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Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke

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A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Applied Biosciences and Bioengineering".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 22511

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Prof. Dr. Joen-Rong Sheu

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Department of Pharmacology, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
Interests: cardiovascular pharmacology; protein bio—chemistry; signal transduction; platelet biology; anti-thrombotic drug development
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Assoc. Prof. Dr. Cheng-ying Hsieh

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Department of Pharmacology, School of Medcine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

Dr. Thanasekaran Jayakumar

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Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I am pleased to invite you to contribute to a Special Issue of the journal Applied Sciences on “Natural or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke”, which aims to present recent developments in the fields of cardiovascular pharmacology, neuroscience, and natural biochemistry.

The implications of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction. Despite the importance of neurovascular disease and subsequent injury after ischemic events, essential knowledge in these areas lags behind our current understanding of neuroprotection and vascular biology in general. According to the current epidemiological data, it is expected that to date, coronary artery disease and cerebral hemorrhage are still the first and second causes of death of human being, a trend that is set to continue into 2020. However, despite various developments in the understanding of the diseases, pharmacological treatment by conventional medicine has not gained satisfactory results.

There is extensive evidence to show that drug treatment of conventional risk factors is effective in reducing cardiovascular events. Apart from the treatment of cardiovascular risk factors with pharmacological agents and the use of antithrombotic drugs, there is growing awareness of the role of herbal medicines and natural products in the prevention of vascular diseases and the possibility of their use in treatment. Therefore, this Special Issue aims to motivate contributions of original as well as review articles that will provoke enduring actions to understand the pathology underlying cerebral–neurovascular diseases and the growth of strategies to prevent and treat these conditions.

Prof. Dr. Joen-Rong Sheu
Assoc. Prof. Dr. Cheng-ying Hsieh
Dr. Thanasekaran Jayakumar
Guest Editors

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Keywords

Platelet activation and thrombosis
Vascular diseases
Drug development
Neuroprotection
Neuroinflammation
Free radicals/oxidative stress
Natural/synthetic compounds in the inflammatory response

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 173 KiB

Open AccessEditorial

Special Issue “Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke”

by Thanasekaran Jayakumar and Joen-Rong Sheu

Appl. Sci. 2022, 12(16), 8194; https://doi.org/10.3390/app12168194 - 16 Aug 2022

Viewed by 950

Abstract

Stroke is the second main cause of mortality and morbidity globally [...] Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

Research

Jump to: Editorial, Review

13 pages, 4401 KiB

Open AccessArticle

Comparison of the Potency of Pterostilbene with NF-κB Inhibitors in Platelet Activation: Mutual Activation by Akt-NF-κB Signaling in Human Platelets

by Chih-Wei Hsia, Wei-Chieh Huang, Chih-Hao Yang, Chih-Hsuan Hsia, Thanasekaran Jayakumar, Periyakali Saravana Bhavan, Joen-Rong Sheu and Kuan-Rau Chiou

Appl. Sci. 2021, 11(13), 6149; https://doi.org/10.3390/app11136149 - 2 Jul 2021

Cited by 7 | Viewed by 2406

Abstract

Myocardial infarction and cerebral ischemic stroke are prominent causes of death worldwide. Platelets play major roles in these diseases, although they are anucleated cells, but also express the NF-κB. Pterostilbene (PTE) possesses some intriguing pharmacological properties, including the capacity to inhibit platelet activation. We investigated the inhibitory role of PTE in NF-κB-mediated signal events and compared the relative potency with that of classical NF-κB inhibitors. PTE and IκB kinase (IKK) inhibitor, BAY11-7082, and proteasome inhibitor, Ro106-9920, inhibited platelet aggregation; the activity of BAY11-7082 and PTE were similar, but Ro106-9920 was weak in this reaction. PTE and BAY11-7082 diminished NF-κB signaling molecules, including IKK, IκBα, and p65 phosphorylation, and reversed IκBα degradation. However, Ro106-9920 was only effective in diminishing p65 phosphorylation and reversing IκBα degradation. In investigating the role of Akt and NF-κB in cell signaling events, MK-2206 (an inhibitor of Akt) markedly abolished IKK and p65 phosphorylation; BAY11-7082 also reduced Akt phosphorylation. PTE exhibited more potent activity in vivo than did BAY11-7082 in acute pulmonary thromboembolism. In conclusion, we identified a distinctive activation pathway of NF-κB and Akt involved in PTE-mediated antiplatelet aggregation, and PTE demonstrated powerful activity as a prophylactic and as clinical therapy for cardiovascular diseases. Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

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12 pages, 2069 KiB

Open AccessArticle

Involvement of Antioxidant Defenses and NF-κB/ERK Signaling in Anti-Inflammatory Effects of Pterostilbene, a Natural Analogue of Resveratrol

by Thanasekaran Jayakumar, Ming-Ping Wu, Joen-Rong Sheu, Chih-Wei Hsia, Periyakali Saravana Bhavan, Manjunath Manubolu, Chi-Li Chung and Chih-Hsuan Hsia

Appl. Sci. 2021, 11(10), 4666; https://doi.org/10.3390/app11104666 - 19 May 2021

Cited by 10 | Viewed by 2427

Abstract

Pterostilbene (PTE), a natural stilbenoid occurring in grapes and berries, is recognized as a dimethylated analogue of resveratrol. This compound shows numerous notable pharmacological activities, including antiaging, anticancer, antidiabetes, antioxidant, and neuroprotection. This study investigates the anti-inflammatory properties of PTE in macrophage cells (RAW 264.7) against the lipoteichoic acid (LTA) stimulation. The expression of inflammatory tumor necrosis factor (TNF-α), interleukin-1β (IL-1 β), and inducible nitric oxide synthase (iNOS) and the content of nitric oxide (NO) were detected in LTA-induced cells. In addition, a Western blot assay was used to detect mitogen-activated protein kinases: extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and c-Jun N-terminal kinase (JNK). The phosphorylation of IκB and p65 and translocation of nuclear factor kappa B (NF-κB) were assessed by Western blot and immuno-fluorescence staining. The results showed that PTE significantly attenuated NO production and TNF-α, IL-1 β, and iNOS expression in LTA stimulated cells. Among the activation of ERK, JNK, and p38 in cells treated with LTA, PTE at higher concentration had only inhibited ERK activation. However, PTE blocked IκB phosphorylation, phosphorylation and nuclear translocation of p65NF-κB. Fascinatingly, PTE enhanced antioxidant defense molecules as verified by the enhanced heme oxygenase-1 (HO-1) expression, catalase (CAT) antioxidant enzyme, and non-enzymatic antioxidant, and reduced glutathione (GSH) in LTA-induced RAW 264.7 cells. These results suggest that PTE exerts an anti-inflammatory property via attenuating NF-κB/ERK signaling pathways as well as enriching antioxidant defense mechanisms. Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

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13 pages, 2913 KiB

Open AccessArticle

Platonin, a Cyanine Photosensitizing Dye, Ameliorates Inflammatory Responses in Vascular Smooth Muscle Cells by Modulating Inflammatory Transcription Factors

by Chih-Wei Chiu, Chih-Hao Yang, Jie-Heng Tsai, Cheng-Ying Hsieh and Shih-Yi Huang

Appl. Sci. 2021, 11(3), 1130; https://doi.org/10.3390/app11031130 - 26 Jan 2021

Cited by 2 | Viewed by 2212

Abstract

Inflammation of the arterial wall is critical to atherosclerosis pathogenesis. The switch of vascular smooth muscle cells (VSMCs) to macrophage-like cells is essential in the exacerbation of vascular inflammation. Platonin, a cyanine photosensitizing dye, exhibits protective effects in sepsis, trauma, and acute ischemic stroke through its anti-inflammatory capacity in macrophages. The present study investigated the effects and underlying mechanisms of platonin in inflammatory VSMCs. Pretreatment with platonin suppressed the expression of inducible nitric oxide synthetase and mature interleukin-1β but not that of monocyte chemoattractant protein-1 (MCP-1) in VSMCs stimulated by a combination of lipopolysaccharide and interferon-γ (LPS/IFN-γ). Furthermore, platonin inhibited LPS/IFN-γ-induced Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation though the direct reduction of p65^Ser536 phosphorylation but not the restoration of Inhibitor of nuclear factor kappa B (IκBα) degradation in VSMCs. However, platonin inhibited Oxidized low-density lipoprotein (ox-LDL)-induced MCP-1 production, possibly through the attenuation of Activator protein 1 (AP-1) binding activity and C-Jun N-terminal kinases ½ (JNK1/2) phosphorylation. Platonin also lowered lipid drop accumulation in VSMCs in Oil red O staining assay. The results collectively indicated that platonin has a vascular protective property with potent anti-inflammatory effects in VSMCs. In conclusion, platonin should be a potential for treating vascular inflammatory diseases such as atherosclerosis. Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

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13 pages, 1947 KiB

Open AccessArticle

TQ-6, a Novel Ruthenium Derivative Compound, Possesses Potent Free Radical Scavenging Activity in Macrophages and Rats

by Kao-Wei Hung, Chao-Chien Chang, Thanasekaran Jayakumar, Marappan Velusamy, Chih-Wei Hsia, Nguyen Thi Thu Trang, Duen-Suey Chou, Cheng-Ying Hsieh and Chih-Hsuan Hsia

Appl. Sci. 2021, 11(3), 1008; https://doi.org/10.3390/app11031008 - 23 Jan 2021

Cited by 1 | Viewed by 2447

Abstract

Reactive oxygen species (ROS) play major role in inducing inflammation and related diseases. Our previous studies have revealed that the ruthenium (II)-compound, [Ru(η⁶-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF₄ (TQ-6), inhibits hydroxyl radical (OH^•) formation in human platelets. TQ-6 also have protective effect against induced inflammation in macrophages and hepatic injury in mice through NF-κB signaling. However, the free radical formation inhibitory mechanism of TQ-6 in macrophages is unclear. Therefore, this study detected the antioxidative ability of TQ-6 in both a cell-free system and in LPS-induced macrophages through electron spin resonance (ESR) spectrometry. TQ-6 reduced 1,1-diphenyl-2-picrylhydrazyl (DPPH), galvinoxyl, and superoxide radicals in a cell-free system and OH^• formation in macrophages. Additionally, TQ-6 activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and upregulated the antioxidant protein heme oxygenase-1 (HO-1) to elevate anti-inflammatory activity in LPS-induced macrophage cells and inhibited carrageenan-induced paw edema in a rat model. Therefore, TQ-6 may prevent oxidative stress and also act as an effective therapeutic agent for the treatment of oxidant-related diseases. Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

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16 pages, 2468 KiB

Open AccessArticle

Magnolol, A Novel Antagonist of Thrombin and PAR-1, Inhibits Thrombin-Induced Connective Tissue Growth Factor (CTGF) Expression in Vascular Smooth Muscle Cells and Ameliorate Pathogenesis of Restenosis in Rats

by Wen-Chin Ko, Chia-Ti Tsai, Kai-Cheng Hsu, Yu-Che Cheng, Tony Eight Lin, Yi-Ling Chen, Chuang-Ye Hong, Wan-Jung Lu, Chun-Ming Shih and Ting-Lin Yen

Appl. Sci. 2020, 10(23), 8729; https://doi.org/10.3390/app10238729 - 5 Dec 2020

Cited by 2 | Viewed by 3164

Abstract

Restenosis and destructive vascular remodeling are the main reasons for treatment failure in patients undergoing percutaneous coronary intervention (PCI). In this study, we explored the efficacy of magnolol (a traditional Chinese medicine) in the treatment of restenosis. The results of this study showed that the activities of thrombin and PAR-1 (protease-activated receptor 1) were significantly decreased by the treatment of magnolol. Based on protein docking analysis, magnolol exhibits its potential to bind to the PAR-1 active site. In addition, thrombin-induced connective tissue growth factor (CTGF) expression and the upstream of CTGF such as JNK-1 (but not JNK-2), c-Jun, and AP-1 were distinctly inhibited by magnolol (50 μM) in vascular smooth muscle cells (VSMC). For the functional assay, magnolol (50 μM) significantly inhibited the migration of VSMC, and rats treated with magnolol (13 mg/kg/day) after balloon angioplasty has observed a significant reduction in the formation of common arterial neointima. In conclusion, we identified a novel mechanism by which magnolol acts as the thrombin activity inhibitor and may be the PAR-1 antagonist. In accordance with these functions, magnolol could decrease thrombin-induced CTGF expression in VSMCs via PAR-1/JNK-1/AP-1 signaling. Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

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15 pages, 2989 KiB

Open AccessArticle

Reduction of NF-κB Signals in Platelets and Prolongation of Platelet Plug Formation against High Shear Flow in Whole Blood on Human Subject by Columbianadin

by Chih-Wei Hsia, Chih-Hao Yang, Joen-Rong Sheu, Chih-Hsuan Hsia, Cheng-Lin Tsai, Wei-Chieh Huang, Ting-Yu Chen, Thanasekaran Jayakumar, Periyakali Saravana Bhavan and Yi Chang

Appl. Sci. 2020, 10(20), 7323; https://doi.org/10.3390/app10207323 - 19 Oct 2020

Cited by 1 | Viewed by 2400

Abstract

Myocardial infarction and cerebral ischemic stroke during the process of arterial thrombosis are prominently causes of death worldwide. Platelets are anucleated cells and play a critical factor in these diseases. Columbianadin (CBN), a coumarin derivative from plants, inhibits effective platelet activation. In this study, platelet function analysis revealed that the closure time of the platelet plug in human whole blood significantly prolonged by CBN, whereas CBN did not pointedly prolong the bleeding time in mice. BAY11-7082 (an inhibitor of IκB kinase) and MG-132 (an inhibitor of proteasome) inhibited collagen-stimulated platelet aggregation and ATP-release in human platelets, BAY11-7082 exhibited a higher potency than MG-132. Moreover, CBN markedly reduced NF-κB activation (e.g., IκBα and p65 phosphorylation) and reversed IκBα degradation in activated platelets. We investigated intercellular signaling events between mitogen-activated protein kinases and NF-κB, and found that BAY11-7082 abolished JNK1/2 and ERK1/2 phosphorylation. Interestingly, SP600125 (an inhibitor of JNK) but not PD98059 (an inhibitor of ERK) had no effect in NF-κB activation in activated platelets. Moreover, CBN but not BAY11-7082 significantly reduced hydroxyl radical (HO^●) formation in platelets. Therefore, we propose that CBN inhibits NF-κB activation in human platelets and could present a potent clinical treatment for thromboembolic diseases. Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

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11 pages, 1337 KiB

Open AccessArticle

A Novel Microchip Technique for Quickly Identifying Nanogranules in an Aqueous Solution by Transmission Electron Microscopy: Imaging of Platelet Granules

by Nguyen Thi Thu Trang, Jungshan Chang, Wei-An Chen, Chih-Chun Chen, Hui-Min Chen, Chao-Chien Chang and Tsorng-Harn Fong

Appl. Sci. 2020, 10(14), 4946; https://doi.org/10.3390/app10144946 - 18 Jul 2020

Cited by 4 | Viewed by 2797

Abstract

Ultrastructural observation of biological specimens or nanogranules usually requires the use of electron microscopy. Electron microscopy takes a lot of time, requires many steps, and uses many chemicals, which may affect the native state of biological specimens. A novel microchip (K-kit) was used as a specimen kit for in situ imaging of human platelet granules in an aqueous solution using a transmission electron microscope. This microchip enabled us to observe the native human platelet granules very quickly and easily. The protocols included blood collection, platelet purification, platelet granule isolation, sample loading into this microchip, and then observation by a transmission electron microscope. In addition, these granules could still remain in aqueous solution, and only a very small amount of the sample was required for observation and analysis. We used this microchip to identify the native platelet granules by negative staining. Furthermore, we used this microchip to perform immunoelectron microscopy and successfully label α-granules of platelets with the anti-P-selectin antibody. These results demonstrate that the novel microchip can provide researchers with faster and better choices when using a transmission electron microscope to examine nanogranules of biological specimens in aqueous conditions. Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

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Review

Jump to: Editorial, Research

16 pages, 961 KiB

Open AccessReview

Heparin-Eluting Tissue-Engineered Bioabsorbable Vascular Grafts

by Yuichi Matsuzaki, Anudari Ulziibayar, Toshihiro Shoji and Toshiharu Shinoka

Appl. Sci. 2021, 11(10), 4563; https://doi.org/10.3390/app11104563 - 17 May 2021

Cited by 14 | Viewed by 2859

Abstract

The creation of small-diameter tissue-engineered vascular grafts using biodegradable materials has the potential to change the quality of cardiovascular surgery in the future. The implantation of these tissue-engineered arterial grafts has yet to reach clinical application. One of the reasons for this is thrombus occlusion of the graft in the acute phase. In this paper, we first describe the causes of accelerated thrombus formation and discuss the drugs that are thought to inhibit thrombus formation. We then review the latest research on methods to locally bind the anticoagulant heparin to biodegradable materials and methods to extend the duration of sustained heparin release. We also discuss the results of studies using large animal models and the challenges that need to be overcome for future clinical applications. Full article

(This article belongs to the Special Issue Nature or Synthetic Compounds for Treating Arterial Thrombosis and Ischemic Stroke)

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