Biology subjects

Suzuki, Y. J.

Publications and source records attributed to Suzuki, Y. J..

10 recordsLinked to original sources

bioRxiv2026

Antioxidant properties of Rhodiola rosea

Rhodiola rosea is a traditional medicinal plant often classified as an adaptogen, with reported effects in supporting the bodys response to physical, environmental, and emotional stressors. The present study investigated the antioxidant properties of Rhodiola rosea extract and its major chemical constituents to provide insight into their potential mechanisms of action. Through in vitro biochemical assays, we demonstrated that Rhodiola rosea extract has the capacity to reduce hydrogen peroxide (H2O2) levels. Among its primary chemical components, rosavin significantly decreased H2O2, whereas salidroside had no effect. Neither compound affected superoxide levels. Structural analysis revealed that the intact phenylpropanoid glycoside architecture of rosavin is required for activity, as its individual components, arabinose and rosin, showed no inhibitory effect. Further investigation demonstrated that rosavin attenuates H2O2-mediated oxidation of thiol groups, supporting a role in cellular redox regulation. In cultured human cells, rosavin mitigated reductions in cell viability induced by exposure to H2O2, indicating cytoprotective effects under oxidative stress conditions. Finally, in an in vivo model, administration of SARS-CoV-2 spike protein increased circulating levels of H2O2, which were subsequently reduced following rosavin treatment. Collectively, these findings identify rosavin as a structurally dependent antioxidant component of Rhodiola rosea that modulates H2O2-associated oxidative stress and supports further investigation of phenylpropanoid glycosides as adaptogens.

biochemistry↗

bioRxiv2025

Oxidant-mediated amino acid conversion of angiotensin II: Effects on gene expression in vascular smooth muscle cells.

Angiotensin II (Ang II) is a major mediator of pathophysiological processes. Angiotensin-converting enzyme 2 (ACE2) regulates Ang II levels by cleaving it into Ang 1-7. Our previous study showed that arginine at the second position (Arg2) of Ang II plays an important role in regulating ACE2 peptidase activity. The present study examined the mechanisms and functions of Arg2 in Ang II. Cleavage of Arg2 from Ang II, or single amino acid replacement of a positively charged Arg with other amino acids, particularly negatively charged amino acids such as glutamic acid (Glu), eliminated Ang IIs ability to compete with the fluorogenic substrate used in the ACE2 activity assay. Arg2-to-Glu substitution also affected the ability of angiotensin I and angiotensin III to interact with ACE2. These results confirmed the important roles of Arg2 in the ACE2 enzymatic mechanism. Since Arg and proline (Pro) residues are susceptible to protein carbonylation, and both residues produce glutamic semialdehyde, which can be further oxidized to Glu, we previously proposed that Arg, Pro, and Glu could be interchangeable, and that ROS promote amino acid conversions within protein structures post-translationally in biological systems. Thus, Arg2 of Ang II could undergo oxidant-mediated amino acid residue conversion to become Glu or Pro. The presence of both circulating Ang II (Arg2Glu) and Ang II (Arg2Pro) in rats were confirmed by mass spectrometry. Global gene expression analyses revealed that Arg2Glu- and Arg2Pro-converted Ang II peptides elicit different cellular signaling responses compared with wild-type Ang II, suggesting that Arg2-modifed Ang II peptides exhibit distinct biological functions.

biochemistry↗

bioRxiv2024

Angiotensin peptides enhance SARS-CoV-2 spike protein binding to its host cell receptors

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that caused the Coronavirus Disease 2019 (COVID-19) pandemic, has a spike glycoprotein that is involved in recognizing and fusing to host cell receptors, such as angiotensin-converting enzyme 2 (ACE2), neuropilin-1 (NRP1), and AXL tyrosine-protein kinase. Since the major spike protein receptor is ACE2, an enzyme that regulates angiotensin II (1-8), this study tested the hypothesis that angiotensin II (1-8) influences the binding of the spike protein to its receptors. While angiotensin II (1-8) did not influence spike-ACE2 binding, we found that it significantly enhances spike-AXL binding. Our experiments showed that longer lengths of angiotensin, such as angiotensin I (1-10), did not significantly affect spike-AXL binding. In contrast, shorter lengths of angiotensin peptides, in particular, angiotensin IV (3-8), strongly increased spike-AXL binding. Angiotensin IV (3-8) also enhanced spike protein binding to ACE2 and NRP1. The discovery of the enhancing effects of angiotensin peptides on spike-host cell receptor binding may suggest that these peptides could be pharmacological targets to treat COVID-19 and post-acute sequelae of SARS-CoV-2 (PASC), which is also known as long COVID.

biochemistry↗

bioRxiv2024

Histopathological Evaluation of Pulmonary Arterial Remodeling in COVID-19

A positive-sense single-stranded RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused the coronavirus disease 2019 (COVID-19) pandemic that devastated the world. While this is a respiratory virus, one feature of the SARS-CoV-2 infection was recognized to cause pathogenesis of other organs. Because the membrane fusion protein of SARS-CoV-2, the spike protein, binds to its major host cell receptor angiotensin-converting enzyme 2 (ACE2) that regulates a critical mediator of cardiovascular diseases, angiotensin II, COVID-19 is largely associated with vascular pathologies. In fact, we have previous reported that postmortem lung tissues collected from patients who died of COVID-19 exhibited thickened pulmonary vascular walls and reduced vascular lumen. The present study extended these findings by further characterizing the pulmonary vasculature of COVID-19 patients using larger sample sizes and providing mechanistic information through histological observations. The examination of 56 autopsy lung samples showed thickened vascular walls of small pulmonary arteries after 14 days of disease compared to H1N1 influenza patients who died before COVID- 19 pandemic started. Pulmonary vascular remodeling in COVID-19 patients was associated with hypertrophy of the smooth muscle layer, perivascular fibrosis, edema and lymphostasis, inflammatory infiltration, perivascular hemosiderosis and neoangiogenesis. We found a correlation between the duration of hospital stay and the thickness of the muscular layer of pulmonary arterial walls. These results further confirm that COVID-19 affects the pulmonary vasculature and warrants an evaluation of patients that survived COVID-19 for possible future development of pulmonary arterial hypertension.

pathology↗

bioRxiv2023

gp120 envelope glycoproteins of HIV-1 Group M Subtype A and Subtype B differentially affect gene expression in human vascular endothelial cells

Cardiovascular complications are seen among human immunodeficiency virus (HIV)-positive individuals who can now survive longer due to successful antiretroviral therapies. Among them, pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased blood pressure in the lung circulation due to vasoconstriction and vascular wall remodeling, resulting in the overworking of the heart. The prevalence of PAH in the HIVpositive population is dramatically higher than that in the general population. While HIV-1 Group M Subtype B is the most prevalent subtype in western countries, the majority of HIV-1 infections in eastern Africa and former Soviet Union countries are caused by Subtype A. Research on the mechanism of vascular complications in the HIV-positive population, especially in the context of subtype differences, however, has not been rigorous. Much of the research on HIV has focused on Subtype B and information on the molecular mechanisms of Subtype A is non-existent. The lack of such knowledge results in health disparities in the development of therapeutic strategies to prevent/treat HIV complications. The present study examined the effects of HIV-1 viral fusion protein gp120 of Subtypes A and B on cultured human pulmonary artery endothelial cells by performing protein arrays. We found that the gene expression changes caused by the gp120s of Subtypes A and B are different. Specifically, Subtype A is a more potent downregulator of perostasin, matrix metalloproteinase-2 (MMP-2), and ErbB/Her3 than Subtype B, while Subtype B is more effective in downregulating monocyte chemotactic protein-2 (MCP-2/CCL8), MCP-3 (CCL7), and thymus- and activation-regulated chemokine (TARC/CCL17) proteins. This is the first report of gp120 proteins affecting host cells in an HIV subtype-specific manner, opening up the possibility that vascular complications may occur differently in HIV patients throughout the world.

cell biology↗

bioRxiv2020

Vasa vasorum lumen narrowing in brain vascular hyalinosis in systemic hypertension patients with ischemic stroke

Ischemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to the vascular lumen narrowing and stroke, the pathogenic mechanism of brain vascular hyalinosis has not been well characterized. Thus, the present study examined the postmortem brain vasculature of human patients who died of ischemic stroke due to systemic hypertension. Hematoxylin and eosin staining and immunohistochemistry showed the occurrence of brain vascular hyalinosis with infiltrated plasma proteins along with the narrowing of vasa vasorum and oxidative stress. Transmission electron microscopy revealed the endothelial cell bulge protrusion into the vasa vasorum lumen and the occurrence of endocytosis in the vasa vasorum endothelium. The treatment of cultured microvascular endothelial cells with adrenaline also promoted the formation of the bulge as well as endocytic vesicles. siRNA knockdown of sortin nexin-9 (a mediator of clathrin-mediated endocytosis) inhibited the adrenaline-induced endothelial cell bulge formation. Adrenaline promoted protein-protein interactions between sortin nexin-9 and neural Wiskott-Aldrich Syndrome protein (a regulator of actin polymerization). We propose that endocytosis-depending endothelial cell bulge narrows the vasa vasorum, resulting in ischemic oxidative damage to the cerebral vessels, the formation of hyalinosis, the occurrence of ischemic stroke, and death in systemic hypertension patients.

pathology↗

bioRxiv2020

Evidence for the role of cell reprogramming in naturally occurring cardiac repair

Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. If untreated, increased pulmonary vascular resistance kills patients within several years due to right heart failure. Even with the currently available therapies, survival durations remain short. By the time patients are diagnosed with this disease, the damage to the right ventricle (RV) has already developed. Therefore, agents that repair the damaged RV have therapeutic potential. We previously reported that cardiac fibrosis that occurs in the RV of adult Sprague-Dawley rats with PAH could naturally be reversed. We herein investigated the mechanism of this remarkable cardiac repair process. Counting of cardiomyocytes showed that the elimination of cardiac fibrosis is associated with the increased RV myocyte number, suggesting that new cardiomyocytes were generated. Immunohistochemistry showed the expression of -smooth muscle actin and Sox-2 in RV myocytes of rats with PAH. Transmission electron microscopy detected the structure that resembles maturing cardiomyocytes in both the RV of PAH rats and cultured cardiomyocytes derived from induced pluripotent stem cells. We propose that the damaged RV in PAH can be repaired by activating the cell reprogramming mechanism that converts resident cardiac fibroblasts into induced cardiomyocytes.

physiology↗

bioRxiv2020

Tau protein in smooth muscle cells and tissues

Tau is a microtubule-associated protein and plays a critical role in the pathophysiology of neurons. However, whether tau protein is expressed in smooth muscle cells is unknown. Here, we report that tau protein is expressed and is constitutively phosphorylated at threonine 181 in various smooth muscle cell types, including human cerebral artery smooth muscle cells, human pulmonary artery smooth muscle cells, and human bronchial airway smooth muscle cells. We also detected the expression of tau protein in the vascular smooth muscle of brain tissues from patients with systemic hypertension who died of ischemic stroke. Immunofluorescence staining revealed that phosphorylated tau at threonine 181 is more organized in the cell than does total tau protein. A protein phosphatase inhibitor, calyculin A induced the formation of higher molecular weight species of phosphorylated tau as visualized by Western blotting, indicating the occurrence of tau aggregation. Immunofluorescence also showed that calyculin A caused the aggregation of phosphorylated tau and disrupted the cytoskeletal organization. These results demonstrate the existence of tau protein in smooth muscle cells and tissues and that smooth muscle tau is susceptible to protein phosphorylation and aggregation.

cell biology↗

bioRxiv2020

SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells

Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. So far, 30 million people have been infected with SARS-CoV-2, and nearly 1 million people have died because of COVID-19 worldwide, causing serious health, economical, and sociological problems. However, the mechanism of the effect of SARS-CoV-2 on human host cells has not been defined. The present study reports that the SARS-CoV-2 spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in lung vascular cells. The treatment of human pulmonary artery smooth muscle cells or human pulmonary artery endothelial cells with recombinant SARS-CoV-2 spike protein S1 subunit (Val16 - Gln690) at 10 ng/ml (0.13 nM) caused an activation of MEK phosphorylation. The activation kinetics was transient with a peak at 10 min. The recombinant protein that contains only the ACE2 receptor-binding domain of SARS-CoV-2 spike protein S1 subunit (Arg319 - Phe541), on the other hand, did not cause this activation. Consistent with the activation of cell growth signaling in lung vascular cells by SARS-CoV-2 spike protein, pulmonary vascular walls were found to be thickened in COVID-19 patients. Thus, SARS-CoV-2 spike protein-mediated cell growth signaling may participate in adverse cardiovascular/pulmonary outcomes, and this mechanism may provide new therapeutic targets to combat COVID-19.

pathology↗

bioRxiv2020

Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimers disease brain

Alzheimers disease is a chronic neurodegenerative disorder and represents the main cause of dementia. Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of Alzheimers disease patients. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimers disease and the ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimers disease, and Alzheimers disease brains examined in this study also exhibited higher carbonylated proteins as well as increased thiol oxidation state of peroxiredoxin 6 (Prx6). The positive correlation was found between the increased ACE2 protein expression and oxidative stress in Alzheimers disease brain. Thus, the present study reveals the relationships between Alzheimers disease and ACE2, the receptor for SARS-CoV-2. These results warrant monitoring Alzheimers disease patients with COVID-19 carefully for the possible higher viral load in the brain and long-term adverse neurological consequences.

biochemistry↗