Chronic vascular diseases such as atherosclerosis, aneurysms, diabetic angiopathy/retinopathy as well as fibrotic and proliferative vascular diseases are generally complicated by the progression of ...degenerative insults, which are characterized by endothelial dysfunction, apoptotic/necrotic cell death in vascular/immune cells, remodeling of extracellular matrix or breakdown of elastic lamella. Increasing evidence suggests that dysfunctional calpain proteolytic systems and defective calpain protein metabolism in blood vessels contribute to degenerative disorders. In vascular endothelial cells, the overactivation of conventional calpains consisting of calpain-1 and -2 isozymes can lead to the disorganization of cell-cell junctions, dysfunction of nitric oxide synthase, sensitization of Janus kinase/signal transducer and activator of transcription cascades and depletion of prostaglandin I2, which contributes to degenerative disorders. In addition to endothelial cell dysfunctions, calpain overactivation results in inflammatory insults in macrophages and excessive fibrogenic/proliferative signaling in vascular smooth muscle cells. Moreover, calpain-6, a non-proteolytic unconventional calpain, is involved in the conversion of macrophages to a pro-atherogenic phenotype, leading to the pinocytotic deposition of low-density lipoprotein cholesterol in the cells. Here, we discuss the recent progress that has been made in our understanding of how calpain contributes to degenerative vascular disorders.
Normalization of the stromal microenvironment is a promising strategy for cancer control. Cancer-associated fibroblasts, tumor-associated macrophages, and mesenchymal stromal cells have a central ...role in stromal functions. Accordingly, understanding these stromal cells is indispensable for the development of next-generation cancer therapies. Growing evidence suggests that calpain-induced intracellular proteolysis is responsible for cancer growth and stromal regulation. Calpain is a family of stress-responsive intracellular proteases and is inducible in cancer and stromal cells during carcinogenesis.
Here, we shed light on the recent advances that have been made in understanding how calpain contributes to stromal regulation in cancer.
Calpains are activated in stromal cells, including pancreatic stellate cells and mesenchymal cells. They induce fibrogenic responses in cancer stroma. Moreover, these molecules contribute to epithelial-mesenchymal transition and endothelial-mesenchymal transition to provide mesenchymal stromal cells in the microenvironment and concomitantly participate in cancer angiogenesis. In addition to the conventional calpains, the unconventional calpain-9 is associated with epithelial-mesenchymal transition. Animal experiments showed that targeting calpain systems antagonizes cancer development; thus, this approach is promising for cancer control.
Thromboembolic ischemic stroke, which is mainly caused by hypertension, as well as plasma dyslipidemia, arterial fibrillation and diabetes, is a leading cause of death in the US and other countries. ...Numerous clinical trials for thrombolytic drugs, which aimed to pharmacologically dissolve thrombi, were conducted in the 1950s, when the first thrombolytic therapy was performed.
In this study, we summarize the pathophysiologic features of ischemic stroke, and the history of thrombolytic therapy, and discuss the recent progress that has been made in the ongoing development of thrombolytic drugs.
Thrombolytic therapy is sometimes accompanied by harmful hemorrhagic insults; accordingly, a window of time wherein therapy can safely be performed has been established for this approach. Several basic and clinical studies are ongoing to develop next-generation thrombolytic drugs to expand the time window.
Changes in root development and growth in upland rice receiving subsurface irrigation were evaluated using root box experiments. Irrigated water was independently applied every day to depths of 0, 5, ...10 and 20 cm from the ground surface, and root morphology and aboveground growth were determined after 2 weeks of treatment. Plant length, stem number and leaf age significantly increased along with the irrigation depth, and the aboveground dry weights of rice grown at 5-, 10- and 20-cm depths were significantly greater than those grown at 0 cm. Root surface area significantly increased along with the irrigation depth, which was attributed to the increasing lengths and branch numbers of roots. Subsurface irrigation significantly increased root lengths in deep layers (below 15 cm) and increased the deep layers' distribution ratios by 1.2 to 5.7 times as the surface layer ratio decreased. This was accompanied with a decrease in the root diameter. This may be associated with the increase in the numbers of branches and the decrease in the numbers of thick nodal roots. These results indicate that subsurface irrigation increases root length and branching in the deep soil layers, inducing deep rooting, even with same amount of irrigation.
The rapidly changing climate affects an extensive spectrum of human-centered environments. The food industry is one of the affected industries due to rapid climate change. Rice is a staple food and ...an important cultural key point for Japanese people. As Japan is a country in which natural disasters continuously occur, using aged seeds for cultivation has become a regular practice. It is a well-known truth that seed quality and age highly impact germination rate and successful cultivation. However, a considerable research gap exists in the identification of seeds according to age. Hence, this study aims to implement a machine-learning model to identify Japanese rice seeds according to their age. Since agewise datasets are unavailable in the literature, this research implements a novel rice seed dataset with six rice varieties and three age variations. The rice seed dataset was created using a combination of RGB images. Image features were extracted using six feature descriptors. The proposed algorithm used in this study is called Cascaded-ANFIS. A novel structure for this algorithm is proposed in this work, combining several gradient-boosting algorithms such as XGBoost, CatBoost, and LightGBM. The classification was conducted in two steps. First, the seed variety was identified. Then, the age was predicted. As a result, seven classification models were implemented. The performance of the proposed algorithm was evaluated against 13 state-of-the-art algorithms. Overall, the proposed algorithm has a higher accuracy, precision, recall, and F1-score than the others. For the classification of variety, the proposed algorithm scored 0.7697, 0.7949, 0.7707, and 0.7862, respectively. The results of this study confirm that the proposed algorithm can be employed in the successful age classification of seeds.
Vascular endothelial cells (ECs) make up the innermost surface of arteries, veins, and capillaries, separating the remaining layers of the vessel wall from circulating blood. Under non-inflammatory ...conditions, ECs are quiescent and form a robust barrier structure; however, exposure to inflammatory stimuli induces changes in the expression of EC proteins that control transcellular permeability and facilitate angiogenic tube formation. Increasing evidence suggests that dysfunction in intracellular proteolytic systems disturbs EC adaptation to the inflammatory environment, leading to vascular disorders such as atherosclerosis and pathological angiogenesis. Recent work has highlighted the contribution of the calpain-calpastatin stress-responsive intracellular proteolytic system to adaptation failure in ECs. In this review, we summarize our current knowledge of calpain-calpastatin-mediated physiologic and pathogenic regulation in ECs and discuss the molecular basis by which disruption of this system perturbs EC adaptation to the inflammatory environment.
Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to ...pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.
NADPH oxidases (NOX) are enzymes that catalyze the production of reactive oxygen species (ROS). Four species of NOX catalytic homologs (NOX1, NOX2, NOX4, and NOX5) are reportedly expressed in ...vascular tissues. The pro-atherogenic roles of NOX1, NOX2, and their organizer protein p47ph°x were manifested, and it was noted that the hydrogen peroxide-generating enzyme NOX4 possesses atheroprotective effects. Loss of NOX1 or p47ph°x appears to ameliorate murine aortic dissection and subsequent aneurysmal diseases; in contrast, the ablation of NOX2 exacerbates the aneurysmal diseases. It is possible that the loss of NOX2 activates inflammatory cascades in macrophages in the lesions. Roles of NOX5 in vascular functions are currently undetermined, owing to the absence of this enzyme in rodents and the limitation of the experimental procedure. Thus, it is possible that the NOX family of enzymes exhibits heterogeneity in the atherosclerotic diseases. In this aspect, subtype-selective NOX inhibitor may be promising when NOX systems serve as a molecular target for atherosclerotic and aneurysmal diseases.
Lymphatic vessels are necessary for maintaining tissue fluid balance, trafficking of immune cells, and transport of dietary lipids. Growing evidence suggest that lymphatic functions are limited under ...hypercholesterolemic conditions, which is closely related to atherosclerotic development involving the coronary and other large arteries. Indeed, ablation of lymphatic systems by Chy-mutation as well as depletion of lymphangiogenic factors, including vascular endothelial growth factor-C and -D, in mice perturbs lipoprotein composition to augment hypercholesterolemia. Several investigations have reported that periarterial microlymphatics were attracted by atheroma-derived lymphangiogenic factors, which facilitated lymphatic invasion into the intima of atherosclerotic lesions, thereby modifying immune cell trafficking. In contrast to the lipomodulatory and immunomodulatory roles of the lymphatic systems, the critical drivers of lymphangiogenesis and the details of lymphatic insults under hypercholesterolemic conditions have not been fully elucidated. Interestingly, cholesterol-lowering trials enable hypercholesterolemic prevention of lymphatic drainage in mice; however, a causal relationship between hypercholesterolemia and lymphatic defects remains elusive. In this review, the contribution of aberrant lymphangiogenesis and lymphatic cholesterol transport to hypercholesterolemic atherosclerosis was highlighted. The causal relationship between hypercholesterolemia and lymphatic insults as well as the current achievements in the field were discussed.
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