scholarly journals S-palmitoylation regulates biogenesis of core glycosylated wild-type and F508del CFTR in a post-ER compartment

2014 ◽  
Vol 459 (2) ◽  
pp. 417-425 ◽  
Author(s):  
Michelle L. McClure ◽  
Hui Wen ◽  
James Fortenberry ◽  
Jeong S. Hong ◽  
Eric J. Sorscher
Keyword(s):  
Cystic Fibrosis ◽  
Molecular Target ◽  
Therapeutic Strategies ◽  
Common Disease ◽  
Wild Type ◽  
New Evidence

This study provides new evidence that palmitoylation contributes to CFTR trafficking and participates during rescue of a common disease-associated mutation. Therapeutic strategies to overcome clinically important defects in cystic fibrosis should consider the role of palmitoylation as a molecular target.

Identification of the target of gabapentinoid action in neuropathic pain

2018 ◽  
Author(s):  
Turo J. Nurmikko
Keyword(s):  
Neuropathic Pain ◽  
Scientific Community ◽  
Oral Absorption ◽  
Molecular Target ◽  
Wild Type ◽  
Seminal Paper ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

The landmark paper discussed in this chapter is ‘Identification of the α‎2-δ‎-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin’, published by Field et al. in 2006. In this seminal paper, Field et al. demonstrated that the anti-allodynic effect of pregabalin is related to its binding to the α‎2δ‎-1 subunit of the voltage-gated calcium channel. In transgenic mice lacking this subunit, pregabalin had no effect on allodynia induced by sciatic nerve ligation, whereas, in wild-type mice, there was a substantial anti-allodynic response. This discovery was well received by the scientific community and was considered to conclusively establish the mechanism of action of pregabalin, which has remarkably similar properties to gabapentin but with increased potency and oral absorption. This exciting result acted as an impetus for further studies on the role of the subunit in the development and maintenance of neuropathic pain.

scholarly journals PATHOGENETIC TREATMENT OF ARTERIAL HYPERTENSION: THE PLACE OF CALCIUM ANTAGONISTS

2013 ◽  
Vol 12 (2) ◽  
pp. 85-88
Author(s):  
E. O. Taratukhin ◽  
N. N. Teplova
Keyword(s):  
Arterial Hypertension ◽  
Calcium Antagonists ◽  
Therapeutic Strategies ◽  
Channel Blockers ◽  
Third Generation ◽  
Peripheral Vascular ◽  
The Third ◽  
Key Aspects ◽  
New Evidence

The paper describes the key aspects of arterial hypertension pathogenesis and the relevant therapeutic strategies. The authors discuss the role of increased peripheral vascular resistance and hypervolemia as factors which can be targeted by calcium channel blockers. The new evidence on this medication class, including the third-generation calcium antagonists, is presented. 

A Zebrafish Model for Severe Congenital Neutropenia with Jagn1b-Deficiency

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Larissa Doll ◽  
Narges Aghaallaei ◽  
Julia Skokowa ◽  
Karl Welte ◽  
Baubak Bajoghli
Keyword(s):  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Therapeutic Strategies ◽  
In Vivo Model ◽  
Severe Congenital Neutropenia ◽  
Wild Type ◽  
Congenital Neutropenia ◽  
Zebrafish Model

Severe congenital neutropenia (CN) is a bone marrow failure characterized by an impaired neutrophil development. This disease can be caused by different germline mutations, which one of them is Jagunal homolog 1 (JAGN1). CN patients are prone to develop life-threatening infections from birth on and the treatment of choice is recombinant human granulocyte colony-stimulating factor (rhG-CSF). However, patients with JAGN1 deficiency poorly respond to this treatment. Therefore, the development of new therapeutic strategies to treat this disease is essential. Thus far, lack of an animal model was the main limitation to study the function of JAGN1 in neutropenia and perform high-throughput compound screening. In this work, we studied the role of jagn1b in zebrafish granulopoiesis and hematopoiesis. Two different approaches were used. First, we injected antisense morpholino that efficiently blocked the translation of jagn1b mRNA. As a second approach, we used the CRISPR-Cas9 technique to introduce mutations in the zebrafish jagn1b gene and analyzed the crispants. Both of these approaches were tested in wild-type embryos as well as the transgenic mpo:GFP reporter line, in which neutrophils are labeled with GFP. Our results showed that interference with Jagn1b reduced the number of neutrophils, without affecting the early myelopoiesis and monocytes/macrophages. Further analysis revealed that apoptosis was enhanced in embryos injected with the jagn1b morpholino, however, this effect was not restricted to the hematopoietic tissues. Our results also suggested that unfolded protein response (UPR) was activated because the expression levels of genes involved in this pathway such as chop, atf4a and atf4b were significantly upregulated in the jagn1b morphants, when compared with the wild-type counterparts. Overall, we have successfully established a novel in vivo model for studying the role of JAGN1 in granulopoiesis, and the possible role of Jagn1b in UPR response might be useful to find new targets for the development of therapeutic strategies for CN. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hax1 Is Indispensable for Neutrophil Development in Zebrafish

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 436-436
Author(s):  
Larissa Doll ◽  
Narges Aghaallaei ◽  
Karl Welte ◽  
Julia Skokowa ◽  
Baubak Bajoghli
Keyword(s):  
Cell Death ◽  
Conflicts Of Interest ◽  
Therapeutic Strategies ◽  
In Vivo Model ◽  
Wild Type ◽  
Zebrafish Model ◽  
Compound Screening ◽  
Life Threatening

Inherited deficiency of HCLS1-associated protein X1 (HAX1) in human leads to the development of severe congenital neutropenia (CN), which is characterized by impaired neutrophil development. Patients with HAX1 deficiency are prone to life-threatening infections beginning in their first months of life unless treated by recombinant human granulocyte colony-stimulating factor (rhG-CSF) or bone marrow transplantation. But approximately 10% of these patients do not respond to the rhG-CSF therapy. Therefore, there is an urgent need for new tailored therapeutic strategies for the treatment of this disease. However, there is a lack of an animal model that allows high-throughput compound screening for the HAX1 associated neutropenia. In this study, we sought to determine the role of hax1 in zebrafish hematopoiesis. We used two approaches to interfere with the zebrafish hax1. First, we injected antisense morpholino that efficiently blocked the translation of hax1 mRNA. As a second approach, we used the CRISPR-Cas9 technique to introduce mutations in the zebrafish hax1 gene. Both approaches were used in the in wild-type embryos and transgenic (mpo:gfp) reporter line, where the neutrophils are labeled with GFP. We found that hax1 knockdown reduced the number of neutrophils, without affecting the development of HSPCs and monocytes/macrophages. Compared with their wild-type counterparts, hax1 morphants exhibited reduced expression levels of hcls1 and cebpa. Whereas the expression level of cebpb, a marker of emergency granulopoiesis, was upregulated. Next, we examined whether hax1 knockdown impairs the cellular viability because CN patients who harbor HAX1 mutations exhibit increased apoptosis of myeloid progenitors. Although zebrafish hax1 morphants showed increased cell death throughout the embryo, apoptosis was not triggered in the hematopoietic site. Therefore, our results suggested that reduced neutrophil numbers in zebrafish hax1 morphants is due to decreased production of neutrophils rather than increased cell death. To determine whether our zebrafish model is suitable for discovering human drugs, we treated zebrafish hax1 morphants with human G-CSF and rescued the quantitative reduction of neutrophils. Overall, we have successfully established a novel in vivo model for studying the HAX-1 role in the granulopoiesis, which might open new avenues for developing therapeutic strategies for CN. Disclosures No relevant conflicts of interest to declare.

Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

1999 ◽  
Vol 81 (04) ◽  
pp. 601-604 ◽  
Author(s):  
Hiroyuki Matsuno ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Shigeru Ueshima ◽  
Osamu Matsuo ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Thrombus Formation ◽  
Endothelial Injury ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Pai 1

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

Is Immune Response Relevant in Interstitial Lung Disease?

2020 ◽  
Vol 16 (1) ◽  
pp. 18-27
Author(s):  
Manzoor M. Khan
Keyword(s):  
Immune Response ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Lung Fibrosis ◽  
Lymphocytic Infiltration ◽  
Therapeutic Strategies ◽  
Mediators Of Inflammation ◽  
Acquired Immune Responses ◽  
Novel Therapeutic Strategies

Interstitial lung disease, a term for a group of disorders, causes lung fibrosis, is mostly refractory to treatments and has a high death rate. After diagnosis the survival is up to 3 years but in some cases the patients live much longer. It involves a heterogenous group of lung diseases that exhibit progressive and irreversible destruction of the lung due to the formation of scars. This results in lung malfunction, disruption of gas exchange, and eventual death because of respiratory failure. The etiology of lung fibrosis is mostly unknown with a few exceptions. The major characteristics of the disease are comprised of injury of epithelial type II cells, increased apoptosis, chronic inflammation, monocytic and lymphocytic infiltration, accumulation of myofibroblasts, and inability to repair damaged tissue properly. These events result in abnormal collagen deposition and scarring. The inflammation process is mild, and the disease is primarily fibrotic driven. Immunosuppressants do not treat the disease but the evidence is evolving that both innate and acquired immune responses a well as the cytokines contribute to at least early progression of the disease. Furthermore, mediators of inflammation including cytokines are involved throughout the process of lung fibrosis. The diverse clinical outcome of the disease is due to different pattern of inflammatory markers. Nonetheless, the development of novel therapeutic strategies requires better understanding of the role of the immune response. This review highlights the role of the immune response in interstitial lung disease and considers the therapeutic strategies based on these observations. For this review several literature data sources were used to assess the role of the immune response in interstitial lung disease and to evaluate the possible therapeutic strategies for the disease.

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