Harnessing affinity-based protein profiling to reveal a novel target of nintedanib

2021 ◽  
Author(s):  
Xiong Chen ◽  
Menglin Li ◽  
Manru Li ◽  
Dongmei Wang ◽  
Jinlan Zhang
Keyword(s):  
Protein Profiling ◽  
Therapeutic Drug ◽  
Tripeptidyl Peptidase ◽  
Photoaffinity Probes ◽  
Novel Target

We identified tripeptidyl-peptidase 1 (TPP1) as one of the direct targets of nintedanib (NDNB) employing clickable photoaffinity probes, which provides insights into the functional meaning of the well-known IPF therapeutic drug.

scholarly journals Azithromycin alleviates the severity of rheumatoid arthritis via targeting UPR component GRP78

2021 ◽  
Author(s):  
Yongli Zhang ◽  
Luna Ge ◽  
Guanhua Song ◽  
Ruojia Zhang ◽  
Shufeng Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Expression Profiles ◽  
Regulatory Element ◽  
Gene Expression Profiles ◽  
Attractive Potential ◽  
Therapeutic Drug ◽  
Inflammatory Factor ◽  
Anti Inflammatory ◽  
Novel Target

Background and Purpose: Azithromycin (AZM) is a macrolide antibiotic with well-described anti-inflammatory properties. This study aimed to substantiate its treatment potential in rheumatoid arthritis (RA). Experimental Approach: Gene expression profiles were collected by RNA-sequencing and the effects of AZM were assessed in functional assays. In vitro and vivo assays for examining the blockade of glucose-regulated protein 78 (GRP78) actions by AZM: assays for defining the anti-inflammatory activity of AZM using fibroblast-like synoviocytes (FLSs) from RA patients as well as collagen-induced arthritis (CIA) in DBA/1 mice. Identification and characterization of the binding of AZM to GRP78 using drug affability responsive target stability assay, proteomics and cellular thermal shift assay. Detect AZM inhibition of GRP78 and dependence of AZM’s anti-arthritis activity on GRP78. Key Results: AZM reduced pro-inflammatory factor production, cell migration, invasion and chemo-attractive potential, enhanced apoptosis, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. AZM ameliorated the severity of CIA lesions. Transcriptional analyses implied that AZM treatment causes impairments in signaling cascades associated with cholesterol and lipid biosynthetic process. GRP78 was isolated as a novel target of AZM. AZM-mediated activation of unfolded protein response (UPR) via inhibiting GRP78 activity is required not only for inducing the expression of C/EBP-homologous protein (CHOP), but also for activation of sterol-regulatory element binding protein (SREBP) and its targeted genes involved in cholesterol and lipid biosynthetic process. Further, deletion of GRP78 abolished AZM’s anti-arthritis activity. Conclusion and Implications: These findings confirmed that AZM is an anti-arthritis therapeutic drug for RA treatment.

scholarly journals A profile of arginine methyltransferase receptors in two immortal glioblastoma cell lines: the precursor to a novel target?

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv18-iv19
Author(s):  
Srihari Deepak ◽  
Miss Sabrina Samuel ◽  
John Greenman ◽  
Shailendra Achawal ◽  
Pedro Beltran-Alvarez
Keyword(s):  
Cell Lines ◽  
Protein Profiling ◽  
Adjuvant Chemoradiotherapy ◽  
Molecular Profile ◽  
Glioblastoma Cell ◽  
Post Translational Modification ◽  
Protein Arginine Methyltransferases ◽  
Novel Target ◽  
Secondary Antibodies ◽  
Glioblastoma Cell Lines

Abstract Background Glioblastoma is a deadly disease with a median survival of 15 months after treatment. While maximal safe surgical resection and adjuvant chemoradiotherapy continues to be the mainstay of treatment, glioblastoma demostrates a remarkably heterogeneous molecular profile, and there is a drive to discover further chemotherapeutic targets that can effectively augment current multimodal therapy. Introduction Post-translational modification of proteins plays a key role in maintenance of regulatory cell networks, and protein arginine methyltransferases (PRMT) are one of the enzymes involved in symmetric and asymmetric methylation of various proteins. We aim to demonstrate the entire range of PRMT proteins expressed in two different glioblastoma cell lines (U87MG and U251) in order to elucidate a consistency in expression of these proteins across cell lines. Methods Cells from 2 different glioblastoma cell lines (U87MG and U251) were cultured and lysed using standard aseptic techniques. Protein profiling was done using SDS-PAGE electrophoresis with a molecular weight marker as the reference and all primary antibodies to various PRMTs (1–10) and respective secondary antibodies. Membranes were visualised with a chemiluminescent protocol. Experiments were repeated in order to reduce bias. Conclusion It was clearly seen that in both cell lines there is a strong tendency for PRMT5 expression and relative under-expresssion of PRMT 9/10. In addition, however, there are varying expressions of other PRMTs as well. We aim to further explore this to improve the strength of this correlation.

Evaluation of α-Pyrones and Pyrimidones as Photoaffinity Probes for Affinity-Based Protein Profiling

2011 ◽  
Vol 76 (15) ◽  
pp. 6075-6087 ◽  
Author(s):  
Oliver A. Battenberg ◽  
Matthew B. Nodwell ◽  
Stephan A. Sieber
Keyword(s):  
Protein Profiling ◽  
Photoaffinity Probes

scholarly journals Blocking HMGB1/RAGE Signaling by Berberine Alleviates A1 Astrocyte and Attenuates Sepsis-Associated Encephalopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Jian Shi ◽  
Huan Xu ◽  
María José Cavagnaro ◽  
Xingmei Li ◽  
Jia Fang
Keyword(s):  
Cognitive Impairment ◽  
Clinical Problem ◽  
Multiple Organ ◽  
Therapeutic Drug ◽  
Host Immune Responses ◽  
Neuron Activation ◽  
Tnf Α ◽  
Life Threatening ◽  
Novel Target ◽  
Poor Outcomes

As a life-threatening multiple organ dysfunction attributable to maladjusted host immune responses to infection, sepsis is usually the common pathway to serious prognosis and death for numerous infectious diseases all over the world. Sepsis-associated encephalopathy (SAE) is frequently complicated by septic conditions, and is one of the most important reasons for increased mortality and poor outcomes in septic patients which is still an urgent clinical problem need to be solved. In this research, a conspicuously discovery of treatment-related translational use for berberine was elaborated. The results revealed that berberine treatment significantly restored cognitive impairment in sepsis mice. Reduced expression levels of TNF-α, IL-1α, and C1qA were exhibited in the hippocampus of the berberine treatment group, and attenuated effect of declining neo-neuron, activation of microglia and astrocytes in the hippocampus of mice with sepsis were also found. Moreover, berberine inhibits microglia-stressed A1 astrocytes by inhibiting HMGB1 signaling was revealed, then the molecular mechanism of HMGB1/RAGE signaling inhibition leads to the better outcome of SAE was elucidated. To summarize, this research indicated that berberine targets HMGB1/RAGE signaling to inhibit microglia-stressed A1 astrocyte and neo-neuron decline, which consequently alleviates sepsis-induced cognitive impairment. Collectively, berberine may serve as potential therapeutic drug and HMGB1/RAGE signaling would be a novel target for medicine development for treating SAE.

Tubulin structure at intermediate resolution

1995 ◽  
Vol 53 ◽  
pp. 852-853
Author(s):  
K. H. Downing ◽  
S. G. Wolf ◽  
E. Nogales
Keyword(s):  
High Resolution ◽  
Structural Data ◽  
Therapeutic Drug ◽  
Zinc Ions ◽  
Two Dimensional ◽  
X Ray Diffraction ◽  
X Ray ◽  
Negative Stain ◽  
Functional Mechanisms ◽  
Tubulin Structure

Microtubules are involved in a host of critical cell activities, many of which involve transport of organelles through the cell. Different sets of microtubules appear to form during the cell cycle for different functions. Knowledge of the structure of tubulin will be necessary in order to understand the various functional mechanisms of microtubule assemble, disassembly, and interaction with other molecules, but tubulin has so far resisted crystallization for x-ray diffraction studies. Fortuitously, in the presence of zinc ions, tubulin also forms two-dimensional, crystalline sheets that are ideally suited for study by electron microscopy. We have refined procedures for forming the sheets and preparing them for EM, and have been able to obtain high-resolution structural data that sheds light on the formation and stabilization of microtubules, and even the interaction with a therapeutic drug.Tubulin sheets had been extensively studied in negative stain, demonstrating that the same protofilament structure was formed in the sheets and microtubules. For high resolution studies, we have found that the sheets embedded in either glucose or tannin diffract to around 3 Å.

Diagnose und Monitoring bei chronisch-entzündlicher Darmerkrankung

2018 ◽  
Vol 75 (5) ◽  
pp. 316-328
Author(s):  
Christian Ansprenger ◽  
Emanuel Burri
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Morbus Crohn ◽  
Therapeutic Drug ◽  
Körperliche Untersuchung

Zusammenfassung. Die Diagnose und auch die Überwachung von chronisch entzündlichen Darmerkrankungen ruht auf mehreren Säulen: Anamnese, körperliche Untersuchung, Laborwerte (im Blut und Stuhl), Endoskopie, Histologie und Bildgebung. Die Diagnose kann nicht anhand eines einzelnen Befundes gestellt werden. In den letzten Jahren hat sich das Therapieziel weg von klinischen Endpunkten hin zu endoskopischen und sogar histologischen Endpunkten entwickelt. Für einige dieser neuen Therapieziele existiert allerdings noch keine allgemein gültige Definition. Regelmässige Endoskopien werden von Patienten schlecht toleriert, weshalb Surrogat-Marker wie Calprotectin untersucht wurden und eine gute Korrelation mit der mukosalen Entzündungsaktivität nachgewiesen werden konnte. Entsprechend zeigte sich bei Morbus Crohn eine Algorithmus-basierte Therapiesteuerung – unter anderem basierend auf Calprotectin – einer konventionellen Therapiesteuerung überlegen. Die Überwachung der medikamentösen Therapie («Therapeutic Drug Monitoring» [TDM]) ist ein zweites Standbein des Monitoring von chronisch entzündlichen Darmerkrankungen. Mit zunehmendem Einsatz vor allem der Biologika-Therapien wurden sowohl reaktives TDM (in Patienten mit klinischem Rezidiv) als auch proaktives TDM (in Patienten in Remission / stabiler Erkrankung) untersucht und haben (teilweise) Eingang in aktuelle Richtlinien gefunden. Zukünftige Studien werden die vorgeschlagenen Therapieziele besser definieren und den Nutzen der medikamentösen Therapieüberwachung auf den Krankheitsverlauf weiter untersuchen müssen.

Therapeutic drug monitoring (TDM) of the recent antipsychotic ziprasidone in dried blood spots (DBS) and plasma

2011 ◽  
Vol 44 (06) ◽  
Author(s):  
L Mercolini ◽  
G Fulgenzi ◽  
M Melis ◽  
G Boncompagni ◽  
LJ Albers ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Dried Blood Spots ◽  
Therapeutic Drug ◽  
Blood Spots

Comparison of CE and HPLC for therapeutic drug monitoring of the antiepileptic drug topiramate

2011 ◽  
Vol 44 (06) ◽  
Author(s):  
R Mandrioli ◽  
L Mercolini ◽  
N Ghedini ◽  
M Amore ◽  
E Kenndler ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Antiepileptic Drug ◽  
Drug Monitoring ◽  
Therapeutic Drug
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