The Roles of Mitogen-Activated Protein Kinase Pathways in TGF-β-Induced Epithelial-Mesenchymal Transition

The mitogen-activated protein kinase (MAPK) pathway allows cells to interpret external signals and respond appropriately, especially during the epithelial-mesenchymal transition (EMT). EMT is an important process during embryonic development, fibrosis, and tumor progression in which epithelial cells acquire mesenchymal, fibroblast-like properties and show reduced intercellular adhesion and increased motility. TGF-β signaling is the first pathway to be described as an inducer of EMT, and its relationship with the Smad family is already well characterized. Studies of four members of the MAPK family in different biological systems have shown that the MAPK and TGF-β signaling pathways interact with each other and have a synergistic effect on the secretion of additional growth factors and cytokines that in turn promote EMT. In this paper, we present background on the regulation and function of MAPKs and their cascades, highlight the mechanisms of MAPK crosstalk with TGF-β signaling, and discuss the roles of MAPKs in EMT

DEC1 negatively regulates AMPK activity via LKB1

Basic helix-loop-helix (bHLH) transcription factor DEC1 (bHLHE40/Stra13/Sharp2) is one of the clock genes that show a circadian rhythm in various tissues. AMP-activated protein kinase (AMPK) activity plays important roles in the metabolic process and in cell death induced by glucose depletion. Recent reports have shown that AMPK activity exhibited a circadian rhythm. However, little is known regarding the regulatory mechanisms involved in the circadian rhythm of AMPK activity. The aim of this study is to investigate whether there is a direct correlation between DEC1 expression and AMPK activity. DEC1 protein and AMPK activity showed a circadian rhythm in the mouse liver with different peak levels. Knocking down DEC1 expression increased AMPK activity, whereas overexpression of DEC1 decreased it. Overexpressing the DEC1 basic mutants had little effect on the AMPK activity. DEC1 bound to the E-box of the LKB1 promoter, decreased LKB1 activity and total protein levels. There was an inverse relationship between DEC1 expression and AMPK activity. Our results suggest that DEC1 negatively regulates AMPK activity via LKB1

Diverse Roles of Macrophages in Atherosclerosis: From Inflammatory Biology to Biomarker Discovery

Cardiovascular disease, a leading cause of mortality in developed countries, is mainly caused by atherosclerosis, a chronic inflammatory disease. Macrophages, which differentiate from monocytes that are recruited from the blood, account for the majority of leukocytes in atherosclerotic plaques. Apoptosis and the suppressed clearance of apoptotic macrophages (efferocytosis) are associated with vulnerable plaques that are prone to rupture, leading to thrombosis. Based on the central functions of macrophages in atherogenesis, cytokines, chemokines, enzymes, or microRNAs related to or produced by macrophages have become important clinical prognostic or diagnostic biomarkers. This paper discusses the impact of monocyte-derived macrophages in early atherogenesis and advanced disease. The role and possible future development of macrophage inflammatory biomarkers are also described

Trps1-deficient transplanted skin gave rise to a substantial amount of hair: Trps1 is unnecessary for hair development

Trps1 is considered as an important gene involved in the interactions between the epithelial and mesenchymal cells during hair follicle morphogenesis. The number of hair follicles in Trps1 Knockout (KO) newborn mouse skin was significantly lower than that in wild-type (WT) newborn skin. To gain insight into the functional role of Trps1 in hair development, we transplanted Trps1 KO newborn mouse skin on the backs of nude mice and examined hair growth at day 42 after transplantation. Surprisingly, transplanted skin from Trps1 KO newborn mice gave rise to substantial amount of hair, although the hair was softer than that of WT mice. Histological examination revealed that the diameter of both hair follicles and hair shafts were significantly lower, whereas the density of hair follicles showed no significant difference between the Trps1 KO and WT mice. We introduce mouse hair follicles as a fascinating model to study the functions of Trps1 in mouse hair growth and pathology. This model suggests that the function of Trps1 is unnecessary for the development of normal hair follicles and hair shafts, although the loss of Trps1 affects the diameters of hair follicles and hair shaft

The function of TRPS1 in the development and differentiation of bone, kidney, and hair follicles

TRPS1 is a gene involved in Tricho-rhino-phalangeal syndrome (TRPS), an autosomal dominant skeletal disorder. TRPS1 encodes a GATA-type transcription factor that has nine zinc-finger motifs. A variety of mutations in TRPS1 including deletions and insertions, have been found in patients with TRPS type I and III. The functions of each domain of TRPS1 have been clarified from study of these mutations. Further studies on the localization and the function of TRPS1 have been performed using TRPS1Δgt and Trps1-deficient mice, which allow examination of the development and differentiation of all tissues with Trps1 expression. These studies suggest that TRPS1 exhibits a variety of functions in cartilage, kidneys, and hair follicles. In the growth plate cartilage, TRPS1 regulates the differentiation, proliferation, and apoptosis of chondrocytes through interaction of several signaling molecules. In addition, TRPS1 has a function downstream of BMP7, which regulates the mesenchymal-epithelial transition when nephrons are formed in renal development. Furthermore, TRPS1 suppresses the epithelial-mesenchymal transition and renal fibrosis induced by unilateral ureteral obstruction by decreasing Arkadia expression. Finally, TRPS1 is expressed in the dermal papillae and the mesenchymal cells surrounding the hair pegs, and the loss of TRPS1 largely influences the development of hair follicles. The molecular mechanisms of the function of TRPS1 in cartilage, kidneys, and hair follicles are discussed in this review

Potential Roles of Dec and Bmal1 Genes in Interconnecting Circadian Clock and Energy Metabolism

The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism. Therefore, defects in the clock genes not only result in the dysregulation of physiological rhythms but also induce metabolic disorders including diabetes and obesity. Among the clock genes, Dec1 (Bhlhe40/Stra13/Sharp2), Dec2 (Bhlhe41/Sharp1), and Bmal1 (Mop3/Arntl) have been shown to be particularly relevant to the regulation of energy metabolism at the cellular, tissue, and organismal levels. This paper reviews our current knowledge of the roles of Dec1, Dec2, and Bmal1 in coordinating the circadian and metabolic pathways

An Autopsy Case of Fulminant Amebic Colitis in a Patient with a History of Rheumatoid Arthritis

Generally, amebic colitis is localized around the mucosal membrane and often accompanied by diarrhea and abdominal pain. We describe a patient with a history of rheumatoid arthritis who had received prolonged steroid therapy. The patient complained of breathing difficulties because of rheumatoid lung disease. Although the patient was given antibacterial agent, the symptoms did not improve until death. We did an autopsy and found that he had fulminant amebic colitis, although the patient was not previously examined. Histochemical analysis revealed severe inflammation and full-thickness necrosis of the colon by ameba, suggesting the involvement of ameba in the progression of the overall condition

Histological analysis of a Becker muscular dystrophy case, diurnal expression of dystrophin in control mice and decreased expression of dystrophin in Bmal1 knockout mice

Becker muscular dystrophy (BMD) is a hereditary disease characterized by dystrophin deletion that consequently induces muscle weakness, cardiac hypertrophy and cardiac failure; These conditions are similar to those in Duchenne muscular dystrophy. The circadian rhythm is a physiological phenomenon that is predominantly regulated by the transcription and translation of clock genes. Bmal1 (Brain and muscle Arnt-like protein 1) is one of the core clock genes, and its deficiency disturbs the circadian rhythm, results in cardiac hypertrophy and cardiac failure. Dystrophin expression under diurnal conditions and in Bmal1 deficiency is yet to be elucidated. In this study, we analyzed the heart and lungs sampled during a BMD autopsy. Macroscopical examination revealed a large heart and dilated cardiomyopathy. Microscopical examination revealed an undulated structure, as well as the degeneration, and necrosis of myocardial cells. We also analyzed dystrophin expression in tissues obtained from human autopsies and mice. In human autopsy cases, dystrophin expression was lower in the heart with BMD compared that in the heart with non-BMD hypertrophy. In the heart and muscle of control mice, dystrophin expression was higher at ZT0 than at ZT12. The dystrophin expression was found to be lower in heart-specific Bmal1 knockout mice compared to that in the control mice. Hence, our study indicated that BMD was closely associated with cardiac hypertrophy and cardiac failure, while dystrophin had a diurnal expression pattern in control mice that was regulated by Bmal1