scholarly journals Distinct Roles of ROCK1 and ROCK2 on the Cerebral Ischemia Injury and Subsequently Neurodegenerative Changes

Pharmacology ◽  
2019 ◽  
Vol 105 (1-2) ◽  
pp. 3-8 ◽  
Author(s):  
Weizhuo Lu ◽  
Jiyue Wen ◽  
Zhiwu Chen
Keyword(s):  
Cerebral Ischemia ◽  
Axonal Regeneration ◽  
Current Knowledge ◽  
Rho Kinase ◽  
Synaptic Function ◽  
Cerebral Injury ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Promising Target ◽  
Cerebral Ischemic

Cerebral ischemic injury is one of the main causes of adult disability and death. Although significant progress has been made, cerebral ischemia continues to be a major risk to public health worldwide. The Rho kinase (ROCK) signaling pathway has been reported to be significantly involved in many mechanisms of cerebral injury. Although ROCK is ubiquitously expressed in all tissues, ROCK2 subtype expression in brain and the spinal cord is more abundant and improves with age. This makes it a promising target for new therapeutic approaches. In this article, we review the current knowledge on the involvement of ROCK in cerebral ischemia injury and neurodegenerative changes after cerebral injury. After a detailed description of the mechanism of ROCK involvement in axonal regeneration and synaptic function, different roles of ROCK1 and ROCK2 in neurons under physiological and pathological conditions are compared and discussed. In addition, different functions of genetic and pharmacological inhibitions of ROCK1 and ROCK2 on cerebral injury are discussed.

scholarly journals GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Guanzheng Liu ◽  
Jiefeng Yu ◽  
Runqiu Wu ◽  
Lin Shi ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Therapeutic Interventions ◽  
Therapeutic Approaches ◽  
Preclinical Models ◽  
Unfolded Protein ◽  
Tumor Bearing ◽  
New Therapeutic Approaches ◽  
Protein Ubiquitination ◽  
Promising Target ◽  
Key Factor ◽  
Protein Response

AbstractGlioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We identified ubiquitin-activating enzyme 1 (UBA1) inhibitor TAK-243 that can strongly induce UPR in GBM cells. In this study, we evaluated the functional activity and mechanism of TAK-243 in preclinical models of GBM. TAK-243 significantly inhibited the survival, proliferation, and colony formation of GBM cell lines and primary GBM cells. It also revealed a significant anti-tumor effect on a GBM PDX animal model and prolonged the survival time of tumor-bearing mice. Notably, TAK-243 more effectively inhibited the survival and self-renewal ability of glioblastoma stem cells (GSCs) than GBM cells. Importantly, we found that the expression level of GRP78 is a key factor in determining the sensitivity of differentiated GBM cells or GSCs to TAK-243. Mechanistically, UBA1 inhibition disrupts global protein ubiquitination in GBM cells, thereby inducing ER stress and UPR. UPR activates the PERK/ATF4 and IRE1α/XBP signaling axes. These findings indicate that UBA1 inhibition could be an attractive strategy that may be potentially used in the treatment of patients with GBM, and GRP78 can be used as a molecular marker for personalized treatment by targeting UBA1.

scholarly journals Immunomodulation as a Therapy for Aspergillus Infection: Current Status and Future Perspectives

2018 ◽  
Vol 4 (4) ◽  
pp. 137 ◽  
Author(s):  
Chris Lauruschkat ◽  
Hermann Einsele ◽  
Juergen Loeffler
Keyword(s):  
Immune Cell ◽  
Current Knowledge ◽  
Antifungal Drugs ◽  
Current Status ◽  
Remission Induction ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Life Threatening ◽  
Broad Variety ◽  
Immunological Recovery

Invasive aspergillosis (IA) is the most serious life-threatening infectious complication of intensive remission induction chemotherapy and allogeneic stem cell transplantation in patients with a variety of hematological malignancies. Aspergillus fumigatus is the most commonly isolated species from cases of IA. Despite the various improvements that have been made with preventative strategies and the development of antifungal drugs, there is an urgent need for new therapeutic approaches that focus on strategies to boost the host’s immune response, since immunological recovery is recognized as being the major determinant of the outcome of IA. Here, we aim to summarize current knowledge about a broad variety of immunotherapeutic approaches against IA, including therapies based on the transfer of distinct immune cell populations, and the administration of cytokines and antibodies.

scholarly journals New therapeutic approaches of mesenchymal stem cells-derived exosomes

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Jana Janockova ◽  
Lucia Slovinska ◽  
Denisa Harvanova ◽  
Timea Spakova ◽  
Jan Rosocha
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Experimental Models ◽  
Target Cells ◽  
Therapeutic Approaches ◽  
Paracrine Factors ◽  
New Therapeutic Approaches ◽  
Cell Based Therapy

AbstractMesenchymal stem cells (MSCs) have been demonstrated to have a great potential in the treatment of several diseases due to their differentiation and immunomodulatory capabilities and their ability to be easily cultured and manipulated. Recent investigations revealed that their therapeutic effect is largely mediated by the secretion of paracrine factors including exosomes. Exosomes reflect biophysical features of MSCs and are considered more effective than MSCs themselves. Alternative approaches based on MSC-derived exosomes can offer appreciable promise in overcoming the limitations and practical challenges observed in cell-based therapy. Furthermore, MSC-derived exosomes may provide a potent therapeutic strategy for various diseases and are promising candidates for cell-based and cell-free regenerative medicine. This review briefly summarizes the development of MSCs as a treatment for human diseases as well as describes our current knowledge about exosomes: their biogenesis and molecular composition, and how they exert their effects on target cells. Particularly, the therapeutic potential of MSC-derived exosomes in experimental models and recent clinical trials to evaluate their safety and efficacy are summarized in this study. Overall, this paper provides a current overview of exosomes as a new cell-free therapeutic agent.

scholarly journals Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis

2020 ◽  
Vol 21 (10) ◽  
pp. 3686 ◽  
Author(s):  
Eva Andreuzzi ◽  
Alessandra Capuano ◽  
Evelina Poletto ◽  
Eliana Pivetta ◽  
Albina Fejza ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Cell Function ◽  
Current Knowledge ◽  
Tumor Development ◽  
Therapy Response ◽  
Therapeutic Approaches ◽  
Endothelial Cell Function ◽  
New Therapeutic Approaches

Gastrointestinal tumors are responsible for more cancer-related fatalities than any other type of tumors, and colorectal and gastric malignancies account for a large part of these diseases. Thus, there is an urgent need to develop new therapeutic approaches to improve the patients’ outcome and the tumor microenvironment is a promising arena for the development of such treatments. In fact, the nature of the microenvironment in the different gastrointestinal tracts may significantly influence not only tumor development but also the therapy response. In particular, an important microenvironmental component and a potential therapeutic target is the vasculature. In this context, the extracellular matrix is a key component exerting an active effect in all the hallmarks of cancer, including angiogenesis. Here, we summarized the current knowledge on the role of extracellular matrix in affecting endothelial cell function and intratumoral vascularization in the context of colorectal and gastric cancer. The extracellular matrix acts both directly on endothelial cells and indirectly through its remodeling and the consequent release of growth factors. We envision that a deeper understanding of the role of extracellular matrix and of its remodeling during cancer progression is of chief importance for the development of new, more efficacious, targeted therapies.

Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

2020 ◽  
Vol 46 (02) ◽  
pp. 125-133 ◽  
Author(s):  
Alexander E. John ◽  
Nathan J. White
Keyword(s):  
Current Knowledge ◽  
Therapeutic Interventions ◽  
Clot Formation ◽  
Therapeutic Approaches ◽  
Early Stages ◽  
New Therapeutic Approaches ◽  
Trauma Induced Coagulopathy ◽  
Transition Points

AbstractTrauma induces a change in nearly every observable aspect of hemostasis, generally tipping the balance toward trauma-induced coagulopathy (TIC) and bleeding in the critical early stages. Two particularly important aspects of TIC are platelets and fibrinogen, which are the primary determinants of clot formation and hemostasis. Their loss and dysfunction represent important transition points between coagulopathy phenotypes, highlighting their mechanistic roles in TIC as well as unveiling new potential avenues toward important diagnostic and therapeutic interventions. This review synthesizes current knowledge of platelets and fibrinogen during TIC, with a focus on emerging concepts related to their dysfunction and development of new therapeutic approaches.

scholarly journals Effects of Etanercept against Transient Cerebral Ischemia in Diabetic Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Naohiro Iwata ◽  
Hiroko Takayama ◽  
Meiyan Xuan ◽  
Shinya Kamiuchi ◽  
Hirokazu Matsuzaki ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemic Injury ◽  
Repeated Administration ◽  
Diabetic Rats ◽  
Transient Cerebral Ischemia ◽  
Cerebral Injury ◽  
Cerebral Damage ◽  
Diabetic State ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Diabetes mellitus is known to exacerbate acute cerebral ischemic injury. Previous studies have demonstrated that infarction volumes caused by transient cerebral ischemia were greater in diabetic rats than in nondiabetic rats. Tumor necrosis factor-α(TNF-α) is a proinflammatory protein produced in the brain in response to cerebral ischemia that promotes apoptosis. Etanercept (ETN), a recombinant TNF receptor (p75)-Fc fusion protein, competitively inhibits TNF-α. Therefore, we evaluated the neuroprotective effects of chronic or acute treatment with ETN on cerebral injury caused by middle cerebral artery occlusion/reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. Furthermore, we evaluated the effects of ETN against the apoptosis and myeloperoxidase activity. Single administration of ETN before MCAO significantly suppressed exacerbation of cerebral damage in nondiabetic rats, as assessed by infarct volume. In contrast, the diabetic state markedly aggravated MCAO/Re-induced cerebral damage despite ETN treatment within 24 h before MCAO. However, the damage was improved by repeated administration of ETN at 900 μg/kg/daily in rats in an induced diabetic state. These results suggested that repeated administration of ETN can prevent exacerbation of cerebral ischemic injury in the diabetic state and is mainly attributed to anti-inflammatory effects.

New therapeutic approaches for polymyositis and dermatomyositis

2011 ◽  
Vol 152 (39) ◽  
pp. 1552-1559 ◽  
Author(s):  
Katalin Dankó ◽  
Melinda Vincze
Keyword(s):  
Immunosuppressive Agents ◽  
Inflammatory Myopathy ◽  
Proximal Muscle ◽  
Therapeutic Approaches ◽  
First Line ◽  
New Therapeutic Approaches ◽  
Remission Period ◽  
Immune Mediated ◽  
Systemic Manifestations ◽  
Line Of Therapy

Inflammatory myopathies are chronic, immune-mediated diseases characterized with progressive proximal muscle weakness. They encompass a variety of syndromes with protean manifestations. The aims of therapy are to increase muscle strength, prevent the development of contractures, and to manage the systemic manifestations of the disease. This is a complex treatment which requires routine and wide knowledge. The most important task is to recognize the disease and guide the patient to immunologic center. Although the first line of therapy continues to include corticosteroids, there are a multitude of agents available for treating patients with myositis. There are several different immunosuppressive agents which may be applied alone or in combination with each other, as well as an increasing number of novel and exciting biologic agents targeting molecules participating in the pathogenesis of inflammatory myopathy. Physiotherapy and rehabilitation in the remission period may significantly improve the functional outcome of patients with these disorders. Orv. Hetil., 2011, 152, 1552–1559.

Exploring the Role of Remote Ischemic Preconditioning In Long Term Cognitive Impairment after Global Ischemia-Reperfusion-Induced Vascular Dementia in Mice

2020 ◽  
Author(s):  
Amteshwar Singh Jaggi
Keyword(s):  
Cognitive Impairment ◽  
Cerebral Ischemia ◽  
Vascular Dementia ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Remote Ischemic Preconditioning ◽  
Global Cerebral Ischemia ◽  
Cerebral Ischemic ◽  
The Brain

Aim: The aim of the present study is to explore the neuroprotective effects of remote ischemic preconditioning in long term cognitive impairment after global cerebral ischemia induced-vascular dementia in mice. Material and methods: The mice were subjected to global cerebral ischemia by occluding the bilateral common carotid arteries for 12 minutes followed by the 24 hours of the reperfusion. The remote ischemic preconditioning stimulus was delivered in the form of 4 cycles of ischemia/reperfusion for 5 minutes each. The cerebral ischemic injury induced-long term cognitive impairment-related learning and memory alterations was assessed using morris water maze, the motor performances of the animals were evaluated using rota-rod test and neurological severity score. The cerebral infract size of the brain were quantified using triphenyltetrazolium chloride staining. Results: Global cerebral ischemia causes long term memory impairment, decreases motor performances and increases the brain infract size in animals. The delivery of remote ischemic preconditioning stimulus significantly abolished the long-term cognitive impairment and ameliorates the motor performances as well as cerebral infract size in brain. Conclusion: The remote ischemic preconditioning mediates neuro protection against global cerebral ischemic injury induced long-term cognitive impairment.

scholarly journals Intradialytic Cerebral Hypoperfusion as Mechanism for Cognitive Impairment in Patients on Hemodialysis

2019 ◽  
Vol 30 (11) ◽  
pp. 2052-2058 ◽  
Author(s):  
Dawn F. Wolfgram
Keyword(s):  
Cognitive Impairment ◽  
Cerebral Perfusion ◽  
Ischemic Injury ◽  
Hemodialysis Patients ◽  
Cognitive Outcomes ◽  
Cerebral Injury ◽  
Cerebral Hypoperfusion ◽  
Increased Risk ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

The high frequency of cognitive impairment in individuals on hemodialysis is well characterized. In-center hemodialysis patients are disproportionately affected by cognitive impairment compared with other dialysis populations, identifying hemodialysis itself as a possible factor. The pathophysiology of cognitive impairment has multiple components, but vascular-mediated cerebral injury appears to contribute based on studies demonstrating increased cerebral ischemic lesions and atrophy in brain imaging of patients on hemodialysis. Patients on hemodialysis may be at increased risk for cerebral ischemic injury disease due to vasculopathy associated with ESKD and from their comorbid diseases, such as hypertension and diabetes. This review focuses on the intradialytic cerebral hypoperfusion that can occur during routine hemodialysis due to the circulatory stress of hemodialysis. This includes a review of current methods used to monitor intradialytic cerebral perfusion and the structural and functional cognitive outcomes that have been associated with changes in intradialytic cerebral perfusion. Monitoring of intradialytic cerebral perfusion may become clinically relevant as nephrologists try to avoid the cognitive complications seen with hemodialysis. Identifying the appropriate methods to assess risk for cerebral ischemic injury and the relationship of intradialytic cerebral hypoperfusion to cognitive outcomes will help inform the decision to use intradialytic cerebral perfusion monitoring in the clinical setting as part of a strategy to prevent cognitive decline.

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