• Molecules and Cells
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• v.46 no.4
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• pp.219-230
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• 2023

Down syndrome (DS) is the most common autosomal aneuploidy caused by trisomy of chromosome 21. Previous studies demonstrated that DS affected mitochondrial functions, which may be associated with the abnormal development of the nervous system in patients with DS. Runt-related transcription factor 1 (RUNX1) is an encoding gene located on chromosome 21. It has been reported that RUNX1 may affect cell apoptosis via the mitochondrial pathway. The present study investigated whether RUNX1 plays a critical role in mitochondrial dysfunction in DS and explored the mechanism by which RUNX1 affects mitochondrial functions. Expression of RUNX1 was detected in induced pluripotent stem cells of patients with DS (DS-iPSCs) and normal iPSCs (N-iPSCs), and the mitochondrial functions were investigated in the current study. Subsequently, RUNX1 was overexpressed in N-iPSCs and inhibited in DS-iPSCs. The mitochondrial functions were investigated thoroughly, including reactive oxygen species levels, mitochondrial membrane potential, ATP content, and lysosomal activity. Finally, RNA-sequencing was used to explore the global expression pattern. It was observed that the expression levels of RUNX1 in DS-iPSCs were significantly higher than those in normal controls. Impaired mitochondrial functions were observed in DS-iPSCs. Of note, overexpression of RUNX1 in N-iPSCs resulted in mitochondrial dysfunction, while inhibition of RUNX1 expression could improve the mitochondrial function in DS-iPSCs. Global gene expression analysis indicated that overexpression of RUNX1 may promote the induction of apoptosis in DS-iPSCs by activating the PI3K/Akt signaling pathway. The present findings indicate that abnormal expression of RUNX1 may play a critical role in mitochondrial dysfunction in DS-iPSCs.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.5
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• pp.469-478
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• 2024

Chronic intermittent hypoxia (CIH) can lead to vascular dysfunction and increase the risk of cardiovascular diseases, cerebrovascular diseases, and arterial diseases. Nevertheless, mechanisms underlying CIH-induced vascular dysfunction remain unclear. Herein, this study analyzed the role of aortic smooth muscle calcium-activated potassium (BK) channels in CIH-induced vascular dysfunction. CIH models were established in rats and rat aortic smooth muscle cells (RASMCs). Hemodynamic parameters such as mean blood pressure (MBP), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were measured in rats, along with an assessment of vascular tone. NO and ET-1 levels were detected in rat serum, and the levels of ET-1, NO, eNOS, p-eNOS, oxidative stress markers (ROS and MDA), and inflammatory factors (IL-6 and TNF-α) were tested in aortic tissues. The Ca²⁺ concentration in RASMCs was investigated. The activity of BK channels (BKα and BKβ) was evaluated in aortic tissues and RASMCs. SBP, DBP, and MBP were elevated in CIH-treated rats, along with endothelial dysfunction, cellular edema and partial detachment of endothelial cells. BK channel activity was decreased in CIH-treated rats and RASMCs. BK channel activation increased eNOS, p-eNOS, and NO levels while lowering ET-1, ROS, MDA, IL-6, and TNF-α levels in CIH-treated rats. Ca²⁺ concentration increased in RASMCs following CIH modeling, which was reversed by BK channel activation. BK channel inhibitor (Iberiotoxin) exacerbated CIH-induced vascular disorders and endothelial dysfunction. BK channel activation promoted vasorelaxation while suppressing vascular endothelial dysfunction, inflammation, and oxidative stress, thereby indirectly improving CIH-induced vascular dysfunction.

• Nutrition Research and Practice
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• v.8 no.5
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• pp.533-538
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• 2014

BACKGROUND/OBJECTIVES: We investigated the effect of Pycnogenol (Pyc) on survival and immune dysfunction of C57BL/6 mice induced by low micronutrient supplementation. MATERIALS/METHODS: Female C57/BL/6 mice were fed a diet containing 7.5% of the recommended amount of micronutrients for a period of 12 wks (immunological assay) and 18 wks (survival test). For immunological assay, lymphocyte proliferation, cytokine regulation, and hepatic oxidative status were determined. RESLUTS: Pyc supplementation with 50 and $100mg{\cdot}kg^{-1}{\cdot}bw{\cdot}d^{-1}$ resulted in partial extension of the median survival time. Pyc supplementation led to increased T and B cell response against mitogens and recovery of an abnormal shift of cytokine pattern designated by the decreased secretion of Th1 cytokine and increased secretion of Th2 cytokine. Hepatic vitamin E level was significantly decreased by micronutrient deficiency, in accordance with increased hepatic lipid peroxidation level. However, Pyc supplementation resulted in a dose-dependent reduction of hepatic lipid peroxidation, which may result from restoration of hepatic vitamin E level. CONCLUSION: Findings of this study suggest that Pyc supplementation ameliorates premature death by restoring immune dysfunction, such as increasing lymphocyte proliferation and regulation of cytokine release from helper T cells, which may result from the antioxidative ability of Pyc.

• Molecules and Cells
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• v.39 no.3
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• pp.186-194
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• 2016

Epidemiological evidence suggests that bone is especially sensitive to oxidative stress, causing bone loss in the elderly. Previous studies indicated that human amnion-derived mesenchymal stem cells (HAMSCs), obtained from human amniotic membranes, exerted osteoprotective effects in vivo. However, the potential of HAMSCs as seed cells against oxidative stress-mediated dysfunction is unknown. In this study, we systemically investigated their antioxidative and osteogenic effects in vitro. Here, we demonstrated that HAMSCs significantly promoted the proliferation and osteoblastic differentiation of $H_2O_2$-induced human bone marrow mesenchymal stem cells (HBMSCs), and down-regulated the reactive oxygen species (ROS) level. Further, our results suggest that activation of the ERK1/2 MAPK signal transduction pathway is essential for both HAMSCs-mediated osteogenic and protective effects against oxidative stress-induced dysfunction in HBMSCs. U0126, a highly selective inhibitor of extracellular ERK1/2 MAPK signaling, significantly suppressed the antioxidative and osteogenic effects in HAMSCs. In conclusion, by modulating HBMSCs, HAMSCs show a strong potential in treating oxidative stress- mediated bone deficiency.

• Toxicological Research
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• v.17
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• pp.205-210
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• 2001

One of the major focuses and perhaps the greatest challenges during the past decade in the discipline of immunotoxicology has been the elucidation of the molecular mechanisms responsible for immunotoxicity by specific agents. Much is currently understood about the basic underlying intracellular processes that control leukocyte effector function. This fundamental information in cell biology can now be applied toward developing systematic approaches, through the application of cell and molecular biology techniques, to identify the intracellular targets and processes disrupted by immunotoxicants. The objective of this paper is two fold. First to discuss fundamental principles of experimental design aimed at elucidation of cellular mechanisms in immunotoxicology; and second to discuss the application of molecular biology techniques in characterizing the mechanism of TCDD-induced B cell dysfunction as a working example.

• Journal of Microbiology and Biotechnology
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• v.18 no.2
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• pp.392-395
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• 2008

In an attempt to delineate the direct effect of arsenite-induced endothelial dysfunction on nitric oxide (NO) production, confluent bovine aortic endothelial cells (BAEC) were incubated with arsenite, and endothelial NO synthase expression and NO production were measured. Exposure of arsenite decreased NO production for up to 24h. This decrease was accompanied by decreases in cAMP, protein kinase A (PKA) activity, and furthermore, significant reduction of pCREB. In conclusion, this study is the first to demonstrate that exposure of arsenite decreases NO production by a reduction of pCREB and PKA activity that may be mediated by cAMP, leading to endothelial dysfunction.

• Molecules and Cells
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• v.25 no.2
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• pp.149-157
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• 2008

Dopamine is a major neurotransmitter in the mammalian central nervous system (CNS) that regulates neuroendocrine functions, locomotor activity, cognition and emotion. The dopamine system has been extensively studied because dysfunction of this system is linked to various pathological conditions including Parkinson's disease, schizophrenia, Tourette's syndrome, and drug addiction. Accordingly, intense efforts to delineate the full complement of signaling pathways mediated by individual receptor subtypes have been pursued. Dopamine D1-like receptors are of particular interest because they are the most abundant dopamine receptors in CNS. Recent work suggests that dopamine signaling could be regulated via dopamine receptor interacting proteins (DRIPs). Unraveling these DRIPs involved in the dopamine system may provide a better understanding of the mechanisms underlying CNS disorders related to dopamine system dysfunction and may help identify novel therapeutic targets.

• Toxicological Research
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• v.30 no.4
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• pp.221-234
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• 2014

Mitochondria dysfunction was first described in the 1960s. However, the extent and mechanisms of mitochondria dysfunction's role in cellular physiology and pathology has only recently begun to be appreciated. To adequately evaluate mitochondria-mediated toxicity, it is not only necessary to understand mitochondria biology, but discerning mitochondrial redox biology is also essential. The latter is intricately tied to mitochondrial bioenergetics. Mitochondrial free radicals, antioxidants, and antioxidant enzymes are players in mitochondrial redox biology. This review will provide an across-the-board, albeit not in-depth, overview of mitochondria biology and mitochondrial redox biology. With accumulating knowledge on mitochondria biology and mitochondrial redox biology, we may devise experimental methods with adequate sensitivity and specificity to evaluate mitochondrial toxicity, especially in vivo in living organisms, in the near future.

• BMB Reports
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• v.52 no.1
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• pp.5-12
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• 2019

Organismal aging is accompanied by a host of progressive metabolic alterations and an accumulation of senescent cells, along with functional decline and the appearance of multiple diseases. This implies that the metabolic features of cell senescence may contribute to the organism's metabolic changes and be closely linked to age-associated diseases, especially metabolic syndromes. However, there is no clear understanding of senescent metabolic characteristics. Here, we review key metabolic features and regulators of cellular senescence, focusing on mitochondrial dysfunction and anabolic deregulation, and their link to other senescence phenotypes and aging. We further discuss the mechanistic involvement of the metabolic regulators mTOR, AMPK, and GSK3, proposing them as key metabolic switches for modulating senescence.

• Anatomy and Cell Biology
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• v.56 no.2
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• pp.166-178
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• 2023

Undeniably, endothelial cells (EC) contribute to the maintenance of the homeostasis of the organism through modulating cellular physiology, including signaling pathways, through the release of highly active molecules as well as the response to a myriad of extrinsic and intrinsic signaling factors. Review the data from the current literature on the EC role in norm and disease. Endothelium maintains a precise balance between the released molecules, where EC dysfunction arises when the endothelium actions shift toward vasoconstriction, the proinflammatory, prothrombic properties after the alteration of nitric oxide (NO) production and oxidative stress. The functions of the EC are regulated by the negative/positive feedback from the organism, through EC surface receptors, and the crosstalk between NO, adrenergic receptors, and oxidative stress. More than a hundred substances can interact with EC. The EC dysfunction is a hallmark in the emergence and progression of vascular-related pathologies. The paper concisely reviews recent advances in EC (patho) physiology. Grasping EC physiology is crucial to gauge their potential clinical utility and optimize the current therapies as well as to establish novel nanotherapeutic molecular targets include; endothelial receptors, cell adhesion molecules, integrins, signaling pathways, enzymes; peptidases.