Endoplasmic reticulum (ER) and mitochondrion are the key organelles in mammal cells and play crucial roles in a variety of biological functions in both physiological and pathological conditions. Valosin-containing protein (VCP), a newly identified calcium-associated ATPase protein, has been found to be involved in both ER and mitochondrial function. Impairment of VCP, caused by structural mutations or alterations of expressions, contributes to the development of various diseases, through an integrating effect on ER, mitochondria and the ubiquitin–proteasome system, by interfering with protein degradation, subcellular translocation and calcium homeostasis. Thus, understanding the role and the molecular mechanisms of VCP in these organelles brings new insights to the pathogenesis of the associated diseases, and leads to the discovery of new therapeutic strategies. In this review, we summarized the progress of studies on VCP, in terms of its regulation of ER and mitochondrial function and its implications for the associated diseases, focusing on the cancers, heart disease, and neurodegenerative disorders.
The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.
Mitochondria undergo structural and functional remodeling to meet the cell demand in response to the intracellular and extracellular stimulations, playing an essential role in maintaining normal cellular function. Merging evidence demonstrated that dysregulation of mitochondrial remodeling is a fundamental driving force of complex human diseases, highlighting its crucial pathophysiological roles and therapeutic potential. In this review, we outlined the progress of the molecular basis of mitochondrial structural and functional remodeling and their regulatory network. In particular, we summarized the latest evidence of the fundamental association of impaired mitochondrial remodeling in developing diverse cardiac diseases and the underlying mechanisms. We also explored the therapeutic potential related to mitochondrial remodeling and future research direction. This updated information would improve our knowledge of mitochondrial biology and cardiac diseases’ pathogenesis, which would inspire new potential strategies for treating these diseases by targeting mitochondria remodeling.
Tissue fibrosis is a major unresolved medical problem, which impairs the function of various systems. The molecular mechanisms involved are poorly understood, which hinders the development of effective therapeutic strategies. Emerging evidence from recent studies indicates that interleukin 36 (IL-36) and the corresponding receptor (IL-36R), a newly-characterized cytokine/receptor signaling complex involved in immune-inflammation, play an important role in the pathogenesis of fibrosis in multiple tissues. This review focuses on recent experimental findings, which implicate IL-36R and its associated cytokines in different forms of organ fibrosis. Specifically, it outlines the molecular basis and biological function of IL-36R in normal cells and sums up the pathological role in the development of fibrosis in the lung, kidney, heart, intestine, and pancreas. We also summarize the new progress in the IL-36/IL-36R-related mechanisms involved in tissue fibrosis and enclose the potential of IL-36R inhibition as a therapeutic strategy to combat pro-fibrotic pathologies. Given its high association with disease, gaining new insight into the immuno-mechanisms that contribute to tissue fibrosis could have a significant impact on human health.
The biological activities of interleukins, a group of circulating cytokines, are linked to the immuno-pathways involved in many diseases. Mounting evidence suggests that interleukin-1β (IL-1β) plays a significant role in the pathogenesis of various types of hypertension. In this review, we summarized recent findings linking IL-1β to systemic arterial hypertension, pulmonary hypertension, and gestational hypertension. We also outlined the new progress in elucidating the potential mechanisms of IL-1β in hypertension, focusing on it’s regulation in inflammation, vascular smooth muscle cell function, and extracellular remodeling. In addition, we reviewed recent studies that highlight novel findings examining the function of non-coding RNAs in regulating the activity of IL-1β and its associated proteins in the setting of hypertension. The information collected in this review provides new insights into understanding the pathogenesis of hypertension and could lead to the discovery of new anti-hypertensive therapies to combat this highly prevalent disease.
Calcium ion (Ca2+) plays a critical role in the cardiac mitochondria function. Ca2+ entering the mitochondria is necessary for ATP production and the contractile activity of cardiomyocytes. However, excessive Ca2+ in the mitochondria results in mitochondrial dysfunction and cell death. Mitochondria maintain Ca2+ homeostasis in normal cardiomyocytes through a comprehensive regulatory mechanism by controlling the uptake and release of Ca2+ in response to the cellular demand. Understanding the mechanism of modulating mitochondrial Ca2+ homeostasis in the cardiomyocyte could bring new insights into the pathogenesis of cardiac disease and help developing the strategy to prevent the heart from damage at an early stage. In this review, we summarized the latest findings in the studies on the cardiac mitochondrial Ca2+ homeostasis, focusing on the regulation of mitochondrial calcium uptake, which acts as a double-edged sword in the cardiac function. Specifically, we discussed the dual roles of mitochondrial Ca2+ in mitochondrial activity and the impact on cardiac function, the molecular basis and regulatory mechanisms, and the potential future research interest.
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