scholarly journals YQFM Alleviates Side Effects Caused by Dasatinib through the ROCK/MLC Pathway in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yuankai Liu ◽  
Yujie Dai ◽  
Han Xu ◽  
Qianliu Zhou ◽  
Fang Li ◽  
...  
Keyword(s):  
Side Effects ◽  
Signaling Pathway ◽  
Tyrosine Kinases ◽  
Antitumor Effect ◽  
Kinase Inhibitor ◽  
Liver Toxicity ◽  
Treatment Method ◽  
Powder Injection ◽  
Effective Prevention ◽  
Mlc Phosphorylation

Dasatinib, as a second-generation broad-spectrum tyrosine kinase inhibitor, presents an antitumor effect by inhibiting tyrosine kinases. However, dasatinib causes serious side effects, such as gastrointestinal bleeding and liver toxicity, possibly through the activation of ROCK kinase and MLC phosphorylation. At present, there is no effective prevention and treatment method. Previous research studies have shown that YQFM (YiQiFuMai powder injection) protects the blood-brain barrier by inhibiting the ROCK/MLC signaling pathway; whether YQFM can alleviate the side effects of dasatinib is unknown. In this study, dasatinib was injected (i.p. 70 mg/kg) and YQFM (i.p. 0.336 g/kg, 0.672 g/kg, 1.342 g/kg) was given in advance for 3 days to mice, to explore the effect of YQFM on side effects induced by Dasatinib. The results confirmed that YQFM significantly decreased Evans blue leakage in the small intestine and increased intestinal blood flow, increased the expression of ZO-1, Occludin, and VE-cadherin, and reduced the contents of D-lactic acid, s-VE-cadherin, Alanine aminotransferase (ALT), and Aspartate aminotransferase (AST) in serum. Finally, YQFM inhibited the expression of ROCK-1 and phosphorylation of MLC induced by Dasatinib. These findings suggested that YQFM could improve the side effects caused by Dasatinib linked with the ROCK/MLC signaling pathway, as shown in the graphical abstract.

scholarly journals Activation of G12/G13 Results in Shape Change and Rho/Rho-Kinase–mediated Myosin Light Chain Phosphorylation in Mouse Platelets

1999 ◽  
Vol 144 (4) ◽  
pp. 745-754 ◽  
Author(s):  
Birgit Klages ◽  
Ursula Brandt ◽  
Melvin I. Simon ◽  
Günter Schultz ◽  
Stefan Offermanns
Keyword(s):  
Light Chain ◽  
Tyrosine Kinases ◽  
Myosin Light Chain ◽  
Kinase Inhibitor ◽  
Shape Change ◽  
Rho Kinase ◽  
Α Subunit ◽  
Camp Analogue ◽  
Txa2 Receptor ◽  
Mlc Phosphorylation

Platelets respond to various stimuli with rapid changes in shape followed by aggregation and secretion of their granule contents. Platelets lacking the α-subunit of the heterotrimeric G protein Gq do not aggregate and degranulate but still undergo shape change after activation through thromboxane-A2 (TXA2) or thrombin receptors. In contrast to thrombin, the TXA2 mimetic U46619 led to the selective activation of G12 and G13 in Gαq-deficient platelets indicating that these G proteins mediate TXA2 receptor-induced shape change. TXA2 receptor-mediated activation of G12/G13 resulted in tyrosine phosphorylation of pp72syk and stimulation of pp60c-src as well as in phosphorylation of myosin light chain (MLC) in Gαq-deficient platelets. Both MLC phosphorylation and shape change induced through G12/G13 in the absence of Gαq were inhibited by the C3 exoenzyme from Clostridium botulinum, by the Rho-kinase inhibitor Y-27632 and by cAMP-analogue Sp-5,6-DCl-cBIMPS. These data indicate that G12/G13 couple receptors to tyrosine kinases as well as to the Rho/Rho-kinase–mediated regulation of MLC phosphorylation. We provide evidence that G12/G13-mediated Rho/Rho-kinase–dependent regulation of MLC phosphorylation participates in receptor-induced platelet shape change.

Ruscogenin Alleviates Intestinal Bleeding and Blood Flow Induced by Dasatinib through ROCK/MLC Pathway

2020 ◽  
Author(s):  
Yuankai Liu ◽  
Yujie Dai ◽  
Han Xu ◽  
Qianliu Zhou ◽  
Fang Li ◽  
...  
Keyword(s):  
Blood Flow ◽  
Side Effects ◽  
Gastrointestinal Bleeding ◽  
Western Blot ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Effective Means ◽  
Laser Doppler ◽  
Myelogenous Leukemia ◽  
Intestinal Bleeding

Abstract BackgroundAs a second-generation broad-spectrum tyrosine kinase inhibitor, Dasatinib has the antitumor effect of inhibiting tyrosine kinases such as BCR-ABL and SRC. It is mainly used to treat chronic and acute patients with chronic myelogenous leukemia. However, Dasatinib has many side effects, including gastrointestinal bleeding, respiratory infections, and renal failure, and effective means to improve the side effects of drugs are lacking.MethodsC57BL/6 mice and HUVECs were used to evaluate the side effects caused by dasatinib, RUS was administered in advance to prevent, protein expression and phosphorylation were measured by western blot, and monitored the intestinal bleeding with Laser Doppler Blood Flow Monitor. ResultsWe found that Ruscogenin (RUS) can improve Side effects caused by Dasatinib. Through the Laser Doppler Blood Flow Monitor, it was found that after Dasatinib was administered, blood flow in mice are decreased, and intestinal Evans blue leakage increased. Western blot results showed that connexin (ZO-1, VE-cadherin, Occludin) is destroyed, the activation of ROCK increases, and the phosphorylation of MLC increases. Ruscogenin can reverse the above phenomenon and improve the side effects of gastrointestinal bleeding caused by Dasatinib. In vitro, giving Ruscogenin in advance can protect the endothelial barrier damage caused by Dasatinib, reduce the remodeling of F-actin, and restore the expression of connexin (ZO-1, VE-cadherin), inhibit the activation of ROCK, and reduce Phosphorylation of MLC. ConclusionsThis study provides a new direction for improving the side effects caused by clinical drugs and confirm that Ruscogenin could improve the side effect from Dasatinib by ROCK/MLC pathway.

scholarly journals Ruscogenin alleviates intestinal bleeding and blood flow induced by Dasatinib through ROCK/MLC pathway

2021 ◽  
Author(s):  
Yuankai Liu ◽  
Yujie Dai ◽  
Han Xu ◽  
Qianliu Zhou ◽  
Fang Li ◽  
...  
Keyword(s):  
Blood Flow ◽  
Side Effects ◽  
Gastrointestinal Bleeding ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Effective Means ◽  
Myelogenous Leukemia ◽  
Endothelial Barrier ◽  
Intestinal Bleeding ◽  
Doppler Flowmeter

Abstract As a second-generation broad-spectrum tyrosine kinase inhibitor, Dasatinib has the antitumor effect of inhibiting tyrosine kinases such as BCR-ABL and SRC. It is mainly used to treat chronic and acute patients with chronic myelogenous leukemia. However, Dasatinib has many side effects, including gastrointestinal bleeding, respiratory infections, and renal failure, and effective means to improve the side effects of drugs are lacking. The occurrence of gastrointestinal bleeding is mainly due to the destruction of the vascular endothelial barrier by Dasatinib. For the first time, we administered a large dose of oral administration and monitored the intestinal bleeding with a laser Doppler flowmeter. We found that Ruscogenin (RUS) can improve dasatin Side effects caused by tinib. Through Doppler flowmeter detection, it was found that after Dasatinib was administered, blood flow in mice decreased, and intestinal Evans blue leakage increased. Western blot results showed that connexin (ZO-1, VE-cadherin, Occludin) is destroyed, the activation of ROCK increases, and the phosphorylation of MLC increases. Ruscogenin can reverse the above phenomenon and improve the side effects of gastrointestinal bleeding caused by Dasatinib. In vitro, giving Ruscogenin in advance can protect the endothelial barrier damage caused by Dasatinib, reduce the remodeling of F-actin, and restore the expression of connexin (ZO-1, VE-cadherin), inhibit the activation of ROCK, and reduce Phosphorylation of MLC. This study provides a new direction for improving the side effects caused by clinical drugs.

Encapsulation of Imatinib in Targeted KIT-5 Nanoparticles for Reducing its Cardiotoxicity and Hepatotoxicity

2020 ◽  
Vol 20 (16) ◽  
pp. 1966-1980
Author(s):  
Jaleh Varshosaz ◽  
Saeedeh Fardshouraki ◽  
Mina Mirian ◽  
Leila Safaeian ◽  
Setareh Jandaghian ◽  
...  
Keyword(s):  
Controlled Release ◽  
Side Effects ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Drug Carrier ◽  
Free Drug ◽  
Jurkat Cells ◽  
Targeted Nanoparticles ◽  
Inhibitor Drug ◽  
Histopathological Results

Background: Using imatinib, a tyrosine kinase inhibitor drug used in lymphoblastic leukemia, has always had limitations due to its cardiotoxicity and hepatotoxicity side effects. The objective of this study is to develop a target-oriented drug carrier to minimize these adverse effects by the controlled release of the drug. Methods: KIT-5 nanoparticles were functionalized with 3-aminopropyltriethoxysilane and conjugated to rituximab as the targeting agent for the CD20 positive receptors of the B-cells. Then they were loaded with imatinib and their physical properties were characterized. The cell cytotoxicity of the nanoparticles was studied by MTT assay in Ramos (CD20 positive) and Jurkat cell lines (CD20 negative) and their cellular uptake was shown by fluorescence microscope. Wistar rats received an intraperitoneal injection of 50 mg/kg of the free drug or targeted nanoparticles for 21 days. Then the level of aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) were measured in serum of animals. The cardiotoxicity and hepatotoxicity of the drug were also studied by hematoxylin and eosin staining of the tissues. Results: The targeted nanoparticles of imatinib showed to be more cytotoxic to Ramos cells rather than Jurkat cells. The results of the biochemical analysis displayed a significant reduction in AST, ALT, ALP, and LDH levels in animals treated with targeted nanoparticles, compared to the free drug group. By comparison with the free imatinib, histopathological results represented less cardiotoxicity and hepatotoxicity in the animals, which received the drug through the current designed delivery system. Conclusion: The obtained results confirmed that the rituximab targeted KIT-5 nanoparticles are promising in the controlled release of imatinib and could decrease its cardiotoxicity and hepatotoxicity side effects.

MAPK: A Key Player in the Development and Progression of Stroke

2020 ◽  
Vol 19 (4) ◽  
pp. 248-256
Author(s):  
Yangmin Zheng ◽  
Ziping Han ◽  
Haiping Zhao ◽  
Yumin Luo
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Complex Disease ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Effective Prevention ◽  
Prevention And Treatment ◽  
Different Cell Types

Conclusion: Stroke is a complex disease caused by genetic and environmental factors, and its etiological mechanism has not been fully clarified yet, which brings great challenges to its effective prevention and treatment. MAPK signaling pathway regulates gene expression of eukaryotic cells and basic cellular processes such as cell proliferation, differentiation, migration, metabolism and apoptosis, which are considered as therapeutic targets for many diseases. Up to now, mounting evidence has shown that MAPK signaling pathway is involved in the pathogenesis and development of ischemic stroke. However, the upstream kinase and downstream kinase of MAPK signaling pathway are complex and the influencing factors are numerous, the exact role of MAPK signaling pathway in the pathogenesis of ischemic stroke has not been fully elucidated. MAPK signaling molecules in different cell types in the brain respond variously after stroke injury, therefore, the present review article is committed to summarizing the pathological process of different cell types participating in stroke, discussed the mechanism of MAPK participating in stroke. We further elucidated that MAPK signaling pathway molecules can be used as therapeutic targets for stroke, thus promoting the prevention and treatment of stroke.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

scholarly journals Rho-kinase inhibitor hydroxyfasudil protects against HIV-1 Tat-induced dysfunction of tight junction and neprilysin/Aβ transfer receptor expression in mouse brain microvessels

2021 ◽  
Vol 476 (5) ◽  
pp. 2159-2170
Author(s):  
Qiangtang Chen ◽  
Yu Wu ◽  
Yachun Yu ◽  
Junxiang Wei ◽  
Wen Huang
Keyword(s):  
Tight Junction ◽  
Signaling Pathway ◽  
Mouse Brain ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Brain Microvessels ◽  
Rho Kinase Inhibitor ◽  
Hiv 1

AbstractHIV-1 transactivator protein (Tat) induces tight junction (TJ) dysfunction and amyloid-beta (Aβ) clearance dysfunction, contributing to the development and progression of HIV-1-associated neurocognitive disorder (HAND). The Rho/ROCK signaling pathway has protective effects on neurodegenerative disease. However, the underlying mechanisms of whether Rho/ROCK protects against HIV-1 Tat-caused dysfunction of TJ and neprilysin (NEP)/Aβ transfer receptor expression have not been elucidated. C57BL/6 mice were administered sterile saline (i.p., 100 μL) or Rho-kinase inhibitor hydroxyfasudil (HF) (i.p., 10 mg/kg) or HIV-1 Tat (i.v., 100 μg/kg) or HF 30 min before being exposed to HIV-1 Tat once a day for seven consecutive days. Evans Blue (EB) leakage was detected via spectrophotometer and brain slides in mouse brains. The protein and mRNA levels of zonula occludens-1 (ZO-1), occludin, NEP, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in mouse brain microvessels were, respectively, analyzed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. Exposure of the mice to HIV-1 Tat increased the amount of EB leakage, EB fluorescence intensity, blood–brain barrier (BBB) permeability, as well as the RAGE protein and mRNA levels, and decreased the protein and mRNA levels of ZO-1, occludin, NEP, and LRP1 in mouse brain microvessels. However, these effects were weakened by Rho-kinase inhibitor HF. Taken together, these results provide information that the Rho/ROCK signaling pathway is involved in HIV-1 Tat-induced dysfunction of TJ and NEP/Aβ transfer receptor expression in the C57BL/6 mouse brain. These findings shed some light on potentiality of inhibiting Rho/Rock signaling pathway in handling HAND.

scholarly journals Toxic Animal-Based Medicinal Materials Can Be Effective in Treating Endometriosis: A Scoping Review

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 145
Author(s):  
Su-In Hwang ◽  
Young-Jin Yoon ◽  
Soo-Hyun Sung ◽  
Ki-Tae Ha ◽  
Jang-Kyung Park
Keyword(s):  
Side Effects ◽  
Clinical Studies ◽  
Malignant Tumors ◽  
Experimental Studies ◽  
Herbal Medicines ◽  
Treatment Method ◽  
Reproductive Age ◽  
Dependent Growth ◽  
Gynecological Disorder ◽  
Preclinical And Clinical Studies

Animal toxins and venoms have recently been developed as cancer treatments possessing tumor cell growth-inhibitory, antiangiogenesis, and proapoptotic effects. Endometriosis is a common benign gynecological disorder in reproductive-age women, and no definite treatment for this disorder is without severe side effects. As endometriosis and malignant tumors share similar characteristics (progressive, invasive, estrogen-dependent growth, and recurrence), animal toxins and venoms are thought to be effective against endometriosis. The objective of this study was to outline studies using toxic animal-based medicinal materials (TMM) as endometriosis treatment and to explore its clinical applicability. Preclinical and clinical studies using TMM were searched for in four databases from inception to October 2020. A total of 20 studies of TMM on endometriosis were included. In eight clinical studies, herbal medicines containing TMM were effective in relieving symptoms of endometriosis, with no side effects. In twelve experimental studies, the main therapeutic mechanisms of TMM against endometriosis were proapoptotic, antiangiogenesis, estrogen level-reducing, and possible anti-inflammatory effects. TMM are thus considered promising sources for the development of an effective treatment method for endometriosis. Further studies are needed to clarify the therapeutic mechanism of TMM against endometriosis and to provide sufficient grounds for clinical application.

Effectiveness and safety of modern treatment against nausea and vomiting induced by chemotherapy and radiotherapy

2021 ◽  
Vol 14 (1) ◽  
pp. 11-15
Author(s):  
Łukasz Hajac ◽  
Martyna Hajac ◽  
Adam Maciejczyk
Keyword(s):  
Side Effects ◽  
Serotonin Syndrome ◽  
Nausea And Vomiting ◽  
Effective Prevention ◽  
Important Group ◽  
Life Threatening ◽  
Treatment Changes ◽  
Long Acting ◽  
Methods Of Treatment

Nausea and vomiting are one of most frequent side effects of chemotherapy and radiotherapy. Effective prevention and treatment of these symptoms is essential for better quality of life for patients undergoing oncological therapies. Nausea and vomiting can be acute, delayed or anticipatory. Leading mechanisms and methods of treatment are different for each of those. Most often used groups of drugs are: 5-HT3-antagonists, glucocorticosteroids, NK1-antagonists. Another important group are neuroleptics, which are therapy of choice for anticipatory vomiting. Modern antiemetic medications are in most cases safe and effective. But as every treatment it causes risks of adverse events which may be serious and difficult to manage. It applies in particular to long-acting drugs. Most common side effects are headache, constipation and sedation. But more severe or life-threatening symptoms may appear, like intestinal obstruction and serotonin syndrome. Some of the drugs also come with risk of interacting with other treatment. Changes in pharmacokinetics may lead to additional toxicities. In elderly, especially with cardiac disease, in risk of ileus or cachexia these drugs shall be used with caution.

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