated mesenteric artery, the increased angiotensin II–induced contraction and the impaired acetylcholine-induced endothelium-dependent relaxation in spontaneously hypertensive rats were reversed by a DAPK inhibitor. The present results for the first time demonstrated in cultured smooth muscle cells and endothelial cells that DAPK3 mediates tumor necrosis factor–induced inflammatory responses via ROS-dependent mechanisms. It is also suggested that DAPK3 mediates the development of hypertension in spontaneously hypertensive rats likely via ROS-dependent inflammation, hypertrophy, and hypercontractility.
PDF
